John W. Petersen

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.

Silent ischemia: clinical relevance.

Myocardial ischemia can occur without overt symptoms. In fact, asymptomatic (or silent) ST-segment depression during ambulatory electrocardiogram monitoring occurs more often than symptomatic ST-segment depression in patients with coronary artery disease. Initial studies documented that silent ischemia provided independent prediction of adverse outcomes in patients with known and unknown coronary artery disease. The ACIP (Asymptomatic Cardiac Ischemia Pilot Study) enrolled patients in the 1990s and found that revascularization was better than medical therapy in reducing silent ischemic episodes and possibly cardiovascular (CV) events. However, the more recent COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial found similar CV event rates between patients treated with optimal medical therapy alone and those treated with optimal medical therapy plus percutaneous revascularization. Therefore, in the current era, medical therapy appears to be as effective as revascularization in suppressing symptomatic ischemia and preventing CV events. COURAGE was not designed to evaluate changes in the frequency of silent ischemia. Therefore, silent ischemia may persist despite current-era treatment and might still identify patients with increased risk of CV events. Also, silent ischemia is likely to occur frequently in heart transplant patients with denervated hearts and coronary allograft vasculopathy, and future study aimed at improving the management of silent ischemia in this population is warranted. Additionally, future research is warranted to study the effect of newer medical therapies such as ranolazine or selected use of revascularization (for example, guided by fractional flow reserve) in those patients with persistent silent ischemia despite optimal current-era medical therapy.

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

Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults

Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance.

Quantification of myocardial segmental function in acute and chronic ischemic heart disease and implications for cardiovascular cell therapy trials: A review from the NHLBI-cardiovascular cell therapy research network

Global left ventricular (LV) ejection fraction (LVEF) has been used as a measure of improvement in LV function following cell therapy. Although the impact of cell therapy on LVEF in short- and long-term follow-up has been generally positive, there is concern that research evaluating regional therapeutics (e.g., cell or gene therapy) may require analysis of regional LV function localized to the site of intervention. Regional LV assessment is traditionally performed with qualitative or quantitative analysis of wall thickening within 16 myocardial segments, but advances in noninvasive imaging permit an increasingly more detailed and accurate evaluation of LV function. Wall-thickness measurements can now include evaluation of over 1,000 myocardial segments. In addition to higher resolution measures of wall thickening, automated assessments of myocardial segment deformation, such as strain imaging, exist. Strain imaging allows for direct evaluation of the mechanical properties that may improve following regional therapeutic intervention. Improvements in regional LV function may also be assessed by determining regional ejection fraction (EF). Regional EF offers the advantage of summarizing the end result of all of the complex deformations in the adjacent myocardial segments. Although regional EF and strain imaging, as compared with wall thickening, enhance detection of improvement in complex measures of regional myocardial function, it remains unclear whether such measures are better able to predict meaningful improvement in clinical outcomes.

Microvascular coronary dysfunction and ischemic heart disease: Where are we in 2014?

Many patients with angina and signs of myocardial ischemia on stress testing have no significant obstructive epicardial coronary disease. There are many potential coronary and non-coronary mechanisms for ischemia without obstructive epicardial coronary disease, and prominent among these is coronary microvascular and/or endothelial dysfunction. Patients with coronary microvascular and/or endothelial dysfunction are often at increased risk of adverse cardiovascular events, including ischemic events and heart failure despite preserved ventricular systolic function. In this article, we will review the diagnosis and treatment of coronary microvascular and endothelial dysfunction, discuss their potential contribution to heart failure with preserved ejection fraction, and highlight recent advances in the evaluation of atherosclerotic morphology in these patients, many of whom have non-obstructive epicardial disease.

A microvascular-myocardial diastolic dysfunctional state and risk for mental stress ischemia: a revised concept of ischemia during daily life.

To improve our understanding of pathophysiological responses to stress in “triggering” adverse events, stressors have been used in the laboratory to evoke “mental stress–induced ischemia” (MSIMI). Our studies found that patients with MSIMI had increased risk for death [(1)][1], and their

Tenascin-X, collagen, and Ehlers–Danlos syndrome: Tenascin-X gene defects can protect against adverse cardiovascular events

Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X. Tenascin-X regulates both the structure and stability of elastic fibers and organizes collagen fibrils in the extra-cellular matrix (ECM), impacting the rigidity or elasticity of virtually every cell in the body. While the impacts of tenascin-X insufficiency or deficiency on the skin and joints have received some attention, its potential cardiovascular impacts remain relatively unexplored. Here we set forth two novel hypotheses. First, TNXB haploinsufficiency or deficiency causes the range of clinical manifestations long identified with both EDS-HT and BJHS. And, second, that haploinsufficiency or deficiency of TNXB may provide some benefits against adverse cardiovascular events, including heart attack and stroke, by lowering levels of arterial stiffness associated with aging, as well as by enhancing accommodation of accrued atherosclerotic plaques. This two-fold hypothesis provides insights into the mechanisms underlying the syndromes previous identified with joint hypermobility, at the same time the hypothesis also sheds light on the role of the composition of the extracellular matrix and its impacts on endothelial sheer stress in adverse cardiovascular events.

Speckle tracking echocardiography-determined measures of global and regional left ventricular function correlate with functional capacity in patients with and without preserved ejection fraction

BackgroundStandard measures of left ventricular systolic and diastolic function often fail to identify left ventricular dysfunction in patients with heart failure and do not correlate with measures of functional capacity.AimTo determine if speckle tracking echocardiography (STE)–determined measures of global and regional myocardial contractility have a linear association with functional capacity in patients with and without preserved ejection fraction.MethodsIn 68 adult patients, functional status was estimated with the Duke Activity Status Index (DASI), left ventricular ejection fraction was determined with Simpson’s biplane method, and QLAB advanced quantification software (Philips, The Netherlands) was used to determine peak measures of strain.ResultsGlobal and regional measures of longitudinal, circumferential, and radial strain had a strong linear association with the DASI score. Longitudinal strain in the inferolateral segments had the strongest correlation with DASI (r = −0.72, P < 0.001). In patients with an ejection fraction ≥45%, ejection fraction and E/e’ had no correlation with DASI, whereas longitudinal strain in the inferolateral segments had significant correlation with DASI (r = −0.53, P = 0.03, n = 16).ConclusionsSTE–determined measures of global and regional left ventricular function have a strong linear association with estimates of functional capacity in patients with and without preserved ejection fraction. STE–determined measures of strain, especially longitudinal strain, are likely to be important targets for therapy and should be considered in future studies aimed at improving our diagnosis of left ventricular inadequacy in patients with heart failure, especially those with preserved ejection fraction.