Coronary artery syndromes in women


Ischemic heart disease has key differences in pathophysiology, presentation, and effectiveness in diagnostic strategies and management between women and men. 

Women present with a higher burden of symptoms and comorbidities, and experience worse outcomes from ischemic heart disease, but are less likely to have flow-limiting stenosis in epicardial coronary arteries than men. 

Coronary microvascular disease, a heterogeneous disorder with multifactorial etiology that predominantly affects women. 

Significant relationship between exists coronary microvascular disease, obstructive coronary artery disease, and the cardiovascular risk associated with it.

Chronic coronary syndromes in women are characterized by a coexistence of both coronary microvascular disease and the development of obstructive atherosclerotic lesions. 

Impaired vasomotor function often precedes  the development of advanced atheroma. 

In the United States  more women die from cardiovascular diseases than cancer and chronic lung disease combined.

Ischemic heart disease in women exceeds, for example, breast cancer mortality by six-times.

Women are treated less aggressively, and experience more adverse events when receiving therapy than men.

Medical practice and research tends to focus on diseases involving the breasts and the reproductive organs, while essentially ignoring many other organ systems, in particular the cardiovascular system and its diseases, as determinants of women’s health.

Inclusion rates of women are as low as 30% in cardiovascular clinical trials.

Studies have consistently shown major sex- and gender-based genetic, cellular, biochemical, and physiological differences in cardiovascular health and disease.

Sex differences result from differential effects of sex chromosomes and sex hormones in males and females. 

Gender differences are based on sociocultural environments and thus unique to humans, such as differences in socioeconomic position, social support, culture, health behaviors, or access and attitudes towards treatment and prevention.

The role of gender plays a social determinant in shaping cardiovascular risk: less physical mobility but a more frequent use of smoking as a weight loss tool in women compared with men, poor workplace conditions such as low job control and high demand that increase cardiovascular risk in men, and poor-quality marriages or high-intensity caregiving for relatives that can increase the prevalence of cardiovascular risk factors in women.

Sex as a determinant of cardiovascular risk: endogenous estrogens play a unique role as potent inhibitors of atherosclerosis due to anti-inflammatory, antioxidative and vasodilator effects, inhibition of vascular smooth muscle cell growth and proliferation, as well as beneficial effects on lipid, glucose metabolism, and coagulation.

In the cardiovascular system, estrogens activate at least three different estrogen receptors.

Estrogens  either act as nuclear transcription factors regulating gene transcription, or induce rapid, non-genomic cellular signaling cascades.

Estrogen receptor signaling detrimentally changes with declining endogenous estrogen levels following menopause, the aging of the vascular wall, and the progression of atherosclerosis.

Because of the protective cardiovascular effects of endogenous estrogens, women are 8 to 10 years older than men when first diagnosed with obstructive coronary artery disease.

Even when accounting for age and concomitant conditions, women undergoing treatment still experience unfavorable outcomes compared with men:  differences in the pathophysiology of atherosclerosis and/or worse performance of currently used diagnostic algorithms and management strategies.

Men predominantly present with focal, flow-limiting stenoses in major epicardial coronary arteries. 

Premenopausal women are largely protected from coronary artery disease.

With estrogen loss following menopause there is rapid clustering of coronary artery disease risk factors such as hypertension, dyslipidemia, and adverse changes in glucose metabolism.

Risk factors that propagate inflammatory changes in the vascular wall, may be amplified by chronic autoimmune diseases affecting mostly women, such as rheumatoid arthritis and systemic lupus erythematosus.

Propagation of inflammation results in early atherosclerotic changes often diffusely affecting  the coronary circulation, promotes abnormal coronary vasomotor function characterized by detrimental changes in endothelial and microvascular vasoreactivity, as well as positive coronary remodeling, plaque erosion, and embolization.

These structural and functional changes of the artery wall may lead to myocardial ischemia with no obstructive coronary artery disease ((MINOCA)).

Ischemic heart disease in women usually begins with detrimental vasomotor changes that may progress to clinical coronary  microvascular disease before flow-limiting atherosclerotic lesions may develop later in life: referred to as chronic coronary syndromes.

Functional changes in the epicardial and microvascular coronary circulation may alone lead to angina, particularly in women. 

The diagnosis of a chronic coronary syndrome can be made in patients both with Microvascular and obstructive CAD. 

The clinical manifestation of chronic coronary syndromes is angina, but it is not  possible to distinguish between obstructive CAD and Microvascular disease based on symptoms alone. 

There may be gender-based differences in communicating bodily discomfort, with women choosing more diverse, detailed, and emotional terms and a broader spectrum of presenting symptoms compared with men when expressing discomfort.

Gender-based differences in communication is referred to as gendered language.

The variable chest pain characteristics in women may be explained by the higher prevalence of microvascular disease, which causes a wide spectrum of clinical manifestations including angina at rest.

The variable chest pain in women may lead to difficulties in clinical practice when characterizing symptoms as typical, atypical, or non-anginal, chest pain: it increases the risk of underdiagnosing and undertreating patients with ischemia and non obstructive coronary artery disease.

Cardiovascular risk factors including diabetes, smoking, and hypertension are more impactful in women compared with men.

Cardiovascular risk factors that predominantly affect women, are rheumatoid arthritis and systemic lupus erythematosus.

Specific cardiovascular risk factors in women have been established including estrogen deficiency due to premature ovarian failure, ovariectomy, polycystic ovarian syndrome, or hypothalamic amenorrhea. 

Hypertensive disorders of pregnancy, preterm delivery, and gestational diabetes indicate premature vascular dysfunction and are associated with increased cardiovascular risk later in life.

Exposing coronary arteries to ionizing radiation during breast cancer radiotherapy and/or administration of chemotherapy such as anthracyclines or trastuzumab increases cardiovascular risk even more than 10 years later in life.

About two-thirds of women referred for invasive coronary angiography based on clinically assessed likelihood of stable CAD alone have no obstructive atherosclerotic stenosis: a substantial proportion of these patients may have ischemia with no obstructive coronary disease  that is associated with reduced quality of life, more frequent office visits, and greater health care costs.

Noninvasive functional diagnostic tests that detect myocardial ischemia: exercise-induced electrocardiogram changes, regional wall motion abnormalities during stress echocardiography, stress-induced perfusion changes assessed by cardiac magnetic resonance (CMR) or single-photon emission computed tomography (SPECT), and metabolic alterations revealed by positron emission tomography (PET).

Exercise electrocardiography has  lower diagnostic accuracy in women,with sensitivity and specificity between 60% and 70%, compared with men at approximately 75%.

The difference may, in part, be due  to lower physical capacity precluding adequate exercise-induced stress that is more frequently observed in women. 

Hormonal changes during the menstrual cycle have been associated with ST-segment depression during exercise.

The positive predictive value of an abnormal exercise electrocardiography in women is only 47%, which results frequently lead to physician uncertainty and contribute to unnecessary testing.

Pharmacological stress tests have significantly higher sensitivity to detect flow-limiting epicardial coronary stenoses.

Stress perfusion CMR has a greater than 90% diagnostic accuracy for significant obstructive CAD particularly in women.

Cardiac magnetic imaging can detect a lack of appropriately increased subendocardial perfusion in response to stress, indicating microvascular disease.

Cardiac microvascular disease (CMD) resulting in impaired coronary flow reserve can be assessed using myocardial perfusion PET, which provides a highly accurate, reproducible measurement of coronary blood flow.

An impaired coronary flow reserve detected by PET, even in the presence of normal stress perfusion imaging, has emerged as a predictor for adverse cardiac events.

Stress myocardial perfusion SPECT imaging also exposes women to ionizing radiation, and may have reduced accuracy than in men due to soft-tissue attenuation artifacts resulting from fat deposits or breast tissue.

Stress myocardial perfusion SPECT imaging has approximately 80% sensitivity and specificity.

Exercise electrocardiography is of limited diagnostic value, except for functional capacity as well as blood pressure and heart rate responses. 

To establish the diagnosis of a chronic coronary syndrome, noninvasive functional tests for myocardial ischemia may be preferably used in symptomatic women, particularly if ischemia with no obstructive coronary artery (INOCA) disease  is considered.

The prognosis of patients with angina, in whom no significantly obstructing CAD is found, is not necessarily benign: such 

patients are at elevated risk for cardiovascular events similar to individuals with single CAD, and appear to be at higher risk for myocardial infarction with no obstructive coronary arteries and heart failure with preserved ejection fraction later in life.

INOCA disease associated with impaired quality of life, repeated  use of health care resources, cardiac catheterization, and therapy.

Cardiac microvascular disease is linked to atherosclerosis in the macrocirculation via diabetes, vascular stiffness, and inflammation dysregulation of myocardial blood flow.

Despite normal-appearing angiograms, almost all patients with INOCA have some coronary atherosclerosis detectable by coronary imaging with intravascular ultrasound or optical coherence tomography.

The  coronary microcirculation is too small to be directly imaged, and conventional stress testing is neither sensitive nor specific for CMD unless methods that detect an impaired functional capacity in regulating myocardial blood flow are used. 

Stress imaging tests occasionally show regional abnormalities that may not follow typical vascular distributions.

Although not all patients with nonobstructive coronary arteries on angiography have INOCA, the diagnosis should be considered.

 The diagnosis of INOCA is made in patients with angina, exclusion of underlying obstructive CAD, and evidence of CMD based on the detection of impaired myocardial perfusion reserve index by CMR, impaired coronary flow reserve by PET, or invasive studies of coronary vasomotor function.

Impaired myocardial blood flow augmentation may occur in response to stress in the absence of obstructive CAD, reflecting downstream vasomotor dysfunction that leads to myocardial ischemia.

Atypical symptoms such as angina at rest may be present.

CMD-mediated left-ventricular diastolic dysfunction may cause exertional dyspnea. 

The coronary microcirculation differs from the epicardial conduit arteries: 

microvessels have a well-developed vascular smooth muscle layer; 

conduit arteries have more elastic properties; endothelium-dependent, 

nitric oxide–mediated vasodilation plays a greater role in the conduit arteries, 

whereas endothelium-dependent hyperpolarization is more important in the microvasculature.

First-line therapeutics for INOCA are considered β-blockers, and calcium antagonists if the former are not tolerated.

Short-acting nitrates should be used for immediate relief of angina or before performing activities known to bring angina.

Long-acting nitrates are ineffective or even detrimental in CMD, which may be due to steal syndromes through myocardial regions without CMD, reduced responsiveness of nitrates in the microvasculature, nitrate-induced oxidative stress, and endothelial dysfunction.

If INOCA is mainly due to vasospasms, therapy consists of calcium antagonists at high doses and nitrates.

Management of underlying cardiovascular risk factors and disease-modifying therapies such as angiotensin-converting enzyme inhibitors and statins should be considered, especially in patients with diffuse nonobstructive CAD.

Optimal medical therapy remains a cornerstone in management of obstructive coronary artery disease in stable patients without heart failure or significant left main disease.

The  International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial found no sex differences in cardiovascular outcomes when myocardial ischemia was treated with coronary revascularization or medical therapy.

Men present more frequently with plaque rupture of a thin-cap fibroatheroma.

Plaque erosions and other causes of myocardial infarction with no obstructive coronary arteries are observed more often in women.

In patients undergoing percutaneous coronary interventions with implantation of drug-eluting stents, sex is not an independent predictor of major adverse cardiovascular events: second- and third-generation drug-eluting stents are equally effective at improving outcomes in women and men with similarly low target-vessel revascularization rates during follow-up.

This efficacy is likely due to their low profile, thin strut designs that enhance stent deliverability in small, tortuous coronary arteries found in some women.

Women who undergo coronary artery bypass grafting have more incomplete revascularization, bleeding complications, and greater hospital and long-term mortality compared with men.

This is due to more diffuse atherosclerotic changes with remodeling of the coronary artery wall as well as concomitant coronary microvascular disease residual angina after revascularization procedures.

Intake of equal doses of aspirin, β-blockers, or statins yields higher plasma levels in women, partly due to smaller distribution volume and lower clearance compared with men.

With regard to pharmacodynamics, however, aspirin more potently inhibits platelet aggregation and β-blockers more efficiently reduce exercise-induced angina in men.

Women have a 1.5- to 1.7-fold greater incidence of adverse drug reactions than men.

Adverse reactions to cardiovascular drugs more frequently observed in women.

Women treated with antiplatelet drugs experience more bleeding complications than men, probably because they are generally older, have worse renal function, and more comorbidities.

Female sex is an established risk factor for statin-associated muscle symptoms and new-onset diabetes.

Women are treated less aggressively with cardiovascular guideline-recommended medications than men: 

Women with chronic coronary syndromes receive less antiplatelet and lipid-lowering drugs, inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and nitrates than men.

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