Angina or ischemia with no obstructive coronary disease (ANOCA/INOCA) is a common but under-treated condition due to poorly understood pathophysiologic mechanisms, limited diagnostic tools, and lack ...of proven targeted therapy. Coronary microvascular dysfunction (CMD) occurs when the microvasculature inadequately perfuses the myocardium under stress, or at rest in the case of microvascular spasm resulting in ANOCA/INOCA. Coronary functional angiography (CFA) measures endothelial independent microvascular dysfunction (coronary flow reduction <2.5) in response to adenosine and endothelial dependent microvascular dysfunction (lack of dilation and/or constriction) to acetylcholine testing as well as epicardial and microvascular spasm. Current treatment for coronary microvascular dysfunction is limited to renin-angiotensin system (RAS) inhibitors and statins as well as antianginal medications. Novel therapies targeting the underlying pathology are under development and include the coronary sinus reducer, CD34+ stem cell therapy, and novel pharmacologic agents such as sGC stimulators or endothelin-receptor blockers. We review the current understanding of pathophysiology, diagnostic tools, and novel therapies for coronary microvascular dysfunction in ANOCA/INOCA.
Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, ...mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34
cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34
stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.
Myocardial infarction with non-obstructive coronary arteries (MINOCA) is evident in up to 15% of all acute myocardial infarctions (AMI) and disproportionally affects females. Despite younger age, ...female predominance, and fewer cardiovascular risk factors, MINOCA patients have a worse prognosis than patients without cardiovascular disease and a similar prognosis compared to patients with MI and obstructive coronary artery disease (CAD). MINOCA is a syndrome with a broad differential diagnosis that includes both ischemic coronary artery plaque disruption, coronary vasospasm, coronary microvascular dysfunction, spontaneous coronary artery dissection (SCAD), and coronary embolism/thrombosis and non-ischemic mechanisms (Takotsubo cardiomyopathy, myocarditis, and non-ischemic cardiomyopathy)-the latter called MINOCA mimickers. Therefore, a standardized approach that includes multimodality imaging, such as coronary intravascular imaging, cardiac magnetic resonance, and in selected cases, coronary reactivity testing, including provocation testing for coronary vasospasm, is necessary to determine underlying etiology and direct treatment. Herein, we review the prevalence, characteristics, prognosis, diagnosis, and treatment of MINOCA -a syndrome often overlooked.
Coronary artery disease (CAD) is the leading cause of morbidity and mortality among both women and men, yet women continue to have delays in diagnosis and treatment. The lack of recognition of ...sex-specific biological and socio-cultural gender-related differences in chest pain presentation of CAD may, in part, explain these disparities. Sex and gender differences in pain mechanisms including psychological susceptibility, the autonomic nervous system (ANS) reactivity, and visceral innervation likely contribute to chest pain differences. CAD risk scores and typical/atypical angina characterization no longer appear relevant and should not be used in women and men. Women more often have ischemia with no obstructive CAD (INOCA) and myocardial infarction, contributing to diagnostic and therapeutic equipoise. Existing knowledge demonstrates that chest pain often does not relate to obstructive CAD, suggesting a more thoughtful approach to percutaneous coronary intervention (PCI) and medical therapy for chest pain in stable obstructive CAD. Emerging knowledge regarding the central and ANS and visceral pain processing in patients with and without angina offers explanatory mechanisms for chest pain and should be investigated with interdisciplinary teams of cardiologists, neuroscientists, bio-behavioral experts, and pain specialists. Improved understanding of sex and gender differences in chest pain, including biological pathways as well as sociocultural contributions, is needed to improve clinical care in both women and men.
In patients with angina and non-obstructive coronary artery disease (ANOCA), diagnosis of coronary microvascular dysfunction (CMD) remains an unmet need. Magnetocardiography (MCG), is a rest-based, ...non-invasive scan that can detect weak electrophysiological changes that occur at the early phase of ischemia.
This study assessed the ability of MCG to detect CMD in ANOCA patients as compared to reference standard, invasive coronary flow reserve (CFR).
Patients with ANOCA and invasive coronary physiologic assessment using intracoronary flow measurements with Doppler and thermodilution methods were enrolled. CMD was defined dichotomously as an invasive CFR < 2.0 by Doppler or thermodilution assessment. Noninvasive 36-channel 90-s MCG scan was performed and quantitative assessment of four distinct MCG features was completed. We evaluated the diagnostic performance of 2 or more abnormal MCG features to detect CMD in the overall cohort and performed a subgroup analysis in the subset of patients with Doppler CFR assessment.
Among 79 ANOCA patients, 25 were CMD positive and 54 patients were CMD negative by CFR. Using invasive CFR as reference, MCG had an ROC AUC of 0.66 with a sensitivity of 68 % and specificity of 65 % for the detection of CMD. In the subgroup with Doppler CFR assessment, MCG had an ROC AUC of 0.76 with a sensitivity of 75 % and specificity of 77 %.
In ANOCA patients, MCG demonstrates the ability to detect CMD using a 90-second non-invasive scan without the need for an intravenous stressor or ionizing radiation. Further investigations are needed to validate an MCG-based diagnostic pathway for CMD.
•Use of magnetocardiography (MCG) in patients with angina and non-obstructive coronary artery disease (ANOCA).•MCG demonstrates the ability to detect coronary microvascular dysfunction (CMD) using a 90-second non-invasive scan.
Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). It can be diagnosed by coronary function testing ...(CFT), which is an invasive coronary angiogram procedure. Frequently, these women have persistent angina despite medical therapy, but it is not clear whether it is due to worsening or persistent CMD or inadequate therapy. In this brief report, we describe findings of repeat CFT in a case series of 12 women undergoing repeat CFT for the assessment of persistent angina in order to better understand the evolving pathology.
Background Recurrent hospitalization is prevalent in women with signs and symptoms of ischemia and no obstructive coronary artery disease. We hypothesized that rates of angina hospitalization might ...have changed over time, given advances in diagnostic and therapeutic approaches. Methods and Results We evaluated 551 women enrolled in the WISE (Women's Ischemia Syndrome Evaluation) study with no obstructive coronary artery disease (CAD) for a follow-up period of 9.1 years. We analyzed angina hospitalization rates using the Kaplan-Meier method. Univariate analysis and multivariable Cox proportional hazard models were developed for prediction of angina hospitalization in women with signs and symptoms of angina and no CAD. A total of 223 women had nonobstructive CAD (>20-50% <stenosis) and 328 had no CAD (<20% stenosis). Among women with either no or nonobstructive CAD, the mean age was 56±11 years, 56% had hypertension, 46% dyslipidemia, 51% were smokers, and 10% had prior myocardial infarction. The rates of angina hospitalization for a maximum of 9.1 years showed near-linear increases in both groups (
=0.03). Hypertension, dyslipidemia, nonobstructive CAD, use of nitrates, statins, and angiotensin-converting enzyme inhibitors were univariate predictors of angina hospitalization. Adjusted multivariate hazard ratios for angina hospitalization were significant for use of nitrates 2.58 (1.80-3.69,
<0.0001), statins 1.80 (1.20-2.70,
=0.004), and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 1.81 (1.22-2.68,
=0.003). Conclusions Angina hospitalization rates continued at a relatively constant rate in all women with no obstructive CAD despite medical advances. Clinical trials aimed at reducing angina hospitalization rates and identifying the pathophysiological mechanisms contributing to angina symptoms in women with no CAD and women with no obstructive CAD.
Cardiovascular disease (CVD) is a major health threat to women worldwide. In addition to traditional CVD risk factors, autoimmune conditions are increasingly being recognized as contributors to ...adverse CVD consequences in women. Chronic systemic autoimmune and inflammatory disorders can trigger premature and accelerated atherosclerosis, microvascular dysfunction, and thrombosis. The presence of comorbid conditions, duration of the autoimmune condition, disease severity, and treatment of underlying inflammation are all factors that impact CVD risk and progression. Early identification and screening of CVD risk factors in those with underlying autoimmune conditions may attenuate CVD in this population. Treatment with non-steroidal anti-inflammatory drugs, corticosteroids, disease modifying agents and biologics may influence CVD risk factors and overall risk. Multi-disciplinary and team-based care, clinical trials, and collaborative team-science studies focusing on systemic autoimmune conditions will be beneficial to advance care for women.
•Chronic autoimmune conditions are more prevalent in women and are associated with increased cardiovascular disease risk.•Non-steroidal anti-inflammatories, corticosteroids, disease-modifying agents, and biologics may influence cardiovascular risk.•Multi-specialty care and pragmatic clinical trials are needed to improve care in women with rheumatologic conditions.
•There are currently no sex-specific guidelines for evaluation and management of lipids.•Lipids are impacted by normal hormonal changes in women throughout their life cycle.•Management of lipids ...should incorporate sex-specific cardiovascular risk factors at each stage.•Future objectives should focus on increasing women's presence in trials of lipid-lowering therapies.
There are currently no sex-specific guidelines for evaluation and management of blood lipids. While previous guidelines acknowledge sex-specific risk enhancing factors for lipid management in women for CVD prevention, this review focuses on how lipids are impacted during normal hormonal changes throughout a woman's life cycle- during adolescence, pre-pregnancy, pregnancy, pre- and perimenopause, menopause, and at older ages. In this review, the authors focus on management of primary prevention of CVD by examining sex-specific cardiovascular risk factors at each stage and pay special attention to statin use, statin side effects and non-statin therapies. Women need to understand their personalized cholesterol goals and ally with their clinicians to ensure successful management. Additionally, we highlight the biases that exist when treating dyslipidemia in women and the special care clinicians should take to ensure appropriate and aggressive therapies are made available to female patients. Finally, the authors recommend future research should focus on increasing enrollment of women in lipid trials. This is of paramount importance in discovering sex-specific difference in lipid management.
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The prevalence of metabolic syndrome continues to increase steadily while fitness remains relatively low. The contribution of fitness on longer-term cardiovascular outcomes and mortality in ...individuals with cardiovascular disease and metabolic syndrome remains unknown.
Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1996–2001) of women undergoing invasive coronary angiography with signs/symptoms of ischemic heart disease.
Investigated the association of fitness, defined as >7METs measured by self-reported Duke Activity Status Index (DASI), and both metabolic syndrome (ATPIII criteria) and dysmetabolism (ATPIII criteria and/or treated diabetes) with long-term cardiovascular outcomes and all-cause mortality risk.
Among the 492 women followed for a median of 8.6 years (range 0–11 years), 19.5% were fit-metabolically healthy (reference), 14.4% fit-metabolic syndrome, 29.9% unfit-metabolically healthy, and 36.2% unfit-metabolic syndrome. Compared to reference, MACE risk was 1.52-fold higher in fit-metabolic syndrome women (HR 1.52, 95% CI 1.03–2.26) and 2.42-fold higher in unfit-metabolic syndrome women (HR 2.42, 95% CI 1.30–4.48). Compared to reference, mortality risk was 1.96-fold higher in fit-dysmetabolism (HR 1.96, 95% CI 1.29–3.00) and 3-fold higher in unfit-dysmetabolism women (HR 3.0, 95% CI 1.66–5.43).
In a high risk cohort of women with signs/symptoms of ischemic heart disease, unfit-metabolically healthy and fit-metabolically unhealthy women were at higher risk of long-term MACE and mortality compared to fit-metabolically healthy women; and women who were unfit and metabolically unhealthy were at the highest risk. Our study demonstrates that metabolic health and fitness play an important role in long term outcomes that warrants further investigation.
https://www.clinicaltrials.gov/ct2/show/NCT00000554 (NCT00000554)
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