case study about coronary artery disease

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Coronary Heart Disease Research

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For almost 75 years, the NHLBI has been at the forefront of improving the nation’s health and reducing the burden of  heart and vascular diseases . Heart disease, including coronary heart disease, remains the leading cause of death in the United States. However, the rate of heart disease deaths has declined by 70% over the past 50 years, thanks in part to NHLBI-funded research. Many current studies funded by the NHLBI focus on discovering genetic associations and finding new ways to prevent and treat the onset of coronary heart disease and associated medical conditions.

NHLBI research that really made a difference

The NHLBI supports a wide range of long-term studies to understand the risk factors of coronary heart disease. These ongoing studies, among others, have led to many discoveries that have increased our understanding of the causes of cardiovascular disease among different populations, helping to shape evidence-based clinical practice guidelines.

• Risk factors that can be changed:  The NHLBI  Framingham Heart Study (FHS)  revealed that cardiovascular disease is caused by modifiable risk factors such as smoking,  high blood pressure ,  obesity , high  cholesterol  levels, and physical inactivity. It is why, in routine physicals, healthcare providers check for high blood pressure, high cholesterol, unhealthy eating patterns, smoking, physical inactivity, and unhealthy weight. The FHS found that cigarette smoking increases the risk of heart disease. Researchers also showed that cardiovascular disease can affect people differently depending on sex or race, underscoring the need to address health disparities. 
• Risk factors for Hispanic/Latino adults:  The  Hispanic Community Health Study/Study of Latinos (HCHS/SOL)  found that heart disease risk factors are widespread among Hispanic/Latino adults in the United States , with 80% of men and 71% of women having at least one risk factor. Researchers also used HCHS/SOL genetic data to explore genes linked with central adiposity (the tendency to have excess body fat around the waist) in Hispanic/Latino adults. Before this study, genes linked with central adiposity, a risk factor for coronary heart disease, had been identified in people of European ancestry. These results showed that those genes also predict central adiposity for Hispanic/Latino communities. Some of the genes identified were more common among people with Mexican or Central/South American ancestry, while others were more common among people of Caribbean ancestry.
• Risk factors for African Americans:  The  Jackson Heart Study (JHS) began in 1997 and includes more than 5,300 African American men and women in Jackson, Mississippi. It has studied genetic and environmental factors that raise the risk of heart problems, especially high blood pressure, coronary heart disease,  heart failure ,  stroke , and  peripheral artery disease (PAD) . Researchers discovered a gene variant in African American individuals that doubles the risk of heart disease. They also found that even small spikes in blood pressure can lead to a higher risk of death. A community engagement component of the JHS is putting 20 years of the study’s findings into action by turning traditional gathering places, such as barbershops and churches, into health information hubs.
• Risk factors for American Indians:  The NHLBI actively supports the  Strong Heart Study , a long-term study that began in 1988 to examine cardiovascular disease and its risk factors among American Indian men and women. The Strong Heart Study is one of the largest epidemiological studies of American Indian people ever undertaken. It involves a partnership with 12 Tribal Nations and has followed more than 8,000 participants, many of whom live in low-income rural areas of Arizona, Oklahoma, and the Dakotas. Cardiovascular disease remains the leading cause of death for American Indian people. Yet the prevalence and severity of cardiovascular disease among American Indian people has been challenging to study because of the small sizes of the communities, as well as the relatively young age, cultural diversity, and wide geographic distribution of the population. In 2019, the NHLBI renewed its commitment to the Strong Heart Study with a new study phase that includes more funding for community-driven pilot projects and a continued emphasis on training and development. Read more about the  goals and key findings  of the Strong Heart Study.

Current research funded by the NHLBI

Within our  Division of Cardiovascular Sciences , the Atherothrombosis and Coronary Artery Disease Branch of its  Adult and Pediatric Cardiac Research Program and the  Center for Translation Research and Implementation Science  oversee much of our funded research on coronary heart disease.

Research funding  

Find  funding opportunities  and  program contacts for research on coronary heart disease. 

Current research on preventing coronary heart disease

• Blood cholesterol and coronary heart disease: The NHLBI supports new research into lowering the risk of coronary heart disease by reducing levels of cholesterol in the blood. High levels of blood cholesterol, especially a type called low-density lipoprotein (LDL) cholesterol, raise the risk of coronary heart disease. However, even with medicine that lowers LDL cholesterol, there is still a risk of coronary heart disease due to other proteins, called triglyceride-rich ApoB-containing lipoproteins (ApoBCLs), that circulate in the blood. Researchers are working to find innovative ways to reduce the levels of ApoBCLs, which may help prevent coronary heart disease and other cardiovascular conditions.
• Pregnancy, preeclampsia, and coronary heart disease risk: NHLBI-supported researchers are investigating the link between developing preeclampsia during pregnancy and an increased risk for heart disease over the lifespan . This project uses “omics” data – such as genomics, proteomics, and other research areas – from three different cohorts of women to define and assess preeclampsia biomarkers associated with cardiovascular health outcomes. Researchers have determined that high blood pressure during pregnancy and low birth weight are predictors of atherosclerotic cardiovascular disease in women . Ultimately, these findings can inform new preventive strategies to lower the risk of coronary heart disease.
• Community-level efforts to lower heart disease risk among African American people: The NHLBI is funding initiatives to partner with churches in order to engage with African American communities and lower disparities in heart health . Studies have found that church-led interventions reduce risk factors for coronary heart disease and other cardiovascular conditions. NHLBI-supported researchers assessed data from more than 17,000 participants across multiple studies and determined that these community-based approaches are effective in lowering heart disease risk factors .

Find more NHLBI-funded studies on  preventing coronary heart disease  on the NIH RePORTER.

Learn about the impact of COVID-19 on your risk of coronary heart disease.

Current research on understanding the causes of coronary heart disease

• Pregnancy and long-term heart disease:  NHLBI researchers are continuing the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b)   study to understand the relationship between pregnancy-related problems, such as gestational hypertension, and heart problems. The study also looks at how problems during pregnancy may increase risk factors for heart disease later in life. NuMoM2b launched in 2010, and long-term studies are ongoing, with the goal of collecting high-quality data and understanding how heart disease develops in women after pregnancy.
• How coronary artery disease affects heart attack risk: NHLBI-funded researchers are investigating why some people with coronary artery disease are more at risk for heart attacks than others. Researchers have found that people with coronary artery disease who have high-risk coronary plaques are more likely to have serious cardiac events, including heart attacks. However, we do not know why some people develop high-risk coronary plaques and others do not. Researchers hope that this study will help providers better identify which people are most at risk of heart attacks before they occur.
• Genetics of coronary heart disease:  The NHLBI supports studies to identify genetic variants associated with coronary heart disease . Researchers are investigating how genes affect important molecular cascades involved in the development of coronary heart disease . This deeper understanding of the underlying causes for plaque buildup and damage to the blood vessels can inform prevention strategies and help healthcare providers develop personalized treatment for people with coronary heart disease caused by specific genetic mutations.

Find more NHLBI-funded studies on understanding the  causes of coronary heart disease  on the NIH RePORTER.

Recent findings suggest that cholesterol-lowering treatment can lower the risk of heart disease complications in people with HIV.

Current research on treatments for coronary heart disease

• Insight into new molecular targets for treatment: NHLBI-supported researchers are investigating the role of high-density lipoprotein (HDL) cholesterol in coronary heart disease and other medical conditions . Understanding how the molecular pathways of cholesterol affect the disease mechanism for atherosclerosis and plaque buildup in the blood vessels of the heart can lead to new therapeutic approaches for the treatment of coronary heart disease. Researchers have found evidence that treatments that boost HDL function can lower systemic inflammation and slow down plaque buildup . This mechanism could be targeted to develop a new treatment approach for coronary heart disease.
• Long-term studies of treatment effectiveness: The NHLBI is supporting the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial EXTENDed Follow-up (EXTEND) , which compares the long-term outcomes of an initial invasive versus conservative strategy for more than 5,000 surviving participants of the original ISCHEMIA trial. Researchers have found no difference in mortality outcomes between invasive and conservative management strategies for patients with chronic coronary heart disease after more than 3 years. They will continue to follow up with participants for up to 10 years. Researchers are also assessing the impact of nonfatal events on long-term heart disease and mortality. A more accurate heart disease risk score will be constructed to help healthcare providers deliver more precise care for their patients.
• Evaluating a new therapy for protecting new mothers: The NHLBI is supporting the Randomized Evaluation of Bromocriptine In Myocardial Recovery Therapy for Peripartum Cardiomyopathy (REBIRTH) , for determining the role of bromocriptine as a treatment for peripartum cardiomyopathy (PPCM). Previous research suggests that prolactin, a hormone that stimulates the production of milk for breastfeeding, may contribute to the development of cardiomyopathy late in pregnancy or the first several months postpartum. Bromocriptine, once commonly used in the United States to stop milk production, has shown promising results in studies conducted in South Africa and Germany. Researchers will enroll approximately 200 women across North America who have been diagnosed with PPCM and assess their heart function after 6 months. 
• Impact of mental health on response to treatment:  NHLBI-supported researchers are investigating how mental health conditions can affect treatment effectiveness for people with coronary heart disease. Studies show that depression is linked to a higher risk for negative outcomes from coronary heart disease. Researchers found that having depression is associated with poor adherence to medical treatment for coronary heart disease . This means that people with depression are less likely to follow through with their heart disease treatment plans, possibly contributing to their chances of experiencing worse outcomes. Researchers are also studying new ways to treat depression in patients with coronary heart disease .

Find more NHLBI-funded studies on  treating coronary heart disease  on the NIH RePORTER.  

Researchers have found no clear difference in patient survival or heart attack risk between managing heart disease through medication and lifestyle changes compared with invasive procedures. 

Coronary heart disease research labs at the NHLBI

• Laboratory of Cardiac Physiology
• Laboratory of Cardiovascular Biology
• Minority Health and Health Disparities Population Laboratory
• Social Determinants of Obesity and Cardiovascular Risk Laboratory
• Laboratory for Cardiovascular Epidemiology and Genomics
• Laboratory for Hemostasis and Platelet Biology

Related coronary heart disease programs

• In 2002, the NHLBI launched  The Heart Truth® ,  the first federally sponsored national health education program designed to raise awareness about heart disease as the leading cause of death in women. The NHLBI and  The Heart Truth®  supported the creation of the Red Dress® as the national symbol for awareness about women and heart disease, and also coordinate  National Wear Red Day ® and  American Heart Month  each February. 
• The  Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC)  facilitates access to and maximizes the scientific value of NHLBI biospecimen and data collections. A main goal is to promote the use of these scientific resources by the broader research community. BioLINCC serves to coordinate searches across data and biospecimen collections and provide an electronic means for requesting additional information and submitting requests for collections. Researchers wanting to submit biospecimen collections to the NHLBI Biorepository to share with qualified investigators may also use the website to initiate the application process. 
• Our  Trans-Omics for Precision Medicine (TOPMed) Program  studies the ways genetic information, along with information about health status, lifestyle, and the environment, can be used to predict the best ways to prevent and treat heart, lung, blood, and sleep disorders. TOPMed specifically supports NHLBI’s  Precision Medicine Activities. 
• NHLBI  population and epidemiology studies  in different groups of people, including the  Atherosclerosis Risk in Communities (ARIC) Study , the  Multi-Ethnic Study of Atherosclerosis (MESA) , and the  Cardiovascular Health Study (CHS) , have made major contributions to understanding the causes and prevention of heart and vascular diseases, including coronary heart disease.
• The  Cardiothoracic Surgical Trials Network (CTSN)  is an international clinical research enterprise that studies  heart valve disease ,  arrhythmias , heart failure, coronary heart disease, and surgical complications. The trials span all phases of development, from early translation to completion, and have more than 14,000 participants. The trials include six completed randomized clinical trials, three large observational studies, and many other smaller studies.

Learn how heart disease may be different for women than for men.

Explore more NHLBI research on coronary heart disease

The sections above provide you with the highlights of NHLBI-supported research on coronary heart disease. You can explore the full list of NHLBI-funded studies on the NIH RePORTER .

To find more studies:

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• Select the  Agencies  arrow, then the  NIH  arrow, then check  NHLBI .

If you want to sort the projects by budget size — from the biggest to the smallest — click on the  FY Total Cost by IC  column heading.

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Chapter 1:  10 Real Cases on Acute Coronary Syndrome: Diagnosis, Management, and Follow-Up

Nisha Ali; Timothy J. Vittorio

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Case review, case discussion.

• Clinical Symptoms
• Risk Factors
• Classification
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Case 1: Diagnostic Evaluation of Chest Pain

A 65-year-old man presented to the emergency department with a complaint of left-sided chest pain radiating to his left arm. There were no alleviating factors. His past medical history included hypertension, uncontrolled diabetes mellitus, and hyperlipidemia. He denied any toxic habits. His baseline exercise tolerance is 2 city blocks limited by fatigue. Upon presentation, vital signs were stable and the physical examination was unremarkable. The chest pain was partially relieved by sublingual nitroglycerin. The 12-lead ECG showed nonspecific T-wave inversions in the inferolateral leads. He was administered aspirin, and the chest pain resolved shortly thereafter. Subsequently, he was admitted to the telemetry floor for further evaluation and observation. His serial cardiac biomarkers were negative. He did not have any recurrent chest pain and remained hemodynamically stable throughout the hospital stay. How would you manage this case?

In this clinical scenario, the patient does not fit the complete picture of anginal symptoms. However, the key here is the presence of risk factors and subtle 12-lead ECG changes, which place him at an elevated risk for coronary artery disease. He can be further evaluated by stress testing for risk stratification.

Angina consists of retrosternal chest pain increased by activity or emotional stress and generally relieved by rest or administration of nitroglycerin. The evaluation of chest pain begins with a thorough history and physical examination to delineate the etiology. The list of differential diagnoses is vast, and a detailed review of systems about pertinent diagnoses can narrow down the list. The presence of comorbid conditions and risk factors might hint toward a diagnosis of coronary artery disease. Both serial 12-lead ECG and highly sensitive cardiac troponin T testing should be performed before excluding ongoing ischemic coronary artery disease. Prior to stress testing, the patient should be chest pain free for 24 hours, without dynamic 12-lead ECG changes, and the highly sensitive cardiac troponin T level should be negative or trending downward.

The differential diagnosis of chest pain includes the following:

Coronary artery disease

Aortic dissection

Pericarditis

Pulmonary embolism

Costochondritis/rib fracture

Peptic ulcer disease

Acute cholecystitis

Cervical radiculopathy

Herpes zoster

Anxiety disorder

Chest pain should be classified as anginal or nonanginal based on the history.

Anginal symptoms can be considered in the setting of risk factors and should be evaluated by an appropriate stress modality if the symptoms are vague.

Serial 12-lead ECG and highly sensitive cardiac troponin T should be performed to exclude ongoing ischemic coronary artery disease before stress testing is performed.

Case 2: Diagnosis of Acute Coronary Syndrome

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Center for Bloodless Medicine and Surgery

Case study: cardiac surgery, case study 1:, radial artery approach for cardiac catheterization followed by an "off-pump" coronary artery bypass surgery.

A 66-year old male Jehovah’s Witness patient was brought to the hospital with chest pain, and referred for a cardiac catheterization. He had a positive nuclear stress test that showed reduced blood flow to the left ventricle with a high suspicion for coronary artery disease.

Dr. John Resar, the director of the cardiac catheterization lab at Johns Hopkins performed the procedure. In order to reduce blood loss from the cardiac catheterization, the approach was planned through the radial artery (in the arm) rather than the femoral artery (in the groin). This approach is associated with reduced bleeding during and after the procedure. The total blood loss during the cardiac catheterization procedure was 50 mls (1% of total blood volume). As expected, the procedure revealed high-grade triple vessel disease (narrowing) that was not treatable with coronary stents. Coronary artery bypass surgery was recommended.

Dr. John Conte performed the coronary bypass surgery. Of interest is the fact that in 1999, Dr. Conte published a case report of the first ever successful bloodless lung transplant in a Jehovah’s Witness patient. In this case presented here, he decided the patient would be best served by performing an "off-pump" cardiac surgery where the heart lung bypass machine is not used. This technique reduces the blood loss that is commonly associated with the bypass machine, since with traditional bypass a substantial amount of the patient’s blood is left behind in the circuit of the machine and is unrecoverable.

The 4-hour surgery went very well. The saphenous vein from his right leg was harvested using an endoscopic approach. Compared to the traditional technique, this method uses a smaller incision to harvest the vein. The internal mammary artery and the saphenous vein were both used to provide blood flow to the narrowed coronary arteries. A special “octopus retractor” was used to stabilize the heart because during off-pump surgery the heart continues to beat (thus the term “beating heart surgery”), unlike the traditional on-pump method where the heart is arrested and completely still. The hemoglobin level was 13.8 before surgery and 13.0 three days later when the patient was discharged from the hospital.  Two weeks after the surgery, the patient attended the open house for our Bloodless Medicine and Surgery Program and looked and felt "as good as ever".

Case Study 2:

Aortic valve and aortic root replacement without blood transfusion.

A 46-year old female Jehovah’s Witness patient had severe aortic valve regurgitation along with an ascending aortic aneurysm. She had been seen at two other major academic centers in hopes of having a valve replacement along with repair of her “aortic root” (the section of aorta that joins the heart above the aortic valve), but was unable to find a team of physicians that would perform the surgery without blood transfusion.

Dr. Duke Cameron, the former Chief of Cardiac Surgery saw her along with Dr. Steven Frank, Director of the Johns Hopkins Bloodless Medicine and Surgery Program. With the patient and her family present, they reviewed the echocardiogram and cardiac catheterization report from another hospital.  At the time, a discussion took place about the various methods of blood conservation and the various alternatives to transfusion. The patient and her family agreed that blood salvage (Cell Saver) and intraoperative autologous normovolemic hemodilution (IANH) were acceptable options. The patient was sent to the lab for routine blood tests and her hemoglobin level was suboptimal (13.0 g/dL) for this type of surgery. One complicating factor was the patient’s body weight of 95 lbs, which means that her total blood volume and red cell mass was about ½ that of a normal sized adult.

The patient was scheduled for a 3-week course of erythropoietin and intravenous iron at the infusion clinic at Johns Hopkins. The patient responded nicely to the treatments and her hemoglobin level increased to 15.1 g/dL, at which time the surgery was scheduled.

After the patient was under general anesthesia, 2 units of her own blood were removed as part of the IANH technique. These 2 units would be given back to her near the end of the surgery. During surgery, the Perfusionist, who operates the heart lung machine, was able to use a method called retrograde autologous prime (RAP), whereby the patient’s own blood is used to prime the circuit in an effort to conserve the patient’s blood volume.

After the surgical procedure, the patient was noted to have some cardiac ischemia (deficient blood flow to the left coronary artery).  She was taken to the cardiac cath lab where a coronary stent was placed by an interventional cardiologist into her left main coronary artery. The next day she was weaned of the ventilator and she recovered nicely. Our Bloodless team Hematology consultant, Dr. Linda Resar guided her postoperative therapy which included IV iron and erythropoietin. She was discharged from the hospital with a hemoglobin of 8.0 g/dL, and she and her family had a Baltimore crab dinner before returning home to Roanoke, VA.

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• Volume 106, Issue 5
• Angina: contemporary diagnosis and management
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• http://orcid.org/0000-0003-4009-6652 Thomas Joseph Ford 1 , 2 , 3 ,
• http://orcid.org/0000-0002-4547-8636 Colin Berry 1
• 1 BHF Cardiovascular Research Centre , University of Glasgow College of Medical Veterinary and Life Sciences , Glasgow , UK
• 2 Department of Cardiology , Gosford Hospital , Gosford , New South Wales , Australia
• 3 Faculty of Health and Medicine , The University of Newcastle , Newcastle , NSW , Australia
• Correspondence to Dr Thomas Joseph Ford, BHF Cardiovascular Research Centre, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow G128QQ, UK; tom.ford{at}health.nsw.gov.au

https://doi.org/10.1136/heartjnl-2018-314661

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• cardiac catheterization and angiography
• chronic coronary disease
• percutaneous coronary intervention
• coronary artery disease

Learning objectives

Around one half of angina patients have no obstructive coronary disease; many of these patients have microvascular and/or vasospastic angina.

Tests of coronary artery function empower clinicians to make a correct diagnosis (rule-in/rule-out), complementing coronary angiography.

Physician and patient education, lifestyle, medications and revascularisation are key aspects of management.

Introduction

Ischaemic heart disease (IHD) remains the leading global cause of death and lost life years in adults, notably in younger (<55 years) women. 1 Angina pectoris (derived from the Latin verb ‘angere’ to strangle) is chest discomfort of cardiac origin. It is a common clinical manifestation of IHD with an estimated prevalence of 3%–4% in UK adults. There are over 250 000 invasive coronary angiograms performed each year with over 20 000 new cases of angina. The healthcare resource utilisation is appreciable with over 110 000 inpatient episodes each year leading to substantial associated morbidity. 2 In 1809, Allen Burns (Lecturer in Anatomy, University of Glasgow) developed the thesis that myocardial ischaemia (supply:demand mismatch) could explain angina, this being first identified by William Heberden in 1768. Subsequent to Heberden’s report, coronary artery disease (CAD) was implicated in pathology and clinical case studies undertaken by John Hunter, John Fothergill, Edward Jenner and Caleb Hiller Parry. 3 Typically, angina involves a relative deficiency of myocardial oxygen supply (ie, ischaemia) and typically occurs after activity or physiological stress ( box 1 ).

Definition of angina (NICE guidelines) 32

Typical angina: (requires all three)

Constricting discomfort in the front of the chest or in the neck, shoulders, jaw or arms.

Precipitated by physical exertion.

Relieved by rest or sublingual glyceryl trinitrate within about 5 min

Presence of two of the features is defined as atypical angina.

Presence of one or none of the features is defined as non-anginal chest pain.

Stable angina may be excluded if pain is non-anginal provided clinical suspicion is not raised based on other aspects of the history and risk factors.

Do not define typical, atypical and non-anginal chest pain differently in men and women or different ethnic groups.

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Reappraisal of ischaemic heart disease pathophysiology. Distinct functional and structural mechanisms can affect coronary vascular function and frequently coexist leading to myocardial ischaemia. CAD, coronary artery disease.

We begin by classifying angina according to pathophysiology. We then consider the current guidelines and their strengths and limitations for assessing patients with recent onset of stable chest pain. We review non-invasive and invasive functional tests of the coronary circulation with linked management strategies. Finally, we point to future directions providing hope for improved patient outcomes and development of targeted disease-modifying therapy. The aim of this educational review is to provide a contemporary approach to diagnosis and management of angina taking into consideration epicardial coronary disease, microcirculatory dysfunction and coronary vasospasm.

Contemporary angina classification by pathophysiology

The clinical history is of paramount importance to initially establish whether the nature of the presenting symptoms is consistent with angina ( box 1 ). Indeed, recent data supports specialist physicians under-recognise angina in up to half of their patients. 10 Furthermore, contemporary clinical trials of revascularisation in stable IHD including the ISCHEMIA trial highlight the importance of good clinical history and listening to our patients to determine the nature and frequency of symptoms which helps to plan management. We propose a classification of angina that aligns with underlying aetiology and related management ( table 1 ).

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Classification of angina by pathophysiology

Angina with obstructive coronary artery disease

2018 ESC guidelines on myocardial revascularisation define obstructive CAD as coronary stenosis with documented ischaemia, a haemodynamically relevant lesion (ie, fractional flow reserve (FFR) ≤0.80 or non-hyperaemic pressure ratio (NHPR) (eg, iwFR≤0.89)) or >90% stenosis in a major coronary vessel ( table 1 ). There is renewed interest in NHPRs (iwFR, resting full-cycle ratio (RFR) and diastolic pressure ratio (dPR)) as data have emerged in support of numerical equivalency between these indices suggesting all can be used to guide treatment strategy. 11 Angina with underlying obstructive CAD allows symptom guided myocardial revascularisation (often with percutaneous coronary intervention (PCI)) and is effective in reducing ischaemic burden and symptoms (in many patients). Recent studies have served evidence that functional coronary disorders overlap and may contribute to angina even in patients with obstructive epicardial CAD. Dynamic changes in lesion or vessel ‘tone’ and propensity to vasoconstriction is important and may cause rest angina that is frequently overlooked in patients with obstructive CAD. 12 During invasive physiological assessment of ischaemia during exercise, Asrress et al showed that ischaemia developed at FFR averaging≈0.76 which is not often observed with adenosine induced hyperaemia. 13 This finding implies there are other important drivers of subendocardial ischaemia (myocardial supply:demand factors). Furthermore, it reinforces that angina is not synonymous with ischaemia or flow-limiting coronary disease (eg, abnormal FFR or NHPR). Coronary anatomy and physiology should not be considered in isolation but in the context of the patient.

Angina-myocardial ischaemia discordance

Although obstructive CAD or microvascular dysfunction may be present, the link between ischaemia and angina is not clearcut. The ‘ischaemic threshold’ (the heart rate-blood pressure product at the onset of angina) has intraindividual and interindividual variability. 14 Innate differences in vascular tone and endocrine changes (eg, menopause) may influence propensity to vasospasm while environmental factors including cold environmental temperature, exertion and mental stress are relevant. The large international CLARIFY registry highlighted the importance of symptoms, showing that angina with or without concomitant ischaemia, was more predictive of adverse cardiac events compared with silent ischaemia alone. 15 Other potential drivers of discordance between angina and ischaemia include variations in pain thresholds and cardiac innervation (eg, diabetic neuropathy).

Symptoms and/or signs of ischaemia but no obstructive coronary artery disease (INOCA)

Cardiologists are inclined to adopt a ‘stenosis centric’ approach to patient management; however, as clinicians we must appreciate that all factors are relevant, including coronary anatomy and function but systemic health and the psychosocial background ( figure 2 ). First, systemic factors including heart rate, blood pressure (and their product) and myocardial supply:demand ratio (Buckberg index) are relevant. 16 Reduced myocardial oxygen supply from problems such as anaemia or hypoxaemia should always be considered.

Contributing factors to myocardial ischaemia. The contributors to the physiological myocardial perfusion gradient and resultant ischaemia can be broken down at patient-level into systemic, cardiac and coronary factors. CAD, coronary artery disease; SEVR, subendocardial viability ratio.<Modified with permission from 47 >.

Second, coronary factors are well recognised but certain nuances are overlooked. In 2018, the first international consensus guidelines clarify that a definite diagnosis of MVA may be made in patients with angina with no underlying obstructive CAD, evidence of reversible ischaemia on functional testing and objective evidence of coronary microvascular dysfunction ( table 1 ). 17 ‘Probable MVA’ is defined by three of the above criteria. Coronary microvascular dysfunction may be structural (eg, small vessel rarefaction or increased media: lumen ratio) or functional (eg, endothelial impairment) and these disorders may coexist. Other coronary causes of INOCA include intramyocardial ‘tunnelled’ segments of epicardial arteries (myocardial ‘bridging’) who may have ischaemia on exercise. These segments are particularly susceptible to vasoconstriction due to endothelial impairment. 18 Coronary arteriovenous malformations are rare but may also cause of myocardial ischaemia. Vasospastic angina (‘Prinzmetal’s angina’) is typically described as recurrent rest angina with focal occlusive proximal epicardial often seen in young smokers with characteristic episodic ST segment elevation during attacks. Notably, the more common form of VSA is distal and diffuse subtotal epicardial vasospasm and is characterised by ST segment depression and may occur during exertion. Typical cardiac risk factors and endothelial impairment may be implicated. 19

The long-term (sometimes lifelong) burden of MVA and/or VSA on physical and mental well-being can be profound. Patients with these conditions commonly attend primary care and are repeatedly hospitalised with acute coronary syndromes, arrhythmias and heart failure driving up health resource utilisation, morbidity and reducing quality of life. 20 21

The third and final group of factors that drive ischaemia in patients with angina but without obstructive CAD include cardiac factors . These include left ventricular hypertrophy or restrictive cardiomyopathy where subendocardial ischaemia results impaired perfusion from arterioles penetrating deeper into myocardial tissue with shorter diastole, enhanced systolic myocardial vessel constriction and enhanced interstitial matrix. 22 Heart failure (with reduced or preserved ejection fraction) can lead to elevated left ventricular end diastolic pressure which reduces the diastolic myocardial perfusion gradient. Valvular heart disease (eg, aortic stenosis (AS)) is an important consideration in patients with INOCA. In AS, most experts support haemodynamic factors as the main cause of ischaemia, especially since symptoms and coronary flow reserve (CFR) improve immediately after valve replacement. 23 Patients with INOCA may have increased painful sensitivity to innocuous cardiac stimuli (eg, radiographic contrast) without inducible ischaemia. Furthermore, some affected patients have a lower pain threshold and tolerance to the algogenic effects of adenosine (thought to be the main effector of ischaemia mediated chest pain). 24

Gender differences and angina presentation

The WISE (Women’s Ischemia Syndrome Evaluation) study highlighted that over 2/3 of women with angina had no obstructive CAD and the majority of these had functional impairments in the coronary microcirculation associated with significant impairments in health-related quality of life. 25 Indeed, women have more non-obstructive CAD and functional IHD which are frequently overlooked and hence undertreated. 26 27 Over time and at different ages, women have a similar or slightly higher prevalence of angina than men across countries independent of diagnostic and treatment practices. 28 Different patterns of IHD may be anticipated to cause different angina symptoms between genders. Nonetheless, recent evidence moves the field away from the ‘male-typical, female-atypical’ model of angina towards a ‘gender continuum’ whereby the objective reports between men and women’s symptoms are more similar than treating physicians perceive. Interestingly, dyspnoea was a feature in around ¾ of angina presentations without any significant difference between the sexes. 29

Assessment: current guidelines

Assessment strategies in current major international guidelines focus on the detection of underlying obstructive CAD. European and American guidelines (ESC and ACC/AHA, respectively) favour a Bayesian approach whereby overall probability of obstructive CAD after testing is determined from pretest probability modified by the diagnostic test results. The ACC/AHA guidelines determine pretest risk from a modified Diamond Forrester model, 30 whereas the Europeans favour the CADC (Coronary Artery Disease Consortium) model which avoids overestimation seen with Diamond-Forrester and appears a more accurate assessment of pretest risk. 31 Both current guidelines stratify pretest risk into low, intermediate or high groups with use of non-invasive testing suggested in the intermediate group (ACC/AHA arbitrarily defined as 10%–90% or 15%–85% in ESC).

In stark contrast, the NICE CG95 2016 update ‘chest pain of recent onset: assessment and diagnosis’ discarded the Bayesian pretest risk assessment. NICE advocates first-line multidetector CT coronary angiography (CTCA) in all patients with typical or atypical chest pain ( box 1 ), those whose history does not suggest angina but who have ST changes or Q waves on a resting ECG. 32 Functional testing (eg, exercise stress echo or stress perfusion magnetic resonance—CMR) are relegated to second-line if CTCA is non-diagnostic or the clinical significance of known CAD needs clarified. Potential benefits of this approach include a much higher diagnostic accuracy for detection of atherosclerotic heart disease than functional testing which potentially carries the best long-term prognostic information for patients with CAD. 27 Extended 5-year outcomes from SCOTHEART showed a reduction in the combined endpoint of death from coronary heart disease or non-fatal myocardial infarction among the group randomised to CTCA compared with standard care (2.3% vs 3.9%; absolute risk reduction (ARR) 1.6% number needed to treat (NNT) 63). This effect was driven by better targeting of preventative therapies. The authors report that although overall prescriptions of preventive cardiovascular medications were only modestly increased (~10% higher) in the CTCA arm, changes in such therapies occurred in around one in four patients allowing more personalised treatment to patients with most coronary atheroma in the CT group.

These results should be considered in relation to design limitations of this trial. There was no control procedure (test vs no test), the threshold for prescribing preventive therapy with statins was 20%–30% likelihood of a CHD event in 10 years (much higher than many contemporary healthcare systems), CTCA was performed on top of treadmill exercise testing which has poor test accuracy in distinct patient groups, notably women, and the procedures were unblinded and open-label. Outcome reporting that is narrowly focused on CHD does not take account of other cardiovascular events, such as hospitalisation for arrhythmias and heart failure, which have implications for quality of life. In PROMISE, a ‘head-to-head’ trial of CTCA versus functional testing, there were no differences in health outcomes. 33 In the interests of providing patients and clinicians with a reliable and accurate test result, a strategy based on anatomical CTCA has fundamental limitations. SCOT-HEART identified that obstructive CAD affects the minority (one in four) patients presenting to the Chest Pain Clinic with known or suspected angina. This means that an anatomical test strategy with CTCA leaving the aetiology and treatment unexplained in the majority of affected patients, which becomes all the more relevant considering that anginal symptoms and quality of life are worse when CTCA is used. 34 Diagnostic options are enhanced by advances in technology and tests for the functional significance of CAD are now feasible, but at significant cost. 35 NICE guidelines state that HeartFlow FFR CT should be considered as an ‘option for patients with stable, recent onset chest pain who are offered CCTA as part of the NICE pathway on chest pain’. Using HeartFlow FFR CT may avoid the need for invasive coronary angiography and revascularisation; however, major randomised controlled trials are ongoing (eg, FORECAST study NCT03187639 ).

We support efforts to provide a definitive diagnosis for patients with ongoing angina symptoms after a ‘negative’ CTCA, initially using non-invasive ischaemia testing. Notably, the recent International Standardised Criteria for diagnosing ‘suspected’ MVA would be met in patients with symptoms of myocardial ischaemia, no obstructive CAD and objective evidence of myocardial ischaemia ( table 1 ). Invasive testing for diagnosis of MVA could be reserved for subjects with refractory symptoms and negative ischaemia testing or diagnostic uncertainty. The criteria for ‘definite MVA’ require the above AND objective evidence of microvascular dysfunction (eg, reduced CFR or raised microvascular resistance).

Limitations of current guidelines

There are limitations to the current NICE-95 guideline, not least the logistics and cost of service provision with an estimated 700% increase in cardiac CT required across the UK. 36 Importantly, what do we report to the majority of patients with anginal chest pain but no obstructive CAD on the CTCA? In fact, only 25% of patients had obstructive CAD and at 6 weeks based on the CTCA findings, 66% of patients were categorised as not having angina due to coronary heart disease. The possibility of false reassurance for the patients with angina and INOCA is an open question and may be one contributing factor for the lack of improvement in angina and quality of life in the CTCA group vs standard care. 34 We must strive to deliver patient-centred care, recognising that most patients seek explanation for their symptoms in combination with effective treatment options. 37 CTCA is an insensitive test for disorders of coronary vascular function, which may affect the majority of patients attending with anginal symptoms. Since the majority of affected patients have no obstructive CAD, and the majority of them are women, an anatomical strategy introduces a sex-bias into clinical practice, whereby a positive test result (obstructive CAD) is more likely to occur in men and a positive test for small vessel disease is less likely to occur in women. Furthermore, patient-reported outcomes including angina limitation, frequency and overall quality of life improve less after CTCA compared with standard care, notably in patients with no obstructive CAD. 34 Non-invasive functional testing with positron emission tomography (PET), echo and most recently stress perfusion CMR has diagnostic value for stratified medicine. Finally, stratification of patients using luminal stenosis severity on angiography overlooks the spectrum of risk associated with overall plaque burden and may miss functional consequences associated with diffuse but angiographically mild disease (particularly when subtending large myocardial mass).

Non-invasive functional testing includes myocardial perfusion scintigraphy, exercise treadmill testing (including stress echocardiography) or contrast-enhanced stress perfusion MRI depending on local availability. Novel pixel-wise absolute perfusion quantification of myocardial perfusion by CMR will likely improve the efficiency of absolute quantification of myocardial blood flow by CMR. 38 PET is the reference-standard non-invasive assessment of myocardial blood flow permitting quantitative flow derivation in mL/g/min. Clinically, PET-derived quantification of myocardial blood flow (MBF) can assist in the diagnosis of diffuse epicardial or microvascular disease; however, limitations include poor availability and exposure to ionising radiation. Non-invasive workup often provides important insights on coronary microvascular function and are reviewed in detail elsewhere. 39

With functional testing relegated to second-line testing, clinicians may forgo additional tests after a negative CTCA particularly in an era of fiscal restraint and if patients’ symptoms are viewed as atypical. One important group that will be disparately affected by an ‘anatomy first’ strategy are women—over half of all patients with suspected angina in the large prospective trials of CTCA are female. While the benefits of CTCA to diagnose CHD and prevent CHD events are similar in women and men, the large majority of patients undergoing CTCA do not have obstructive CAD potentially leading to misdiagnosis and suboptimal management in patients with INOCA. 33 Women, are most likely to have no obstructive CAD and their cardiac risk is associated with severely impaired CFR and not obstructive CAD. 40 Overall, there is growing awareness of sex-specific differences in coronary pathophysiology and potential for different patterns of CAD in women. This is a rapidly evolving fertile area for further research.

Invasive coronary angiography and physiological assessment

UK NICE guidelines suggest that invasive coronary angiography is a third-line investigation for angina when the results of non-invasive functional imaging are inconclusive. Patients with typical symptoms, particularly those in older age groups with higher probability of non-diagnostic CTCA scans, often proceed directly to invasive coronary angiography. During cardiac catheterisation, assuming that epicardial CAD is responsible for their symptoms, visual assessment for severe angiographic stenosis (>90%) is sufficient to establish significance and treatment plan for these patients. Two common pitfalls for visual interpretation of angiograms were recently highlighted by two coronary physiology pioneers Gould and Johnson. Using their quantitative myocardial perfusion database of over 5900 patients showing that occult coronary diffuse obstructive coronary disease or flush ostial stenosis may be both be overlooked on angiography and mislabelled as microvascular angina with suboptimal treatment. 41 The ischaemic potential of indeterminate coronary lesions (~40%–70% diameter stenosis) is best assessed using pressure-derived indices, such as FFR, and non-hyperaemic pressure ratios (NHPR: dPR, nstantaenous wave free ratio (iwFR) and others) to guide revascularisation decisions. However, as is the case with coronary angiography, these indices do not inform the clinician about disorders of coronary artery vasomotion.

Invasive tests of coronary artery function are the reference standard for the diagnosis of coronary microvascular dysfunction 17 and vasospastic angina ( table 1 ; figure 1 ). 42 Coronary microvascular resistance may be directly measured using guidewire-based physiological assessment during adenosine induced hyperaemia. Methods to assess this include using a pressure-temperature sensitive guidewire by thermodilution (index of microcirculatory resistance; IMR) or Doppler ‘ComboWire’ (hyperaemic microvascular resistance; HMR). These metrics have been the focus of a recent review article in Heart. 43 There are several other haemodynamic indices of microvascular function including instantaneous hyperaemic diastolic pressure velocity slope, wave intensity analysis and zero flow pressure. A detailed description of these parameters is out with the scope of this review. 41 Elevated coronary microvascular resistance (eg, IMR >25) carries prognostic utility in patients with reduced CFR but unobstructed arteries. Lee et al found over fivefold higher risk of adverse cardiac events in these subjects compared with controls with normal microvascular function. 44

CFR is the ratio of maximum hyperaemic blood flow to resting flow. CFR in the absence of obstructive CAD can signify impaired microvascular dilation. Lance Gould first introduced this concept almost 50 years ago but more recently proposed that CFR should be considered in the context of the patient and the hyperaemic flow rate. 41 The absolute threshold for abnormal CFR varies depending on the method of assessment, the patient population studies and the controversy reflects the dichotomous consideration of the continuous physiological spectrum of ischaemia. Abnormal CFR thresholds vary from ≤2.0 or ≤2.5 with more restrictive criteria for abnormal CFR (<1.6) being more specific for myocardial ischaemia and worse outcomes but at the cost of reduced sensitivity. On the other hand, studies of transthoracic Doppler derived CFR (which has less reproducibility) often use cut-offs of 2.5 with some observational evidence of worse outcomes in the INOCA population with CFR below this threshold. 45 The influence of rate-pressure product on resting flow and its correction for CFR determination should be considered.

Systolic endocardial viability ratio (SEVR) is a ratio of myocardial oxygen supply:demand derived from the aortic pressure-time integral (diastole:systole). However, it is well known that blood pressure, pulse and SEVR perturbations influence CFR more closely than microcirculatory resistance. Reduced CFR without raised microvascular resistance still portends increased cardiovascular risk 44 and may be a distinct subgroup with different drivers of ischaemia (eg, abnormal supply:demand systemic haemodynamic factors; figure 2 ). Alternatively, these patients may be at an earlier stage of disease prior to more established structural microvascular damage. Sezer et al showed the pattern of coronary microvascular dysfunction early in type II diabetes was driven by disturbed coronary regulation and high resting flow. 46 In longstanding diabetes however, elevated microvascular resistance was observed reflecting established structural microvascular disease. This process matches the paradox of microvascular disease in diabetic nephropathy where increased glomerular filtration rate (GFR) typifies the early stages of disease prior to later structural damage and reduction in GFR.

The third mechanism of microvascular dysfunction is inappropriate propensity to vasoconstriction of the small coronary arteries, typically this is assessed using intracoronary acetylcholine infusions as a pharmacological probe.

Rationale and benefit of invasive coronary function testing in INOCA

We contend that a complete diagnostic evaluation of the coronary circulation should assess structural and functional pathology. 47 The British Heart Foundation CorMicA trial provides evidence about the opportunity to provide a specific diagnosis to patients with angina using an interventional diagnostic procedure (IDP) when obstructive CAD is excluded by invasive coronary angiography. Consenting patients were randomised 1:1 to the intervention group (stratified medical therapy, IDP disclosed) or the control group (standard care, IDP sham procedure, results not disclosed). The diagnostic intervention included pressure guidewire-based assessment of FFR, CFR and IMR during adenosine induced hyperaemia (140 µg/kg/min). Vasoreactivity testing was performed by infusing incremental concentrations of acetylcholine (ACh) followed by a bolus vasospasm provocation (up to 100 µg). The diagnosis of a clinical endotype (microvascular angina, vasospastic angina, both, none) was linked to guideline-based management. The primary endpoint was the mean difference in angina severity at 6 months (as assessed by the Seattle Angina Questionnaire summary score—SAQSS) which was analysed using a regression model incorporating baseline score. A total of 391 patients were enrolled between 25/11/2016 and 11/12/2017. Coronary angiography revealed obstructive disease in 206 (53.7%). One hundred and fifty-one (39%) patients without angiographically obstructive CAD were randomised. The underlying abnormalities revealed by the IDP included: isolated microvascular angina in 78 (51.7%), isolated vasospastic angina in 25 (16.6%), mixed (both) in 31 (20.5%) and non-cardiac chest pain in 17 (11.3%). The intervention was associated with a mean improvement of 11.7 units in the SAQSS at 6 months (95% CI 5.0 to 18.4; p=0.001). In addition, the intervention led to improvements in the quality of life (EQ5D index 0.10 units; 0.01 to 0.18; p=0.024). After disclosure of the IDP result, over half of treating clinicians changed their diagnosis about the aetiology of their patients’ symptoms. There were no procedural serious adverse events and no differences in major adverse cardiac events (MACE) at 6 months. Interestingly, there were sustained quality of life benefits at one year for INOCA patients helped by correct diagnosis and linked treatment started at the index invasive procedure. 48 Future trials are anticipated to determine the wider external validity of this approach.

Medical therapy to prevent new vascular events should be considered and these include consideration of aspirin, ACE inhibitors (ACEi) and statins. The latter two agents have pleiotropic properties including beneficial effects on endothelial function and so may be helpful in treating coronary microvascular dysfunction. Sublingual glyceryl trinitrate tablets or spray should be used for the immediate relief of angina and before performing activities known to bring on angina.

Non-pharmacological

As with many cardiovascular diseases, lifestyle modification including risk factor control and patient education are key. Lifestyle recommendations are covered in detail in recent ESC guidelines. The adverse effect of angina on patient well-being and quality of life can be substantial. It is crucial that we assess for this and manage appropriately. After diagnosis with angina, cardiac rehabilitation can be useful to educate and build confidence. One useful patient led education aid is called the ‘Angina plan’. This tool is a workbook and relaxation plan delivered in primary care, which helps improve angina symptoms (frequency and limitation) while reducing anxiety and depression. 49 The ORBITA trial highlights the benefits of placebo effect and we support that the positive diagnosis may be therapeutic in itself. Angina symptoms are often subjective and multifactorial in origin, so patient education and validation of symptoms may facilitate further improvement.

Management: Non-obstructive CAD

Generic guidelines on angina management frequently overlooks the precision medicine goal whereby treatment is targeted to underlying pathophysiology. There is a lack of high-quality clinical trial data for treating microcirculatory dysfunction. The current article thus proposes a reasoned approach to management based on evaluation of pathophysiological mechanisms.

We contest that angina and INOCA are syndromes and not a precise diagnosis (akin to myocardial infarction with no obstructive CAD—MINOCA). As such, by stratifying treatment according to underlying pathophysiology, we may realise better outcomes for our patients.

Impaired coronary vasodilator capacity (reduced CFR)

Bairey Merz et al performed a randomised controlled trial of ranolazine in the WISE population. Notably, there was no net benefit effect on the INOCA population as a whole; however, in patients with reduced CFR (<2.5), there was a benefit suggestion of improved myocardial perfusion reserve index (MPRi) after established treatment. 50 Lanza and Crea highlight that subjects with reduced CFR might preferentially be treated with drugs that reduce myocardial oxygen consumption (eg, beta-blockers (BB)—for example, Nebivolol 1.25–10 mg daily). 51 There is accumulating evidence that long acting nitrates are ineffective or even detrimental in MVA. Lack of efficacy may relate to poor tolerability, steal syndromes through regions of adequately perfused myocardium and/or related to the reduced responsiveness of nitrates within the coronary microcirculation. 52 Furthermore, chronic therapy with nitrate may induce endothelial dysfunction and oxidative stress, predominantly via endothelin dependent pathways. 53

Increased microvascular constriction (structurally increased microvascular resistance or functional propensity to microvascular spasm)

Subjects with increased microvascular vasoconstriction may be treated with vasodilator therapies acting on the microcirculation. These include calcium channel blockers (CCB—for example, amlodipine 2.5–10 mg daily) or nicorandil (eg, 5–30 mg two times a day). Hyper-reactivity to constrictor stimuli resulting in propensity to microvascular spasm may be provoked by endothelial dysfunction. This was first described my Mohri et al over three decades ago with recent physiological studies suggesting treatment aimed at improving endothelial function (eg, ACEi, Ramipril 2.5–10 mg) may improve the microvascular tone and/or the susceptibility to inappropriate spasm. 54 55 A detailed discussion of all potentially therapeutic options for coronary microvascular dysfunction is beyond the scope of this article; however, a systematic review by Marinescu et al may be of interest to readers wishing further information. 56

Epicardial spasm (vasospastic angina)

The poor nitrate response or tolerance seen in MVA contrasts with patients with vasospastic angina, in whom nitrates are a cornerstone of therapy and BB are relatively contraindicated. 7 Dual pathologies (VSA with underlying microvascular disease) is increasingly recognised. A diagnosis of VSA facilitates treatment using non-dihydropiridine calcium antagonists (eg, diltiazem-controlled release up to 500 mg daily). Overall, CCB are effective in treating over 90% of patients. 57 High doses of calcium antagonists (non-dihydropiridine and dihydropyridine) may be required either alone or in combination. Unfortunately, ankle swelling, constipation and other side effects may render some patients intolerant. In these cases, long-term nitrates may be used with good efficacy in this group. In about 10% of cases, coronary artery spasm may be refractory to optimal vasodilator therapy. Japanese VSA registry data shows nitrates were not associated with MACE reduction in VSA, and importantly when added to Nicorandil were potentially associated with higher rates of adverse cardiac events. 58 Alpha blockers (eg, clonidine) may be helpful in selected patients with persistent vasospasm. In patients with poor nitrate tolerance the K+-channel opener nicorandil (5–10 mg two times a day) can be tried. Consider secondary causes in refractory VSA (eg, coronary vasculitis) and in selected patients with ACS presentations, coronary angioplasty may be considered as a bailout option.

Management: Obstructive CAD

Pharmacological.

Although NICE guidelines offer either BB or CCB first line, although we support BB initially because they are generally better tolerated ( table 2 ). 59 Long-term evidence of efficacy is limited between BB and CCB and there are no proven safety concerns favouring one or the other. Dihydropyridine calcium may be added to BB if blood pressure permits. NICE CG126 states third line options can be either added on (or substituted if BB/CCB not tolerated). These include nitrates (eg, isosorbide mononitrate 30–120 mg controlled release), ivabradine (eg, 2.5–7.5 mg two times a day), nicorandil (5–30 mg two times a day) or ranolazine (375–500 mg two times a day). These are all third line medications that can be used based and combined with BB and/or CCB depending on comorbidities, contraindications, patient preference and drug costs ( figure 3 ). The RIVER-PCI study found that anti-ischaemic pharmacotherapy with ranolazine did not improve the prognosis of patients with incomplete revascularisation after percutaneous coronary intervention. 60 This was a reminder that alleviation of ischaemia may not improve ‘hard’ endpoints in patients with chronic coronary syndromes but helps us to remain focused on improving their quality of life.

Angina pharmacotherapy

Empirical pharmacological treatments for patients with angina. ACEi, Angiotensin converting enzyme inhibitor; ASP, aspirin; BB, beta-blocker; Endo, endothelial; IVA, ivabradine; MVA, microvascular angina; NIC, nicorandil; NIT, nitrate; Obs CAD, obstructive coronary artery disease;, RAN, ranolazine; RF, risk factor.

Revascularisation

Recently revised 2018 ESC guidelines suggest that myocardial revascularisation is indicated to improve symptoms in haemodynamically significant coronary stenosis with insufficient response to optimised medical therapy. Patients’ wishes should be accounted for in relation to the intensity of antianginal therapy as PCI can offer patients with angina and obstructive CAD a reduced burden from polypharmacy. Angina persists or recurs in more than one in five patients following PCI and microvascular dysfunction may be relevant. Guidelines support consideration of revascularisation for prognosis in asymptomatic ischaemia in patients with large ischaemic burden (left main/proximal left anterior descending artery stenosis >50%) or two/three vessel disease in patients with presumed ischaemia cardiomyopathy (LVEF<35%).

Refractory angina is common in patients with complex CAD including those with previous coronary artery bypass grafting (CABG) and chronic total occlusions (CTOs). Over the last decade, vast strides in technique, training and tools have delivered major increases in the success of CTO PCI. These angina patients often have incomplete revascularisation with lesions or anatomy previously considered ‘unsuitable for intervention’ but now amenable to treatment by trained operators. A recent review article in Heart summarises non-pharmacological therapeutic approaches to patients with refractory angina including cognitive behavioural therapy (CBT), stellate ganglion nerve blockade, Transcutaneous Electrical Nerve Stimulation (TENS)/spinal cord stimulation and pain modulating antidepressants (eg, imipramine). 61 Of note, coronary sinus reducers deployed using a transcatheter venous system have shown early promise in clinical studies.

Future directions

Based on test accuracy, health and economic benefits, non-invasive and invasive functional tests should be considered a standard of care in patients with known or suspected angina, especially if obstructive CAD has been excluded by CT or invasive coronary angiography. Computational fluid dynamic modelling of the functional significance of CAD, notably with FFRct, is an emerging option and clinical trials, including FORECAST (ClinicalTrials.gov Identifier: NCT03187639 ) and PRECISE ( NCT03702244 ), are ongoing. The use of computational modelling as a diagnostic tool in patients with microvascular angina or coronary vasomotion disorders remains to be determined.

Systemic vascular abnormalities were recently highlighted in patients with INOCA potentially supporting a therapeutic role for targeted vascular therapy, for example, using selective endothelin-A receptor antagonists. 19 The MRC Framework for Stratified Medicine is applicable to patients with angina and we believe genetic testing with precision medicine holds future promise.

The optimal management of patients with known or suspected angina begins with establishing the correct diagnosis.Around one half of angina patients have no obstructive coronary disease; many of these patients have microvascular and/or vasospastic angina.Non-invasive assessment with CTCA is a sensitive anatomical test for plaque which assists in initial treatment and risk stratification. Anatomical imaging has fundamental limitations to rule in or rule out coronary vasomotion disorders in patients with symptoms and/or signs of ischaemia but no obstructive CAD (INOCA). Women are disproportionately represented in this group with MVA and/or VSA, the two most common causes of diagnoses. A personalised approach to invasive diagnostic testing permits a diagnosis to be made (or excluded) during the patients’ index presentation. This approach helps stratify medical therapy leading to improved patient health and quality of life. Physician appraisal of ischaemic heart disease (IHD) should consider all pathophysiology relevant to symptoms, prognosis and treatment to improve health outcomes for our patients. More research is warranted, particularly to develop disease modifying therapy.

ESC curriculum: stable CAD

Precipitants of angina.

Prognosis of chronic IHD.

Clinical assessment of known or suspected chronic IHD.

Indications for, and information derived from, diagnostic procedures including ECG, stress test in its different modalities (with or without imaging, exercise and stress drugs) and coronary angiography.

Management of chronic IHD, including lifestyle measures and pharmacological management.

Indications for coronary revascularisation including PCI/stenting and CABG.

Angina pectoris is a clinical syndrome occurring in patients with or without obstructive epicardial coronary artery disease.

Diagnostic testing in angina is symptom driven and so should provide patients and their physicians with an explanation for their symptoms and used to stratify management and offer prognostic insights.

Microvascular and/or vasospastic angina are common disorders of coronary artery function that may be overlooked by anatomical coronary testing, leading to false reassurance and adverse prognostic implications.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Twitter @tomjford

Contributors TJF devised and wrote the article and figures. CB edited and approved the final manuscript.

Funding British Heart Foundation (PG/17/2532884; RE/13/5/30177; RE/18/634217).

Competing interests CB is employed by the University of Glasgow which holds consultancy and research agreements with companies that have commercial interests in the diagnosis and treatment of angina (Abbott Vascular, AstraZeneca, Boehringer Ingelheim, GSK, Menarini, Opsens, Philips and Siemens Healthcare.)

Patient consent for publication Not required.

Provenance and peer review Commissioned; externally peer reviewed.

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The impact of immunity on the risk of coronary artery disease: insights from a multiomics study

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Rutao Bian, Dongyu Li, Xuegong Xu, Li Zhang, The impact of immunity on the risk of coronary artery disease: insights from a multiomics study, Postgraduate Medical Journal , 2024;, qgae105, https://doi.org/10.1093/postmj/qgae105

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Immune inflammation is intricately associated with coronary artery disease (CAD) progression, necessitating the pursuit of more efficacious therapeutic strategies. This study aimed to uncover potential therapeutic targets for CAD and myocardial infarction (MI) by elucidating the causal connection between regulatory immune-related genes (RIRGs) and these disorders.

We performed summary data-based Mendelian randomization analysis to assess the therapeutic targets linked to expression quantitative trait loci and methylation quantitative trait loci of RIRGs in relation to CAD and MI. Independent validation cohorts and datasets from coronary artery and left ventricular heart tissue were analyzed. To strengthen causal inference, colocalization analysis and PhenoScanner phenotype scans were employed.

Utilizing multiomics integration, we pinpointed EIF2B2, FCHO1, and DDT as CAD risk genes. Notably, EIF2B2 and FCHO1 displayed significant associations with MI. High EIF2B2 expression, regulated by cg16144293, heightened CAD and MI risk at rs175438. In contrast, enhanced FCHO1 expression, modulated by cg18329931, reduced CAD and MI risk at rs13382133. DDT upregulation influenced by cg11060661 and cg09664220 was associated with decreased CAD risk at rs5760120. Colocalization analysis firmly established these relationships.

EIF2B2, FCHO1, and DDT represent risk loci for CAD progression within RIRGs. Our identification of these genes enhances understanding of CAD pathogenesis and directs future drug development efforts.

What is already known on this topic:  

Coronary artery disease (CAD) is the leading cause of death worldwide. Despite significant advances in treatment, it remains a major burden on healthcare systems and economies around the world.

Immunity and inflammation are integral to the complex pathological mechanisms underlying coronary artery disease.

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EIF2B2, FCHO1, and DDT were confirmed as risk loci for coronary artery disease. The genes EIF2B2 and FCHO1 are significant risk loci for myocardial infarction.

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This study provides valuable insights into the involvement of CAD risk genes in the pathogenesis of the disease and directs future drug development efforts.

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A Case Study on Geriatric Patient with Coronary Artery Disease-Associated Diabetic Foot Ulcer

A clinical pharmacist management care.

Kumar, A. Bharath; Umashankar, M. S. 1, ; Sriram, V. 2 ; Kumar, G. Bharath 3

Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India

1 Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India

2 Department of Cardiology, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India

3 Department of Cardiology, Gleneagles Global Health City, Kancheepuram, Tamil Nadu, India

Address for correspondence: Dr. M. S. Umashankar, Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 603 203, Tamil Nadu, India. E-mail: [email protected]

Received August 02, 2019

Received in revised form January 20, 2020

Accepted January 28, 2020

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

A 66-year-old male patient was presented to the cardiology ward with complaints of chest pain for couple of days, breathlessness, sweating, and cough. He had complaints of loss of sensation over foot. He had past medical history of type 2 diabetes mellitus with hypertension. He had a history of ulcer with right big toe gangrene and trauma to right big toe before 20 days. Following with this condition, he developed a small ulcer. He has previous history of wound debridement. His echocardiogram detected moderate left ventricular systolic function and left ventricular ejection fraction was 38% which confirmed the presence of coronary artery disease. He underwent coronary angiogram which showed the presence of calcific coronary artery disease with triple vessel disease. The patient was diagnosed with diabetic foot ulcer with coronary artery disease. He was continuously monitored for a week and prescribed with medications. The patient was found stable and he was discharged from the hospital with advise of scheduled Physician's follow-up. The patient was forwarded to a clinical pharmacist counseling services for medication usage, foot care, wound care, lifestyle modifications' advices, physical exercise, stress management strict medication adherence, dietary intake suggestions, and disease-based information to alleviate the progress of disease complications. The medications advice by clinical pharmacist services in such complex disease association management is an imperative need in clinical practice. The clinical pharmacist intervention was proved to be an implementation to effective therapeutic outcomes in the patient.

INTRODUCTION

The diabetes mellitus prevalence is steadily increasing worldwide. The international diabetes federation estimated that diabetic incidence may even rise to 592 million by the year 2035. World diabetes atlas predict around 51 million population got affected with diabetes mellitus in India. The study exhibited that the urban population had poor knowledge on diabetes mellitus as compared to rural population. The International diabetes federation had predicted that the Indian population around 74 million was affected with diabetes in comparison with other countries in the world.[ 1 ] The uncontrolled levels of type 2 diabetes mellitus drastically increase the progression of diabetic complications such as retinopathy, renal failure, neuropathy, foot ulcer and amputations, cerebrovascular disease, and also rising the higher incidences of mortality due to coronary artery diseases. Diabetic foot ulcer is allied with formation of ulcer in the foot with neuropathy symptoms with different grades of infection. It shows a long-term complication of diabetes mellitus, which leads to leg amputations and further reduces the health status of the individual patients. The presence of neuropathy, trauma, deformity, hyperglycemia, high plantar pressures, peripheral arterial disease, and poor ischemic levels reduce the defense mechanism which increases the risk of occurring diabetic foot ulcer. The diabetic foot ulcer patients were represented with potential risk of infection, ulceration, destruction of deep tissues, and neuropathic abnormalities in the lower limb.[ 2 ] Coronary artery disease is a chronic burden of the cardiovascular disease which needs long-term treatment care for effective management of the disease complications among diabetic patients. Diabetes mellitus can increase two–four folds of coronary artery disease risk. The effective prescribing of statins and oral hypoglycemic agents is the practice of treatment for the coronary artery disease among the diabetic patients. The altered lifestyle practices increase the alarming incidences of coronary artery disease burden among diabetic patients. The well-known triggering factors such as smoking, dyslipidemia, obesity, diabetes, and hypertension can greatly influence the development of cardiovascular diseases. Henceforth effective diagnostic strategies and treatment options is to be thrived for a better management of cardiovascular complications among diabetic foot ulcer affected patients.[ 3 ]

CASE REPORT

A 66-year-old male was presented with chest pain, breathlessness, sweating and cough with complaints of numbness in his left foot.

Family history

His family history showed that his father and mother both were diabetics and suffered with coronary artery disease, and father had died with coronary artery disease.

Personal and social history

He is professionally a car driver with usual habit of smoking periodically around5–8 cigarettes per day since 10 years. He regularly eats meat, sea foods, and pickles.

Past medical history

He had previous medical history of type 2 diabetes mellitus with hypertension. He had a history of ulcer with right big toe gangrene and trauma to right big toe before 20 days. Following with this condition, he developed a foot ulcer. He also had previous history of wound debridement.

Past medication history

He takes drugs of antidiabetic medications, antihyperlipidemic drugs, antihypertensives, diuretics, neuropathic drugs, antibiotics, antiplatelets, and proton pump inhibitors.

The patient's clinical and laboratory test characteristics demonstrated that he was suffering with diabetic foot ulcer and coronary artery disease.

General examination reports

The patient was conscious, oriented, and afebrile, with heart rate of 80 bpm. His blood pressure was 150/90 mmHg; the cardiovascular sounds S1 and S2 were normal and respiratory sounds (B/L AE) were normal. His ankle brachial index was 0.85 which detected mild peripheral artery disease. His electrocardiogram demonstrated sinus arrhythmia, depressed ST segment in L1, LII, and LIII. The echocardiogram of the patient confirmed the presence of coronary artery disease, moderate left ventricular systolic function, mild dilated left ventricle, left ventricular ejection fraction of 38% with left ventricular grade III. He underwent coronary angiogram which showed the presence of calcific coronary artery disease with triple-vessel disease.

Hematology laboratory examinations exhibited hemoglobin 13.2 g/dl, packed cell volume 39%, white blood cells 8360/cum, neutrophils 81%, eosinophils 5%, basophils 1%, lymphocytes 9%, monocytes 36%, red blood cells 4.7 × 10 6 /mm 3 , erythrocyte sedimentation rate 41/h, mean corpuscular volume 87 fl, mean corpuscular hemoglobin 32 pg/cell, mean corpuscular hemoglobin concentration 38 g/dl, and platelets 189,000 cells/cum. Serum electrolyte value as follows Na+ =135 meq/L (Hyponatremia), K+ =3.6 meq/L. cl− =93 meq/L and HCO 3 = 21 meq/L. Blood sugar test showed fasting blood sugar 210 mg/dl, post prandial blood sugar level 309 mg/dl, HbA1c 6.6 (%), and eAG 143 (mg/dl).

Liver function test report showed alkaline phosphatase 51 IU/L, total bilirubin 0.3 mg/dl, direct bilirubin 0.4 mg/dl, albumin 1.9 g/dl, globulin 0.9 g/dl, total protein 4.3 g/dl, Gamma-glutamyl transferase: 32, aspartate aminotransferase: 15 U/L, and alanine aminotransferase: 21 U/L. Renal function test revealed serum creatinine 1.0 mg/dl, serum urea 16 mg/dl, blood urea nitrogen 11 mg/dl, and uric acid 8.3 mg/dl. His cardiac enzyme test showed creatine kinase 71 U/L and creatine kinase–MB 18 IU/L. His serum cholesterol was 142 mg/dl, high-density lipoprotein was 43 mg/ dl, serum triglyceride was 97 mg/dl, very low-density lipoprotein cholesterol was 29 mg/dl and low-density lipoprotein cholesterol was 114 mg/dl etc.

Medications

He was found asymptomatic and treated with oral hypoglycemic agents, anti hypertensives, proton pump inhibitors, diuretic drugs, antibiotics, antiplatelets, and statins, and the details were summarized in Table 1 . He was discharged after a week stay in the hospital with continuous treatment monitoring by the healthcare team. The patient was advised to attend clinical pharmacist counseling sessions on medication usage, medication compliance, lifestyle modifications advices, physical exercise, stress management and dietary intake suggestions and disease-based information to reduce the cardiovascular complications promoting diabetic foot ulcer patients.

Atherosclerosis is more common in diabetic patients, and its burden negatively impacts the health of affected population. The aggregation of lipid lesions in the vascular path can contribute the advancement of cardiovascular disease events such as heart failure and myocardial infarction. The hyperglycemia, hyperlipidemia, smoking, and excessive pressure in the blood stream can alter the functioning of the vascular cells. The injury to the endothelial cells causes decrease in the release of endothelial nitric oxide synthase, which leads to vasoconstriction in the blood vessels. Hypercholesterolemia increases superoxide free radicals production in the vessels which causes the release of inflammatory cells such as IL-1β and TNF, interferon-gamma inhibits the matrix synthesis which causes proliferation of smooth muscles in blood vessels leads to formation of plaques and ultimately increase the risk of coronary artery disease. Previous studies suggested that regular cardiovascular disease and diabetic screening test can identify the future risk of cardiovascular abnormalities. American college of cardiology strongly recommends that the coronary artery disease screening test should be performed to summarize the risk profile characteristics of the diseased patients as an event of health care.

The pathological association between diabetes mellitus and cardiovascular disease is multifactorial which includes abnormal molecular mechanisms causing insulin resistance and hyperglycemia which ensues cardiovascular complications. The formation of atheromatous plaque-associated hardening of coronary artery with common mechanism of endothelial cell injury, smooth muscle cell proliferation, inflammatory reactivity, and plaque deposition leads to development of coronary artery disease.

The hyperglycemia levels are associated with various biochemical mechanisms which lead to converts the nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide hydrogen by cellular oxidation and form the uridine diphosphate Nacetyl glucosamine and increase the risk of metabolic abnormalities in the body. The glycosylation of proteins in the arterial wall of the heart is responsible for the development of atherosclerotic cardiovascular diseases in diabetes mellitus.[ 4 ] Diabetic foot ulcer pathogenesis is associated with multiple etiological factors. Higher glycemic levels results in the development of more oxidative stress on nerve cells are responsible for the occurrence of neuropathic problems. Hyperglycaemia and dyslipidaemia activates advanced glycation end product and polyol pathways and lowers the nerve function and thickening of hyalinization of the walls of small blood vessels causes impairment of endothelial dysfunction and reduces blood supply to the nerve cells increase the risk of nerve problems. These cellular changes show motor, autonomic, and sensory components of neuropathic diabetic foot ulcers. The persistent hyperglycemia alters the functions of the endothelial cells and increase the thromboxane A2 levels leads to vasoconstriction in the blood vessels that can enhance the risk of plasma hypercoagulability.

The injury to motor neurons in the foot muscles imbalance foot movements that can increase the risk of diabetic foot ulcer. The lower levels of blood supply to the wounds can increase the risk of chronic foot ulcers. The changes in the immune system reduce the wound healing. The increased levels of T lymphocytes and cellular apoptosis mechanisms can lower the wound-healing rate and induces the risk of diabetic foot ulcers. A study by Miteku Andualem Limenih et al . demonstrated that early recommendation of foot ulcer preventive measures and regular patient follow-up care services and patient education about foot ulcer management practices can decrease the incidences of foot ulcer.[ 5 6 ] The proper foot care, maintaining controlled glycemic levels, dressing of wounds, foot surgery, and antibiotic therapy can reduce the mortality and also reduce progress of risk of foot infections in diabetic patients. Regular health screening pr ogrammes can be initiated at hospitals by the health care team to identify the patients with high a risk of diabetic foot infections and to prevent them from diabetic foot ulcer complications among coronary artery disease patients. Eating low fatty foods, adherence to diabetic diet with antidiabetic mediations and maintaining controlled levels of blood sugar, lipid, and blood pressure can help in the prevention of coronary artery disease complications with diabetes.[ 7 ] The prevention of diabetic foot ulcer through early initiation of clinical pharmacist interventions on lifestyle modifications, medication adherence and dietary intake and healthcare team-based effective treatment modalities can reduce the lower-extremity amputations and improves the ulcer healing duration. Educating the patients about routine monitoring of foot hygiene, proper wearing of footwear, and early treatment options can reduce the development of wound infections.[ 8 ]

Diabetes mellitus is a complex endocrine disorder which is characterized by persistent glycemic levels associated with various macrovascular and microvascular complications. Diabetic foot ulcer is a complication of diabetes mellitus and seems to affect both groups of patients equally. Early assessment of risk factors, clinical features of the diseased patients, understating the etiopathogenesis of the coronary artery disease, novel cardiovascular diagnostic tools, and therapeutic approaches can pave the way for better management of coronary artery disease among diabetic foot ulcer patients.[ 9 ]

The effective glycemic control, lipid control and blood pressure levels and forceful treatment of coronary artery disease risk reduction strategies can improve the therapeutic outcomes among diabetic foot ulcer patients. Quick amalgamation of preventive measures and foot care and physical examination of the foot by the podiatrist are recommended to the diabetic patients and to stop the progress of further infections. Reinforcement of newer treatment guidelines by the physician and successful implementation of clinical pharmacist services in the clinical practice can lower the risk incidences of diabetic foot infections and also the healthcare cost among coronary artery disease patients.[ 10 ] Early amalgamation of clinical pharmacist interventions with the health care team on lifestyle changes such as medication adherence, eating low fat foods, physical exercises, and termination of smoking and alcohol practices, stress management can ultimately improve the health outcomes of coronary artery disease associated with diabetic complications.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

Acknowledgment

We thank Dr. K.S. Lakshmi, Dean, SRM College of Pharmacy, SRM Institute of Science and Technology, for her encouragement and support.

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Clinical pharmacist counseling services; coronary artery disease; diabetic foot ulcer; hypertension

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Perivascular fat: a novel risk factor for coronary artery disease.

1. Introduction

2. pathophysiology of eat, 3. the interplay between the vascular wall and pvat, 4. pvat attenuation as a biomarker of vascular inflammation, 5. fai in assessing coronary atherosclerosis, 6. fai as a biomarker of dynamic changes in coronary inflammation, 6.1. fai as a biomarker of plaque instability, 6.2. the effect of anti-inflammatory treatment on fai, 7. fai as a prognostic tool, fai vs. circulating biomarkers of vascular inflammation, 8. fai in clinical practice, 9. conclusions, author contributions, conflicts of interest.

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Simantiris, S.; Pappa, A.; Papastamos, C.; Korkonikitas, P.; Antoniades, C.; Tsioufis, C.; Tousoulis, D. Perivascular Fat: A Novel Risk Factor for Coronary Artery Disease. Diagnostics 2024 , 14 , 1830. https://doi.org/10.3390/diagnostics14161830

Simantiris S, Pappa A, Papastamos C, Korkonikitas P, Antoniades C, Tsioufis C, Tousoulis D. Perivascular Fat: A Novel Risk Factor for Coronary Artery Disease. Diagnostics . 2024; 14(16):1830. https://doi.org/10.3390/diagnostics14161830

Simantiris, Spyridon, Aikaterini Pappa, Charalampos Papastamos, Panagiotis Korkonikitas, Charalambos Antoniades, Constantinos Tsioufis, and Dimitris Tousoulis. 2024. "Perivascular Fat: A Novel Risk Factor for Coronary Artery Disease" Diagnostics 14, no. 16: 1830. https://doi.org/10.3390/diagnostics14161830

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Prevalence of classic and non-classic pain sites of coronary artery disease: a cross-sectional study

• Mayar Abdullatef   ORCID: orcid.org/0009-0005-9293-4349 1 ,
• Maya Omran   ORCID: orcid.org/0009-0006-5901-4150 1 ,
• Anas Bitar 1 &
• Bayan Alsaid 2  

BMC Cardiovascular Disorders volume  24 , Article number:  445 ( 2024 ) Cite this article

167 Accesses

Metrics details

Study objective

This study aims to assess the prevalence of both classic and non-classic pain sites in patients with ischemic heart disease, emphasizing the importance of recognizing and not disregarding non-classic symptoms.

This cross-sectional study included 100 patients diagnosed with coronary artery disease (CAD) who were admitted to two major hospitals in Syria. classic pain was identified as pain located in the precordial area, with or without radiation to the neck, jaw, left shoulder or arm. Patients’ demographics and previous medical history were documented to investigate any potential associations with non-classic pain.

62% of the patients experienced non-classic pain, while 12% had no precordial pain. For those without precordial pain, the most common pain site was the left chest (66.7%). Non-classic pain was significantly associated with smoking, with 72.2% of smokers experiencing non-classic pain compared to 35.7% non-smokers ( p  = 0.001). Additionally, patients with previous heart disease were more likely to have non-classic pain (71.7%), compared with patients with no history of heart disease (51.1%) ( p  = 0.03). Other factors such as age, sex, and diabetes were not statistically significant.

Non-classic pain is common, affecting 62% of individuals, primarily in the right shoulder, right arm, and back. This type of pain could be associated with smoking and prior heart disease. Misdiagnosing coronary artery disease can have serious consequences, as patients with non-classic symptoms may miss important pre-hospital procedures like ECG.

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Introduction

Coronary artery disease (CAD) is one of the major cardiovascular diseases affecting the global human population [ 1 ]. Environmental factors, genetic factors, unhealthy lifestyle, chronic diseases and many other factors could cause CAD, culminating in cardiac ischemia and ultimately progressing to myocardial infarction [ 2 ].

Pain induced by CAD is called angina pectoris, and it is commonly characterized by a slow onset of retrosternal chest discomfort, which can be brought on by physical or emotional stress and may even occur at rest in cases of acute coronary syndrome. The discomfort may spread to the left arm, neck, or jaw, teeth, and, ear [ 3 ]. This radiation may be caused by the convergence of the vagus, trigeminal and cervical spinal nerves (C2-C3) [ 4 , 5 ]. In addition, the discomfort is often accompanied by symptoms such as difficulty breathing, nausea, and dizziness [ 6 ]. A study found that the majority of female and male participants exhibited symptoms of chest pain, and this type of pain is more common than atypical symptoms [ 6 , 7 ]. Atypical pain is frequently defined as epigastric or back pain or pain that is described as burning, stabbing, or characteristic of indigestion [ 8 ].

Angina pectoris has two types: stable angina and unstable angina. Unlike stable angina, which is usually induced by exertion, unstable angina presents sudden symptoms even while at rest [ 9 ]. Patients with unstable angina have a worse prognosis and are more likely to develop MI [ 9 ]. Patients with CAD may experience classic/typical or non-classic/atypical pain. Classic pain site presentation has been defined as having midsternal or having midsternal with radiating left neck, shoulder or arm pain/discomfort of any or at least moderate intensity [ 10 ]. A previous study revealed that in certain cases, craniofacial pain was the only complaint during the ischemic episode [ 5 ].

Patients with atypical pain are less likely to receive a diagnosis and consequently have a mortality rate three times higher than patients with typical/classic angina symptoms [ 5 ]. Furthermore, a significant proportion of myocardial infarctions (MIs) are asymptomatic or present with minor and non-classic symptoms, and are incidentally detected during routine electrocardiogram (ECG) screenings that show the presence of abnormal Q waves [ 11 ]. Nonetheless, the patient may present with heterotopic pain (pain occurring in a region despite the real source being elsewhere in the body) in this region, with the real source potentially being of cardiac origin [ 12 ]. The cardiac heterotopic pain can lead to misdiagnosis and unnecessary medical procedures as was shown in several reports [ 13 ].

Several patients with CAD present with non-classic symptoms that are not detected in the emergency department using the standard diagnostic methods of history taking, physical examination, and 12-lead ECG. If these patients are not hospitalized for additional assessment, the diagnosis may be missed. The 2–5% of MI patients who are inadvertently discharged home frequently have poor outcomes, making them a significant source of malpractice claims in emergency medicine [ 14 ]. Misdiagnosed cases could develop lethal complications. Absence of chest pain and the lack of elevation of ST segment in electrocardiogram “ECG” were the main causes of misdiagnosis, as was shown in a previous study [ 15 ].

It is important to note that the term “Atypical pain” is a misleading way to describe chest pain, and its use is not recommended [ 6 ]. In our study, we opted for the terms “classic” and “non-classic” to describe different types of pain, as these terms provide a more accurate representation of the symptoms experienced.

To our knowledge, this is the first paper to study the prevalence of classic and non-classic pain sites of cardiac origin in Syria. The objective of this study was to assess the prevalence of pain sites in CAD patients, focusing on both classic and non-classic angina pain sites. In addition, we aimed to explore the factors that are associated with having non-classic pain presentation.

Materials and methods

This cross-sectional study examined 100 consecutive patients who were admitted to two cardiology departments in two major hospitals in Damascus, Syria (Assad University Hospital and University Heart Surgery Center), and were diagnosed with coronary artery disease (CAD) by a cardiologist after having signs and/or symptoms indicating coronary artery disease according to the American College of Cardiologists’ (ACC) definition, and angiography was performed on each of the patients to determine cardiac ischemia [ 16 ]. The study period was divided into two time periods between November 2021 and December 2023, with a one-year gap in between. Exclusion criteria encompassed individuals under the age of 18, those with dental issues, psychiatric disorders, chronic headaches, or jaw masses, as they did not fulfill the study’s eligibility requirements.

Each patient was shown an anatomical illustration that depicts the chest, abdomen, back, shoulders, arms, face, neck and mouth [ 5 ] (Fig. 1 ), and was asked to identify the location of their pain or discomfort in this current situation, with the corresponding site of pain being marked. Additional required information was obtained from the patients: demographic details, risk factors (smoking, alcohol consumption, diabetes mellitus, hypertension, personal and family history of cardiac disease, and medication), personal medical and surgical history, recent dental examination and/or treatment and physical activity, and the information was recorded in data forms.

Illustration of the body and craniofacial structures divided into areas

Classic pain was identified as pain located in the precordial area, with or without radiation to the neck, jaw, left shoulder or left arm [ 11 ]. Any other distribution of pain was considered non-classic. Due to discrepancies in the definition of typical/classic pain, we conducted two types of analyses: one considering the neck and jaw as possible classic pain radiation sites, and the other excluding these sites. This approach allowed us to determine if there were any differences between the two definitions.

Ethical approval

Informed consent was obtained from each patient and the participation of the patients was voluntary.

Consent for publication

the study protocol was approved by the Ethical Committee of Damascus University, Faculty of Medicine, Syria (document number: 4597, 25-10-2021).

Statistical analysis

The data presentation included frequencies (%) for categorical variables and mean ± standard deviation (SD) for continuous variables. The analysis was done using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, N.Y., USA). The Chi-Squared test was used to examine the relationship between the type of pain (classic or non-classic) and the studied variables. The age variable was dichotomized based on the median of the patients’ age (58 years). For variables where the expected frequency was less than 5 in more than 20% of the cells, the Fisher exact test was used as an alternative to the chi-squared test. The absolute Phi (Φ) factor was calculated to assess the strength of the associations. The values of ‘1’ indicate a complete association, ‘0’ indicates no association, ‘0.1 indicates a small association, ‘0.3’ indicates a medium association, and ‘0.5’ indicates a large association. Phi (Φ) was only illustrated when there was a statistical significance when using a chi-squared test. Statistical significance was set at p  ≤ 0.05.

Characteristics of the included sample

The study included 100 participants with a mean age of 57.88 ± 9.05. Males (79%) constituted the majority of the sample. The mean age of the male patients was 58.1 ± 8.7 years, while the mean age of the female patients was 57.1 ± 10.6 years. A significant portion of the patients (70%) lived in urban areas. Most of the patients were smokers (72%), while only a small percentage (9%) reported consuming alcohol. Diabetes was present in 38% of the patients, and more than half of them (53%) had hypertension and a history of heart disease. Additionally, 59% reported a familial history of heart disease. Detailed characteristics of the patients are presented in Table  1 .

Pain distribution

The precordial area was the most commonly reported pain site, experienced by 88% of the sample. This was followed by the left shoulder and left arm, reported by 47% and 41% of the sample, respectively. Common sites of pain also included the right shoulder (27%) and the back (24%).

Of the patients, 38% presented with classic pain, with 36.8% of the patients complaining of left shoulder pain and 36.8% experiencing left arm pain. Meanwhile, 62% of the patients presented with non-classic pain, or pain radiating to other locations such as the right shoulder, right arm, abdomen, back, or the craniofacial area. Important areas for non-classic pain patients were the right shoulder (43.5%), the back (38.7%), and the right arm (27.4%).

12% of the patients presented with no precordial pain. The most common site of pain in those patients was the left chest (66.7%), followed by both the left arm and the back in 33.3% of patients. While 8.3% complained from pain in the occipital area with no chest pain. Figure  2 provides additional information on the reported pain sites, and Table  2 demonstrates the distribution of reported pain amongst smokers.

A . Distribution of reported pain sites (n = 100)/ B . Distribution of reported pain sites in non-classic patients (n = 62)/ C . Distribution of reported pain sites in patients with no precordial pain (n = 12)

Variables associated with classic and non-classic pain

Smoking and previous heart disease were associated with the type of pain. Most of the patients who were smokers presented with non-classic pain (52 patients, 72.2%), compared to 20 smokers (27.84%) who presented with classic pain. While among non-smokers, 10 patients (35.7%) had non-classic pain and 18 patients ( 64.3%) had classic pain, X 2 (1, N  = 100) = 11.41, p  = 0.001, and the association was medium (Φ = 0.34). Patients with previous heart disease were more likely to have non-classic pain (71.7%), compared with patients with no history of heart disease (51.1%) ( p  = 0.03), X 2 (1, N  = 100) = 4.50, p  = 0.03. The association between previous heart disease and the type of pain was small (Φ = 0.21). Other variables such as age, sex, and diabetes were not significantly associated with the type of pain. Details on the variables associated with classic and non-classic pain are presented in Table  3 .

No significant difference was observed when the jaw and neck were excluded as classic pain radiation sites, as the prevalence differed by only two patients.

Cardiovascular disease (CVD) is a widespread cause of socio-economic and healthcareissues globally. Morbidity, mortality, and disability caused by CVD are on the rise annually [ 17 ], accounting for 30% of all-cause mortality. Coronary heart disease (CHD) is the primary cause of death globally [ 18 ]. Patients who experience pain triggered by physical activity and relieved by rest are considered ideal candidates for cardiac pain diagnosis.

Patients with CAD may experience referred pain in different regions, such as the head, neck, arms, back, and abdominal region [ 13 ]. Several studies have explored the referred pain experienced by patients with ischemic heart disease. The objective of this study was to determine the frequency of classic and non-classic pain and to caution doctors against disregarding non-classic symptoms in hospitalized patients.

The terms typical and atypical are not consistently agreed on in the current literature, with differences in defining what defines a typical pain. However, the term “atypical” is misleading when describing chest pain and is not recommended [ 6 ]. Some of the subsequently mentioned studies utilized the terms “typical” and “atypical” anginal pain, where “typical pain” referred to discomfort felt in the chest and upper left arm, and “atypical pain” denoted discomfort in the back, neck, or jaw. In our study, we adopted the terms classic and non-classic anginal pain, and we adhered to the idea that the classic pain can be radiated to the neck and jaw, as well as to the left shoulder and arm [ 10 ]. It is noteworthy that our analysis found no significant difference in the association between non-classic pain and various variables when considering the neck and jaw as classic radiation sites for retrosternal chest pain, compared to when these sites were not included.

A previous study has indicated that men are more likely to report typical anginal pain, characterized by discomfort in the chest and upper arm, whereas women tend to experience atypical angina, manifested as pain in the jaw, neck, shoulders, and back [ 19 ]. Another study found that women were more likely to experience atypical symptoms, compared to men [ 20 ]. However, our study found that men experienced non-classic/atypical pain more frequently than women, with rates of 64.6% and 52.4%, respectively. This difference, however, was not statistically significant. This discrepancy may be attributed to the lower rates of alcohol consumption and smoking among women in our country, which reduces their risk of developing CAD. This aligns with our study results, which identified a correlation between smoking and non-classic pain.

Another study discovered that 30% of patients did not report chest pain [ 8 ], and it was found that chest pain is the dominant and most frequent symptom for both men and women ultimately diagnosed with acute coronary syndrome [ 6 ]. While our study indicated that the precordial area was the most frequently reported site of pain, experienced by 88% of the participants. A previous study found that women with MI tend to be older than men with MI. However, our study found no significant age difference between genders for CAD, but did observe that men with CAD tend to be older than women with CAD [ 20 ]. A croatian study reported that diabetes mellitus is associated with atypical symptoms, meanwhile our study found no significant association with the type of pain [ 21 ]. Specifically, our study revealed that 42.1% of diabetic patients reported experiencing classic pain symptoms.

It is noteworthy that 81.9% of the patients in our study reported experiencing referred pain, which is significant, as many patients tend to overlook this type of pain. Various studies have linked referred pain to the convergence projection theory, which suggests that central neurons receive combined visceral and somatic stimuli, resulting in the perception of both visceral pain and referred somatic pain. Initial research focused on the spinothalamic tract (STT) and the spinoreticular tract (SRT) in the upper thoracic spinal cord due to their role in transmitting somatic pain signals and receiving sensory input from the heart. These pathways were chosen based on their established roles in transmitting somatic pain signals to the thalamus and reticular formation, respectively, and in receiving sensory input from the heart in the upper thoracic cord [ 19 ]. Studies in animals demonstrated that stimulating cardiac spinal afferents activated around 80% of STT and SRT cells in the upper thoracic segments T1-T5. Neurons responsible for processing cardiac pain were identified in specific laminae of the spinal gray matter. These neurons exhibited responses to bradykinin applied either epicardially or intracardially to the heart, as well as to coronary artery occlusion. All neurons receiving input from the heart received somatic input, primarily nociceptive signals from the chest and upper limb muscles, which provides support for the convergence projection theory concerning STT and SRT neurons in the upper thoracic cord. They indicate that these neurons may play a role in generating sensations of angina and contributing to the referral of pain to nearby somatic structures [ 19 ]. However, 18.1% of the patients reported experiencing localized pain transmitted via spinal cardiac afferent fibers.

In cases of CAD, fissures or erosions in atherosclerotic plaques lead to the release of various chemical mediators such as serotonin, histamine, thromboxane A2, bradykinin, reactive oxygen species including hydroxyl radicals, lactic acid causing proton release, and adenosine which triggers the production of prostaglandins (PGE2 and PGI2) within the coronary artery lumen. These chemical agents, either individually or in combination, interact with specific receptors primarily located on chemically sensitive terminals, resulting in the depolarization of cardiac visceral spinal afferent fibers [ 19 ].

Furthermore, our study highlighted that most smokers (72.2%) among our patients presented with non-classic pain, indicating a potential link between smoking and non-classic angina. Previous studies suggested that smokers are at a higher risk to develop back pain and other chronic pain conditions [ 22 , 23 ]. Another study showed that among patients with chronic pain, smokers complained of higher pain intensity and increased number of pain sites [ 24 , 25 ]. One underlying mechanism might be that cigarette smoking impairs oxygen delivery to tissues by increasing sympathetic outflow and carboxyhemoglobin levels and causing vasoconstriction. Thus, smoking may accelerate degenerative processes which make the body more vulnerable to injury. This can explain why smoking is a risk factor for osteoporosis, lumber disk diseases and impaired bone healing [ 26 ]. This aligns with the results of our study, which found that 25% of smokers had back pain, 26.4% had pain the the right shoulder and 19.4% had pain in the right arm.

In our study, we found that only 38% of patients complained of classic pain, which indicates that the majority of patients suffered from non-classic pain sites. This is a significant result, since atypical symptoms of AMI were associated with less invasive therapy and poor outcome, and in-hospital mortality was significantly higher in atypical than in typical group in a previous study conducted in Japan [ 27 ]. Moreover, 12% of patients presented with no precordial pain, whereas a study in Poland [ 28 ] showed that only 6.4% presented without chest pain. This is especially important because previously, if the patient did not report chest pain, then they were disadvantaged from even receiving a prehospital ECG [ 29 ]. Another important result of our research was that patients with previous heart disease where more likely to have atypical pain, which is consistent with the results of the Japanese study [ 20 ]. While in the Polish study [ 18 ], previous heart diseases and hypertension were more linked with typical symptoms of MI. It is crucial to highlight all the different symptoms of CAD because these symptoms are the cues for further diagnostic exams such as ECG and cardiac catheterization.

There are a few limitations in this study. The sample size included 100 patients, which may be considered relatively small. However, the extended study period overcomes this limitation by encompassing a wide range of climate changes and conditions, thereby enriching the results. It is worth noting that the study was conducted in a single city, limiting the generalizability of the findings. Nevertheless, Damascus, being the capital of Syria, and the inclusion of hospitals among the largest in the country lend credibility to the study. Another limitation pertains to the potential for patients to exaggerate or misidentify the location of pain. Additionally, as cross-sectional studies do not establish causality, further research is required. As per our findings, it is recommended for healthcare professionals to exercise caution in diagnosing patients and to remain vigilant in recognizing and addressing atypical symptoms, particularly in individuals with known risk factors. Future researchers interested in exploring similar topics are encouraged to conduct studies with larger sample sizes across multiple cities to capture a broader range of variations. Furthermore, investigating the precise relationship between smoking and non-classic pain is also recommended.

Our study found that non-classic pain is common (62%), occurring mostly in the right shoulder, right arm and the back, and is associated with smoking and previous heart disease. Hopefully, this study will assist doctors in acknowledging the previous risk factors and their contributions to different types of pain, ultimately aiding in the diagnosis of CAD across various pain sites. This study underscores the importance of recognizing all the pain sites that might indicate CAD, especially in smokers who present with non-classical pain sites. Misdiagnosing CAD can have fatal outcomes. Many patients with non-classical CAD symptoms might be deprived of vital pre-hospital procedures, such as ECG, which can be lifesaving.

Data availability

Data is provided within the supplementary information files.

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Mayar Abdullatef, Maya Omran & Anas Bitar

Laboratory of Anatomy, Faculty of Medicine, Damascus University, Damascus, Syria

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M.O. and M.A. contributed equally to this work. M.O. and M.A. are marked as first author. B.A. is the supervisor of the research and is responsible on Project administration. B.A.: Supervision, Project Administration, Conceptualization, Writing- Review & Editing, Methodology, Visualization, Validation. M.O.: Conceptualization, Methodology, Investigation, Resources, Writing-Original Draft, Writing- Review & Editing, Visualization, Validation. M.A.: Conceptualization, Methodology, Investigation, Resources, Writing-Original Draft, Writing- Review & Editing, Visualization, Validation. A.B.: Data Curation, Formal analysis, Writing- Original Draft, Writing- Review & Editing, Methodology, Visualization. Mayar Abdullatef and Maya Omran contributed equally to this work. In light of their equal contributions, we kindly request that they be recognized as first authors in any publications or acknowledgments related to this work.

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Abdullatef, M., Omran, M., Bitar, A. et al. Prevalence of classic and non-classic pain sites of coronary artery disease: a cross-sectional study. BMC Cardiovasc Disord 24 , 445 (2024). https://doi.org/10.1186/s12872-024-04127-z

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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies

Affiliation.

• 1 Department of Medicine, Stanford University School of Medicine, Stanford, California 94304-1334, USA. [email protected]
• PMID: 20933357
• PMCID: PMC3084526
• DOI: 10.1016/j.jacc.2010.06.022
• J Am Coll Cardiol. 2011 Jan 25;57(4):520

Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).

Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.

Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.

Results: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.

Conclusions: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PubMed Disclaimer

• The KIF6 collapse. Topol EJ, Damani SB. Topol EJ, et al. J Am Coll Cardiol. 2010 Nov 2;56(19):1564-6. doi: 10.1016/j.jacc.2010.06.023. Epub 2010 Oct 1. J Am Coll Cardiol. 2010. PMID: 20888161 No abstract available.

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A 52-Year-Old Man With Atherosclerosis

A 52-year-old executive was referred to our clinic for risk factor management after undergoing coronary computed tomography angiography (CTA) as part of an Executive Physical. He has no history of coronary artery disease and exercises regularly without experiencing anginal symptoms.

His family history is notable for a myocardial infarction (MI) in his father at the age of 52 years. He is a lifelong non-smoker. He does not take medications.

His blood pressure was 110/75. His exam was notable for being overweight with a BMI of 27, but was otherwise unremarkable.

His total cholesterol is 206 mg/dL, HDL-C is 46 mg/dL, triglycerides are 178 mg/dL, calculated LDL-C is 124 mg/dL, and non HDL-C is 160 mg/dL. His fasting glucose is 86 mg/dL. His Hgb A1c is 5.6%.

His 10-year risk based on the 2013 ACC/AHA pooled ASCVD risk estimator is 3.7%.

His coronary artery calcium (CAC) score is 120, which places him in the 87th percentile for his age, gender, and ethnicity.

His coronary CTA shows the following in the proximal LAD:

In addition to maximizing therapeutic lifestyle changes (exercise, weight loss), what is the next step in this patient’s management? A. There is nothing more to do since his estimated 10-year risk is low. B. Maximize risk factor modification by starting a low-dose aspirin and statin therapy. C. Pursue stress testing. D. Pursue coronary catheterization. E. B and C. Show Answer The correct answer is: B. Maximize risk factor modification by starting a low-dose aspirin and statin therapy. Atherosclerosis is necessary for nearly all coronary events. The development of atherosclerosis is multifactorial. There is significant heterogeneity in the contribution of common traditional modifiable risk factors including apolipoprotein B (apoB)-containing lipoproteins, smoking, diabetes, hypertension, and sedentary lifestyle to atherogenesis. 1 In participants from the Multi-Ethnic Study of Atherosclerosis (MESA) without atherosclerosis as measured by coronary artery calcium (CAC), even the presence of multiple modifiable risk factors was associated with low event rates (3.1%). In contrast, in those with elevated CAC and no modifiable risk factors, the event rates were significantly higher at nearly 11%. 1 While risk estimators are improving in accuracy, 2,3 the presence of subclinical atherosclerosis (primarily by CAC) has consistently been an additive predictor of coronary events in individuals and further discriminates between those at higher and lower risk for events. 4-6 The case patient is at elevated risk because of the burden of subclinical atherosclerosis and, therefore, answer choice A is incorrect. The recent 2013 ACC/AHA guidelines on cholesterol treatment take a risk-based approach to recommendations for statin therapy. 7 The patient in this case has a low estimated 10-year risk at 3.7%. The current guidelines suggest a risk discussion in this case based on the patient's family history of premature coronary heart disease (CHD). Subclinical atherosclerosis imaging by CAC scanning can help with this discussion. 8 Recently, eight-year follow-up from the Dallas Heart Study showed that among participants with a family history of MI, those without CAC experienced a significantly lower CHD event rate of 1.9% compared to 8.8% in those with any CAC. 9 The case patient has a CAC score >100 that places him above the 75th percentile for his age, gender, and ethnicity. We would recommend moderate- or high-intensity statin therapy during a risk discussion based on an estimated 10-year event rate that exceeds 7.5%. Furthermore, recent data support the use of aspirin in those with CAC >100. Therefore, answer choice B is the correct answer. Subclinical atherosclerosis imaging with CAC scanning has been endorsed by several committees to assist with risk assessment. The 2010 ACC/AHA risk assessment guidelines gave CAC scanning a IIA recommendation in those deemed to be at intermediate risk for CHD events. 11 In the 2010 appropriate use criteria for cardiac CT endorsed by multiple societies, CAC scanning was deemed appropriate among low-risk asymptomatic patients with a family history of premature CHD in addition to those at intermediate risk. 12 Most recently, the 2013 ACC/AHA risk assessment guidelines gave CAC scoring a IIB recommendation. Specifically, the committee suggests that if there is uncertainty about whether to start pharmacotherapy after risk estimation, then CAC scoring could be considered. 2 An important consideration in this case is the use of CTA to identify subclinical atherosclerosis. While coronary CTA is a more specific and sensitive test for atherosclerosis, there is no evidence that CTA adds significantly to CAC scanning in an asymptomatic population. However, CTA may identify vulnerable features of plaque that are not picked up by CAC scanning, such as those present in the case example. 13 Motoyama et al. identified high-risk features for acute coronary syndromes (ACS) in asymptomatic subjects on CTA including positive remodeling and low-attenuation plaque, in addition to spotty calcification in those presenting with ACS. 14,15 A small preliminary study suggested a benefit of statin therapy on plaque volume and the amount of low-attenuation plaque. 16 The role of CTA in asymptomatic, primary prevention patients is actively under investigation. 17 The benefits of CTA should be weighed against exposure to contrast, expense, and the need to train readers. With rapidly advancing technology, CTAs can now be performed with the equivalent radiation exposure of two mammograms. 18 Currently, the use of CTA is useful in appropriate symptomatic patients, particularly in chest pain protocols in the emergency department. 19 Many of these patients have mild or moderate, non-obstructive atherosclerosis that is unlikely to be the cause of their presenting symptoms, but should be managed with aggressive preventive therapies. In symptomatic patients from the CONFIRM registry, there is an increased hazard of mortality in those with non-obstructive atherosclerosis on CTA compared to those without atherosclerosis on CTA. 20 Some have advocated for stress testing in those with CAC scores > 400; however, the patient in this case does not meet this criteria. 21,22 Therefore, answer choices C and D are incorrect as the patient is asymptomatic. Silverman MG, Blaha MJ, Krumholz HM, et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J. 2013 Dec 13 [Epub ahead of print]. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA 2014;311:1406-15. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 2010;303:1610-6. Erbel R, Möhlenkamp S, Moebus S, et al. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol 2010;56:1397-406. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-95. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889–934. Nasir K, Budoff MJ, Wong ND, et al. Family history of premature coronary heart disease and coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007;116:619-26. Paixao AR, Berry JD, Neeland IJ, et al. Coronary artery calcification and family history of myocardial infarction in the Dallas Heart Study. JACC Cardiovasc Imaging . 2014 June [Epub ahead of print]. Miedema MD, Duprez DA, Misialek JR, et al. Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis. Circ Cardiovasc Qual Outcomes 2014;7:453-60. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2010;56:e50-103. Taylor AJ, Cerqueira M, Hodgson JM, et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56:1864-94. Voros S, Rinehart S, Qian Z, et al. Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovasc Imaging 2011;4:537-48. Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49-57. Motoyama S, Kondo T, Sarai M et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007;50:319-26. Inoue K, Motoyama S, Sarai M, et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging 2010;3:691-8. U.S. National Institutes of Health.Detection of Subclinical Atherosclerosis in Asymptomatic Individuals (Decide CTA). (ClinicalTrials.gov website). 2009-2014. Available at: http://clinicaltrials.gov/ct2/show/NCT00862056?term=DECIDE-CTA . Accessed June 22, 2014. Achenbach S, Marwan M, Ropers, D et al. Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J 2010;31:340-6. Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med 2012;367:299-308. Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849-60. Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009;53:2201-29. Berman DS, Hachamovitch R, Shaw LJ, et al. Roles of nuclear cardiology, cardiac computed tomography, and cardiac magnetic resonance: Noninvasive risk stratification and a conceptual framework for the selection of noninvasive imaging tests in patients with known or suspected coronary artery disease. J Nucl Med 2006;47:1107-18. You must be logged in to save to your library. Jacc journals on acc.org. 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All rights reserved. 489 IMAGES SOLUTION: Coronary artery disease case study Case Study Coronary Artery Disease 5 2 .docx Case Study Coronary artery disease for health education Vector Image Coronary arteriography; prevention of complications in the high-risk patient Coronary Artery Disease and Pacemakers.docx COMMENTS Case 24-2020: A 44-Year-Old Woman with Chest Pain, Dyspnea, and Shock A telemedicine visit was arranged as part of a local public health strategy to reduce the spread of coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome ... Case 6 A 67-year-old woman sought emergency medical care due to prolonged chest pain. In April 2009 the patient had prolonged chest pain and at that time she sought medical care. She was admitted at the hospital and diagnosed with myocardial infarction. The patient had hypertension, diabetes mellitus, dyslipidemia and was a smoker. Case 5/2015 The recommendation of optimized drug treatment as the initial option for patients with chronic coronary artery disease is supported by a meta-analysis with 63 studies (1852 symptomatic and asymptomatic patients diagnosed with chronic coronary artery disease, mean age ranging from 56 to 65 years), comparing four possibilities of procedures ... A case of coronary artery disease with rapid progress triggered by We report a case of coronary artery disease, which rapidly progressed and led to severe ischemic cardiomyopathy. Based on the risk factors, typical symptoms of angina, and the results of the first angiography, the initial stenosis was most probably caused by atherosclerosis and was managed with a DES followed by dual antiplatelet therapy. Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. Methods ... Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease Patients with left main coronary artery disease have a poor prognosis because of the large amount of myocardium at risk. 13 Survival among patients with left main coronary artery disease is longer ... Colchicine in Patients with Chronic Coronary Disease In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than ... Exploring Sex Differences in Pain Manifestation of Coronary Artery Pain manifestation following coronary artery disease (CAD) disease differs between men and women. Here, we aimed to provide evidence favoring possible differences in pain manifestation between men and women following CAD using Mendelian randomization (MR). We used summary-level data from sex-stratified genome-wide association studies on CAD and self-reported and clinically diagnosed chest ... Case Reports in Coronary Artery Disease: 2022 Case Report. August 10, 2022. Case report: Spontaneous coronary artery rupture presenting with acute coronary syndrome: A rare diagnosis of common disease. Ahmed Ibrahim Sayed. Acute coronary syndrome (ACS), myocardial infarction, and sudden death have all been linked to spontaneous coronary artery rapture (SCAR). Coronary Heart Disease Research Heart disease, including coronary heart disease, remains the leading cause of death in the United States. However, the rate of heart disease deaths has declined by 70% over the past 50 years, thanks in part to NHLBI-funded research. Many current studies funded by the NHLBI focus on discovering genetic associations and finding new ways to ... Coronary Artery Disease (CAD): Symptoms & Treatment Coronary artery disease (CAD) limits blood flow in your coronary arteries, which deliver blood to your heart muscle. Cholesterol and other substances make up plaque that narrows your coronary arteries. Chest pain is the most common CAD symptom. CAD can lead to a heart attack, abnormal heart rhythms or heart failure. Long-term prognostic value of contemporary stress ... Methods Multiple electronic databases were searched for studies evaluating long-term outcome (>12 months) of stress echocardiography in patients suspected of coronary artery disease since year 2000. A common-effect model was used to derive pooled estimates. The primary outcome was a composite of all-cause mortality or cardiovascular death and non-fatal myocardial infarction, depending on the ... 10 Real Cases on Acute Coronary Syndrome ... Both serial 12-lead ECG and highly sensitive cardiac troponin T testing should be performed before excluding ongoing ischemic coronary artery disease. Prior to stress testing, the patient should be chest pain free for 24 hours, without dynamic 12-lead ECG changes, and the highly sensitive cardiac troponin T level should be negative or trending ... Case Study: Cardiac Surgery Case Study 1: Radial Artery Approach for Cardiac Catheterization followed by an "Off-Pump" Coronary Artery Bypass Surgery ... He had a positive nuclear stress test that showed reduced blood flow to the left ventricle with a high suspicion for coronary artery disease. Dr. John Resar, the director of the cardiac catheterization lab at Johns ... A case report of right coronary artery agenesis diagnosed... : Medicine Congenital agenesis of the right coronary artery (RCA) is a coronary anomaly characterized by a single coronary ostium from which the whole coronary tree takes origin. Coronary anomalies are often incidental findings in patients undergoing coronary angiography for coronary artery disease (CAD) exclusion. Cardiovascular computed tomography ... Prevalence of classic and non-classic pain sites of coronary artery Study objective: This study aims to assess the prevalence of both classic and non-classic pain sites in patients with ischemic heart disease, emphasizing the importance of recognizing and not disregarding non-classic symptoms. Methods: This cross-sectional study included 100 patients diagnosed with coronary artery disease (CAD) who were admitted to two major hospitals in Syria. classic pain ... Case 4/2014 This patient had some risk factors that contributed to the development of coronary artery disease: age, male gender, hypertension and smoking. Patients with chest pain and ACS often have a nonspecific physical examination, with less than 20% of them showing significant alterations in the initial evaluation 2. This becomes important by helping ... Angina: contemporary diagnosis and management Subsequent to Heberden's report, coronary artery disease (CAD) was implicated in pathology and clinical case studies undertaken by John Hunter, John Fothergill, Edward Jenner and Caleb Hiller Parry.3 Typically, angina involves a relative deficiency of myocardial oxygen supply (ie, ischaemia) and typically occurs after activity or ... impact of immunity on the risk of coronary artery disease: insights Coronary artery disease (CAD) is the leading cause of death worldwide. Despite significant advances in treatment, it remains a major burden on healthcare systems and economies around the world. Immunity and inflammation are integral to the complex pathological mechanisms underlying coronary artery disease. What this study adds: ... The impact of immunity on the risk of coronary artery disease ... Background: Immune inflammation is intricately associated with coronary artery disease (CAD) progression, necessitating the pursuit of more efficacious therapeutic strategies. This study aimed to uncover potential therapeutic targets for CAD and myocardial infarction (MI) by elucidating the causal connection between regulatory immune-related genes (RIRGs) and these disorders. A Case Study on Geriatric Patient with Coronary Artery Disease ... A Case Study on Geriatric Patient with Coronary Artery Disease-Associated Diabetic Foot Ulcer: A Clinical Pharmacist Management Care : Journal of Datta Meghe Institute of Medical Sciences University ... proliferation of smooth muscles in blood vessels leads to formation of plaques and ultimately increase the risk of coronary artery disease ... Treatment of Hypertension in Patients With Coronary Artery Disease Several studies (Heart Outcomes Prevention Evaluation [HOPE], 16 Survival and Ventricular Enlargement [SAVE], 17 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease [EUROPA]) 18 have shown a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on CVD outcomes in individuals, some ... Perivascular Fat: A Novel Risk Factor for Coronary Artery Disease Perivascular adipose tissue (PVAT) interacts with the vascular wall and secretes bioactive factors which regulate vascular wall physiology. Vice versa, vascular wall inflammation affects the adjacent PVAT via paracrine signals, which induce cachexia-type morphological changes in perivascular fat. These changes can be quantified in pericoronary adipose tissue (PCAT), as an increase in PCAT ... Physical Activity in the Prevention and Treatment of Coronary Artery Endothelial dysfunction, which precedes coronary sclerosis by many years, is the first step of a vicious cycle culminating in overt atherosclerosis, significant coronary artery disease (CAD), plaque rupture, and, finally, myocardial infarction. 1, 3 In addition to classic risk factors, such as hypertension, smoking, diabetes mellitus, and hypercholesterolemia, physical inactivity has been ... Case Reports in Coronary Artery Disease: 2024 Keywords: Coronary Artery Disease, Case Reports, Unique Clinical Cases, Diagnostic Assessment, Therapeutic Interventions . Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Prevalence of classic and non-classic pain sites of coronary artery This study aims to assess the prevalence of both classic and non-classic pain sites in patients with ischemic heart disease, emphasizing the importance of recognizing and not disregarding non-classic symptoms. This cross-sectional study included 100 patients diagnosed with coronary artery disease (CAD) who were admitted to two major hospitals in Syria. classic pain was identified as pain ... Case Report: Rapidly progressive coronary artery disease as the first Cardiovascular manifestations also include valvular heart disease, ventricular thrombi and higher risk for coronary artery disease (CAD). In this case report, we describe a 61-year-old woman who had no significant risk factors for CAD, and presented with aggressive disease in native and graft vessels that required multiple coronary interventions. A 63-Year-Old Man With Diabetes and Coronary Artery Disease Given his symptoms, coronary disease risk factors and ECG changes, he undergoes a one-day exercise Tc-99m myocardial perfusion study. He exercises a total of seven minutes, 49 seconds on a standard Bruce protocol and achieves 9.8 METS. Peak heart rate is 135 bpm (86% of his maximum predicted heart rate). Lack of association between the Trp719Arg polymorphism in ... Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 ... A 52-Year-Old Man With Atherosclerosis A 52-Year-Old Man With Atherosclerosis. A 52-year-old executive was referred to our clinic for risk factor management after undergoing coronary computed tomography angiography (CTA) as part of an Executive Physical. He has no history of coronary artery disease and exercises regularly without experiencing anginal symptoms. essay homework paper phd project resume review study thesis