Microvascular coronary dysfunction (MCD) is prevalent in approximately 50% of women with signs and symptoms of myocardial ischemia but no obstructive coronary artery disease (CAD) and carries an adverse cardiovascular (CV) prognosis, comparable to obstructive CAD. Previously thought to be benign and labeled """"""""Cardiac Syndrome X"""""""" (CSX), there is a 3-fold increase in major adverse cardiac events (MACE) in women with no obstructive CAD compared to asymptomatic women. Traditional CV risk factors poorly predict MCD;therapeutics are poorly developed. While animal and human data demonstrate the importance of the cardiac autonomic nervous system (ANS) in the mechanistic pathways for myocardial ischemia and sudden cardiac death, this has not been studied in MCD with well-defined measures of coronary blood flow and myocardial ischemia. Women with MCD have low heart rate/mental stress-related angina, myocardial infarctions, and links to """"""""broken heart syndrome"""""""" (Takotsubo cardiomyopathy). We hypothesize that cardiac ANS sympathovagal balance characterized by sympathetic predominance is positively associated with the presence and severity of MCD. To further test ANS as a mechanistic pathway of MCD, we hypothesize that MCD subjects randomized to paced breathing will have beneficially altered ANS sympathovagal balance and improved ischemic symptoms as a marker of MCD. Three groups will be compared: (1) Women with MCD;(2) Women with CSX (symptomatic controls without MCD);(3) Reference Control women (asymptomatic normal controls). Subjects will be recruited from the on-going NIH-NHLBI funded Women's Ischemia Syndrome Evaluation (WISE) - Coronary Vascular Dysfunction study (R01 HL090957, PI: Bairey Merz) to test the following Aims: 1) To characterize the association between cardiac ANS sympathovagal balance in MCD compared to CSX and reference control subjects by (1a) measuring cardiac sympathetic activity by 123iodine-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) imaging, and (1b) testing the effect of low heart rate stress on ANS sympathovagal balance in the three groups via mental stress testing and peripheral vascular testing;2) To test ANS sympathovagal balance as a mechanistic pathway in MCD using device- based paced breathing. We propose to study three groups of women including CSX subjects without evidence of MCD because prior work in CSX has suggested a role for ANS balance but has not linked this to measures of MCD (coronary flow and ischemia), leaving an important knowledge gap regarding whether ANS balance is a mechanistic pathway in MCD or simply a benign consequence of symptoms. Addressing this knowledge gap will provide guidance regarding whether the ANS should be targeted as a mechanistic pathway in clinical trials designed to reduce MACE in this at-risk MCD population.

Public Health Relevance

This application for Puja Mehta MD incorporates a multi-disciplinary, mentored patient-oriented research plan to prepare her for independent, translational investigation in cardiovascular medicine. The project aims to investigate the role of cardiac autonomic nervous system in women with microvascular coronary dysfunction using mental stress testing, advanced cardiac imaging, heart rate variability testing, peripheral vascular testing, and paced-breathing to explore causal mechanistic pathways for novel treatment targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Kaufmann, Peter G
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Cedars-Sinai Medical Center
Los Angeles
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Mehta, Puja K; Hermel, Melody; Nelson, Michael D et al. (2018) Mental stress peripheral vascular reactivity is elevated in women with coronary vascular dysfunction: Results from the NHLBI-sponsored Cardiac Autonomic Nervous System (CANS) study. Int J Cardiol 251:8-13
Sharma, Shilpa; Mehta, Puja K; Arsanjani, Reza et al. (2018) False-positive stress testing: Does endothelial vascular dysfunction contribute to ST-segment depression in women? A pilot study. Clin Cardiol 41:1044-1048
Wei, Janet; Bakir, May; Darounian, Navid et al. (2018) Myocardial Scar Is Prevalent and Associated With Subclinical Myocardial Dysfunction in Women With Suspected Ischemia But No Obstructive Coronary Artery Disease: From the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Study. Circulation 137:874-876
Elboudwarej, Omeed; Wei, Janet; Darouian, Navid et al. (2018) Maladaptive left ventricular remodeling in women: An analysis from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study. Int J Cardiol 268:230-235
Wei, Janet; Mehta, Puja K; Grey, Elizabeth et al. (2017) Sex-based differences in quality of care and outcomes in a health system using a standardized STEMI protocol. Am Heart J 191:30-36
Humphries, K H; Izadnegahdar, M; Sedlak, T et al. (2017) Sex differences in cardiovascular disease - Impact on care and outcomes. Front Neuroendocrinol 46:46-70
Rambarat, Cecil A; Elgendy, Islam Y; Johnson, B Delia et al. (2017) Migraine Headache and Long-Term Cardiovascular Outcomes: An Extended Follow-Up of the Women's Ischemia Syndrome Evaluation. Am J Med 130:738-743
Birkeland, Kade; Khandwalla, Raj M; Kedan, Ilan et al. (2017) Daily Activity Measured With Wearable Technology as a Novel Measurement of Treatment Effect in Patients With Coronary Microvascular Dysfunction: Substudy of a Randomized Controlled Crossover Trial. JMIR Res Protoc 6:e255
AlBadri, Ahmed; Leong, Derek; Bairey Merz, C Noel et al. (2017) Typical angina is associated with greater coronary endothelial dysfunction but not abnormal vasodilatory reserve. Clin Cardiol 40:886-891
Kenkre, Tanya S; Malhotra, Pankaj; Johnson, B Delia et al. (2017) Ten-Year Mortality in the WISE Study (Women's Ischemia Syndrome Evaluation). Circ Cardiovasc Qual Outcomes 10:

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