Janet Wei

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).

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).

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.

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.

Diastolic Dysfunction in Women with Signs and Symptoms of Ischemia in the Absence of Obstructive Coronary Artery Disease: A Hypothesis-Generating Study

Background—Angina, in the absence of obstructive coronary artery disease, is more common in women, is associated with adverse cardiovascular morbidity and mortality, and is a major burden to the healthcare system. Although advancements have been made to understand the mechanistic underpinning of this disease, the functional consequence remains unclear. Methods and Results—Cardiac magnetic resonance imaging was performed to assess left ventricular function in 20 women with signs and symptoms of ischemia, but no obstructive coronary artery disease (cases), and 15 age- and body mass index–matched reference controls. Functional imaging included standard cinematic imaging to assess left ventricular morphology and global function, along with tissue tagging to assess left ventricular tissue deformation. Systolic function was preserved in both cases and controls, with no differences in ejection fraction (mean±SE: 63.1±8% versus 65±2%), circumferential strain (−20.7±0.6% versus −21.9±0.5%), or systolic circumferential strain rate (−105.9±6.1% versus −109.0±3.8% per second). In contrast, we observed significant differences between cases and controls in diastolic function, as demonstrated by reductions in both diastolic circumferential strain rate (153.8±8.9% versus 191.4±8.9% per second; P<0.05) and peak rate of left ventricular untwisting (−99.4±8.0° versus −129.4±12.8° per second; P<0.05). Conclusions—Diastolic function is impaired in women with signs and symptoms of ischemia in the absence of coronary artery disease, as assessed by cardiac magnetic resonance tissue tagging. These results are hypothesis-generating. Larger studies are needed to define the exact mechanism(s) responsible and to establish viable treatment strategies.

Sex differences in cardiovascular disease : Impact on care and outcomes

KH Humphries, University of British Columbia M Izadnegandar, BC Centre for Improved Cardiovascular Health T Sedlak, University of British Columbia J Saw, University of British Columbia N Johnston, Uppsala University Hospital K Schenck-Gustafsson, Karolinska University Hospital and Karolinska Institutet RU Shah, University of Utah V Regitz-Zagrosek, Charité University Medicine Berlin and DZHK J Grewal, University of British Columbia Viola Vaccarino, Emory University

Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function.

Coronary Microvascular Dysfunction ― Epidemiology, Pathogenesis, Prognosis, Diagnosis, Risk Factors and Therapy ―

Angina has traditionally been thought to be caused by obstructive coronary artery disease (CAD). However, a substantial number of patients with angina are found to not have obstructive CAD when undergoing coronary angiography. A significant proportion of these patients have coronary microvascular dysfunction (CMD), characterized by heightened sensitivity to vasoconstrictor stimuli and limited microvascular vasodilator capacity. With the advent of non-invasive and invasive techniques, the coronary microvasculature has been more extensively studied in the past 2 decades. CMD has been identified as a cause of cardiac ischemia, in addition to traditional atherosclerotic disease and vasospastic disease. CMD can occur alone or in the presence obstructive CAD. CMD shares many similar risk factors with macrovascular CAD. Diagnosis is achieved through detection of an attenuated response of coronary blood flow in response to vasodilatory agents. Imaging modalities such as cardiovascular magnetic resonance, positron emission tomography, and transthoracic Doppler echocardiography have become more widely used, but have not yet completely replaced the traditional intracoronary vasoreactivity testing. Treatment of CMD starts with lifestyle modification and risk factor control. The use of traditional antianginal, antiatherosclerotic medications and some novel agents may be beneficial; however, clinical trials are needed to assess the efficacy of the pharmacologic and non-pharmacologic therapeutic modalities. In addition, studies with longer-term follow-up are needed to determine the prognostic benefits of these agents. We review the epidemiology, prognosis, pathogenesis, diagnosis, risk factors and current therapies for CMD.

Frequency of coronary artery fistulae is increased after orthotopic heart transplantation

Frequency of coronary artery fistulae is increased after orthotopic heart transplantation Janet Wei, MD, Babak Azarbal, MD, Sarabjeet Singh, MD, Matthew Rafiei, BS, Richard Cheng, MD, Jignesh Patel, MD, Fardad Esmailian, MD, Jesse Currier, MD, and Jon Kobashigawa, MD From the Division of Cardiology, Heart Institute, Cedars–Sinai Medical Center, Los Angeles, California; and the Division of Cardiology, West Los Angeles Veterans Administration Medical Center, Los Angeles, California