Puja K. Mehta

Ranolazine Improves Angina in Women With Evidence of Myocardial Ischemia But No Obstructive Coronary Artery Disease

OBJECTIVES We conducted a pilot study for a large definitive clinical trial evaluating the impact of ranolazine in women with angina, evidence of myocardial ischemia, and no obstructive coronary artery disease (CAD). BACKGROUND Women with angina, evidence of myocardial ischemia, but no obstructive CAD frequently have microvascular coronary dysfunction. The impact of ranolazine in this patient group is unknown. METHODS A pilot randomized, double-blind, placebo-controlled, crossover trial was conducted in 20 women with angina, no obstructive CAD, and ≥ 10% ischemic myocardium on adenosine stress cardiac magnetic resonance (CMR) imaging. Participants were assigned to ranolazine or placebo for 4 weeks separated by a 2-week washout. The Seattle Angina Questionnaire and CMR were evaluated after each treatment. Invasive coronary flow reserve (CFR) was available in patients who underwent clinically indicated coronary reactivity testing. CMR data analysis included the percentage of ischemic myocardium and quantitative myocardial perfusion reserve index (MPRI). RESULTS The mean age of subjects was 57 ± 11 years. Compared with placebo, patients on ranolazine had significantly higher (better) Seattle Angina Questionnaire scores, including physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). There was a trend toward a higher (better) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074) on ranolazine. Among women with coronary reactivity testing (n = 13), those with CFR ≤ 3.0 had a significantly improved MPRI on ranolazine versus placebo compared to women with CFR > 3.0 (Δ in MPRI 0.48 vs. -0.82, p = 0.04). CONCLUSIONS In women with angina, evidence of ischemia, and no obstructive CAD, this pilot randomized, controlled trial revealed that ranolazine improves angina. Myocardial ischemia may also improve, particularly among women with low CFR. These data document approach feasibility and provide outcome variability estimates for planning a definitive large clinical trial to evaluate the role of ranolazine in women with microvascular coronary dysfunction. (Microvascular Coronary Disease In Women: Impact Of Ranolazine; NCT00570089).

Effects of Yoga on Inflammation and Exercise Capacity in Patients With Chronic Heart Failure

BACKGROUND Despite recent advances in pharmacologic and device therapy, morbidity and mortality from heart failure (HF) remain high. Yoga combines physical and breathing exercises that may benefit patients with HF. We hypothesized that an 8-week regimen of yoga in addition to standard medical therapy would improve exercise capacity, inflammatory markers, and quality of life (QoL) in patients with HF. METHODS AND RESULTS New York Heart Association Class I-III HF patients were randomized to yoga treatment (YT) or standard medical therapy (MT). Measurements included a graded exercise test (GXT) to V O(2Peak) and the following serum biomarkers: interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and extracellular superoxide dismutase (EC-SOD). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was administered to assess changes in QoL. A total of 19 patients were enrolled after the initial screening. Of the 19 patients, 9 were randomized to YT and 10 to MT. Patients had a mean EF of 25%. GXT time and V O(2Peak) were significantly improved in the YT versus MT groups (+18% in the YT and -7.5% in MT; P = .03 vs. control and +17 in YT and -7.1 in MT; P = .02, respectively). There were statistically significant reductions in serum levels of IL-6 and hsCRP and an increase in EC-SOD in the YT group (all P < .005 vs. MT). MLHFQ scores improved by 25.7% in the YT group and by 2.9% in the MT group. CONCLUSIONS Yoga improved exercise tolerance and positively affected levels of inflammatory markers in patients with HF, and there was also a trend toward improvements in QoL.

Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.

OBJECTIVES This study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD). BACKGROUND Microvascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown. METHODS The authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded. RESULTS CRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%). CONCLUSIONS In women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Womens Ischemia Syndrome Evaluation [WISE]; NCT00832702).

Benefits of Yoga for African American Heart Failure Patients

BACKGROUND The number of African American (AA) patients living with heart failure (HF) has been increasing, especially among the economically disadvantaged. Yoga therapy has been found to improve physical and psychological parameters among healthy individuals, but its effect in patients with HF remains unknown. The purpose of this study was to examine the effects of yoga therapy on cardiovascular endurance (VO2peak), flexibility, quality of life (QoL), and inflammatory markers on medically stable HF patients. METHODS Forty patients (38 AA, 1 Asian, and 1 Caucasian) with systolic or diastolic HF were randomized to the yoga group (YG, n = 21) or the control group (CG, n = 19). All patients were asked to follow a home walk program. Premeasurement and postmeasurement included a treadmill stress test to peak exertion, flexibility, interleukin-6 (IL-6), C-reactive protein (CRP), and extracellular superoxide dismutase (EC-SOD). QoL was assessed by the Minnesota Living with Heart Failure Questionnaire (MLwHFQ). RESULTS The statistical analyses (assessed by ANOVA and t-tests) were significant for favorable changes in the YG, compared with those in the CG, for flexibility (P = 0.012), treadmill time (P = 0.002), VO2peak (P = 0.003), and the biomarkers (IL-6, P = 0.004; CRP, P = 0.016; and EC-SOD, P = 0.012). Within the YG, pretest to posttest scores for the total (P = 0.02) and physical subscales (P < 0.001) of the MLwHFQ were improved. CONCLUSIONS Yoga therapy offered additional benefits to the standard medical care of predominantly AA HF patients by improving cardiovascular endurance, QoL, inflammatory markers, and flexibility.

A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve

Abstract Aims The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling. Materials and results Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500–1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (−3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041). Conclusions In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects. Trial registration clinicaltrials.gov Identifier: NCT01342029.

Provocative Testing for Coronary Reactivity and Spasm

Coronary spasm is an important and often overlooked etiology of chest pain. Although coronary spasm, or Prinzmetals angina, has been thought of as benign, contemporary studies have shown serious associated adverse outcomes, including acute coronary syndrome, arrhythmia, and death. Definitive diagnosis of coronary spasm can at times be difficult, given the transience of symptoms. Numerous agents have been historically described for provocative testing. We provide a review of published data for the role of provocation testing in the diagnosis of coronary spasm.

Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women's Ischemia Syndrome Evaluation.

Background—Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population. Methods and Results—Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71±0.43 versus 2.23±0.37; P<0.0001). Lower MPRI was predictive of ≥1 abnormal CRT variables (odds ratio =0.78 [0.70, 0.88], P<0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%. Conclusions—Noninvasive cardiac MRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the noninvasive identification and management of CMD patients. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00832702.Background— Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population. Methods and Results— Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71±0.43 versus 2.23±0.37; P <0.0001). Lower MPRI was predictive of ≥1 abnormal CRT variables (odds ratio =0.78 [0.70, 0.88], P <0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%. Conclusions— Noninvasive cardiac MRI MPRI can detect CMD defined by invasive CRT. Further work is aimed to optimize the noninvasive identification and management of CMD patients. Clinical Trial Registration— URL: . Unique identifier: [NCT00832702][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00832702&atom=%2Fcirccvim%2F8%2F4%2Fe002481.atom

Ischemic heart disease in women: A focus on risk factors

Heart disease remains a major contributor to morbidity and mortality in women in the United States and worldwide. This review highlights known and emerging risk factors for ischemic heart disease (IHD) in women. Traditional Framingham risk factors such as hypertension, hyperlipidemia, diabetes, smoking, as well as lifestyle habits such as unhealthy diet and sedentary lifestyle are all modifiable. Health care providers should be aware of emerging cardiac risk factors in women such as adverse pregnancy outcomes, systemic autoimmune disorders, obstructive sleep apnea, and radiation-induced heart disease; psychosocial factors such as mental stress, depression, anxiety, low socioeconomic status, and work and marital stress play an important role in IHD in women. Appropriate recognition and management of an array of risk factors is imperative given the growing burden of IHD and need to deliver cost-effective, quality care for women.

Cardiac magnetic resonance imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls

OBJECTIVE We sought to comparatively assess cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) in women with confirmed microvascular coronary dysfunction (MCD) cases and reference control women. BACKGROUND Women with signs or symptoms of myocardial ischemia in the absence of obstructive coronary artery disease (CAD) frequently have MCD which carries an adverse prognosis. Diagnosis involves invasive coronary reactivity testing (CRT). Adenosine CMRI is a non-invasive test that may be useful for the detection of MCD. METHODS Fifty-three women with MCD confirmed by CRT and 12 age- and estrogen-use matched reference controls underwent adenosine CMRI. CMRI was assessed for MPRI, calculated using the ratio of myocardial blood flow at hyperemia/rest for the whole myocardium and separately for the 16 segments as defined by the American Heart Association. Statistical analysis was performed using repeated measures ANOVA models. RESULTS Compared to reference controls, MCD cases had lower MPRI values globally and in subendocardial and subepicardial regions (1.63±0.39 vs. 1.98±0.38, P=0.007, 1.51±0.35 vs. 1.84±0.34, P=0.0045, 1.68±0.38 vs. 2.04±0.41, P=0.005, respectively). A perfusion gradient across the myocardium with lower MPRI in the subendocardium compared to the subepicardium was observed for both groups. CONCLUSIONS Women with MCD have lower MPRI measured by perfusion CMRI compared to reference controls. CMRI may be a useful diagnostic modality for MCD. Prospective validation of a diagnostic threshold for MPRI in patients with MCD is needed.

Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy

Cardiovascular disease is the leading cause of death worldwide. In the presence of signs and symptoms of myocardial ischaemia, women are more likely than men to have no obstructive coronary artery disease (CAD). Women have a greater burden of symptoms than men, and are often falsely reassured despite the presence of ischaemic heart disease because of a lack of obstructive CAD. Coronary microvascular dysfunction should be considered as an aetiology for ischaemic heart disease with signs and symptoms of myocardial ischaemia, but no obstructive CAD. Coronary microvascular dysfunction is defined as impaired coronary flow reserve owing to functional and/or structural abnormalities of the microcirculation, and is associated with an adverse cardiovascular prognosis. Therapeutic lifestyle changes as well as antiatherosclerotic and antianginal medications might be beneficial, but clinical outcome trials are needed to guide treatment. In this Review, we discuss the prevalence, presentation, diagnosis, and treatment of coronary microvascular dysfunction, with a particular emphasis on ischaemic heart disease in women.