Arterial stiffness assessment in coronary microvascular dysfunction and heart failure with preserved ejection fraction: An initial report from the WISE-CVD continuation study.

Background: Heart failure with preserved ejection fraction (HFpEF) is the most common cardiac complication in patients with coronary microvascular dysfunction (CMD), yet its underlying pathways remain unclear. Aortic pulse-wave velocity (aPWV) is an indicator of large artery stiffness and a predictor for cardiovascular disease. However, aPWV in CMD and HFpEF is not well characterized and may provide understanding of disease progression. Methods: Among participants without obstructive coronary artery disease, we evaluated 51 women with suspected CMD and 20 women and men with evidence of HFpEF. All participants underwent aPWV measurement (SphygmoCor, Atcor Medical) with higher aPWV indicating greater vascular stiffness. Cardiac magnetic resonance imaging (CMRI) assessed left ventricular (LV) ejection fraction, CMD via myocardial perfusion reserve index (MPRI), and ventricular remodeling via LV mass-volume ratio. . Statistical analysis was performed using Wilcoxon rank sum tests, Pearson correlations and linear regression analysis. Results: Compared to the suspected CMD group, the HFpEF participants were older (65 ± 12 vs 56 ± 11 yrs., p = 0.002) had higher BMI (31.0 ± 4.3 vs 27.8 ± 6.7 kg/m2, p = 0.013), higher aPWV (10.5 ± 2.0 vs 8.0 ± 1.6 m/s, p = 0.05) and lower MPRI (1.5 ± 0.3 vs1.8 ± 0.3, p = 0.02), but not remodeling. In a model adjusted for cardiovascular risk factors, the HFpEF group had a lower LVEF (estimate -4.78, p = 0.0437) than the suspected CMD group. Conclusions: HFpEF participants exhibit greater arterial stiffness and lower myocardial perfusion reserve, with lower LVEF albeit not remodeling, compared to suspected CMD participants. These findings suggest arterial stiffness may contribute to progression from CMD to HFpEF. Prospective work is needed and ongoing.

Cold Pressor Testing and Sympathetic Nervous System Contribution to Ischemia with No Obstructive Coronary Artery Disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project.

Study Objective: Cold Pressor Testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. Design: Prospective cohort. Setting: Academic hospital. Participants: 107 women with suspected INOCA and 21-age-matched reference women. Interventions: CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n=42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main Outcome Measure: MPRIRPP. Results: Compared to reference women, the INOCA group demonstrated higher resting RPP (p=0.005) and CPT MPRIRPP (1.09±0.36 vs 0.83±0.18, p=0.002). Furthermore, INOCA women with impaired ΔCBF (n=23) had higher CPT MPRIRPP (p=0.044) compared to reference women despite lower left ventricular ejection fraction (64±7 % vs 69±2 %, p=0.005) and mass-to-volume ratio (0.79±0.15 vs 0.62±0.09, p<0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. Conclusions: Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. CPT induced a higher MPRIRPP also in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Further investigation in a larger cohort is needed.

The vascular biology of hypertension and atherosclerosis and intervention with calcium antagonists and angiotensin-converting enzyme inhibitors.

Recent advances in the understanding of vascular disease genesis suggest that atherosclerosis and hypertension, primary targets of therapy in the INternational VErapamil SR/trandolapril STudy (INVEST), are closely related. A unified model for the development of cardiovascular disease (CVD) is emerging from recent advances related to atherosclerosis and hypertension. The process of vascular disease appears to begin early in life, when signs of endothelial dysfunction first appear. A primary cause of CVD progression is increased oxidative stress in the endothelium caused by multiple risk factor conditions, including heredity, dyslipidemia, smoking, diabetes, and elevated systolic blood pressure (SBP > 110 mmHg). The renin-angiotensin and kallikrein-kinin systems are important regulators of blood pressure and atherosclerosis. In the renin-angiotensin system, angiotensin-converting enzyme (ACE) mediates generation of angiotensin II (ang II) at local vascular sites and in the plasma and also degrades bradykinin. Information derived from INVEST will help to identify treatment strategies, such as those containing a calcium antagonist and an ACE inhibitor, that are targeted directly at the vascular disorder responsible for hypertension and atherosclerosis.

Electronic prescribing via the internet for a coronary artery disease and hypertension megatrial.

A unique feature of the International Verapamil SR/Trandolapril Study (INVEST) is the Internet-based, electronic data capture system developed at the University of Florida for this trial. This system allows for direct collection of patient enrollment data, randomization, study drug prescribing, and real-time monitoring of patient data online. In this trial, immediate transmission of patient-specific data occurs using online data collection forms. Investigators only need a personal computer with access to the Internet: no complicated hardware, software systems, or paper storage files are necessary. INVEST is the first large randomized clinical trial to use electronic prescribing systems in the research setting. Electronic prescribing eliminates errors associated with illegible handwriting, inappropriate dosing, and inappropriate medication choice. Because the INVEST protocol allows flexibility of medication choice and dosage range within randomly assigned treatment strategies based on patient tolerance and blood pressure response, physician investigators may use individual practice patterns and preferences. The electronic system provides guidance to physicians relative to the addition of medication or dosage adjustments within the protocol. Electronic tracking and reporting mechanisms have enabled investigators in this complex megatrial to enroll, randomize, and manage patients in real time with great accuracy.

Characteristics of patients with coronary artery disease and hypertension: a report from INVEST.

In all, 22,599 patients with coexisting hypertension and coronary artery disease (CAD) from around the world are enrolled in the INternational VErapamil SR/trandolapril STudy (INVEST). As a result, much will be learned regarding the use of treatment strategies using verapamil SR and atenolol with and without trandolapril and/or hydrochlororthiazide in patients with hypertension and CAD, all of whom are at high risk for adverse cardiovascular outcomes. This trial will provide meaningful data on optimal treatment strategies for hypertension, especially among patients who are elderly, have diabetes, have left ventricular hypertrophy, or who are dyslipidemic. This trial will be the first to use Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) guidelines as blood pressure goals to determine the relative benefits of a calcium antagonist versus a beta-blocker strategy in reducing morbidity and mortality. In addition, women and Hispanic patients participating in INVEST will provide the largest controlled experience in the management of hypertensive patients with CAD, facilitating the development of future guidelines.

Young at heart: understanding the unique psychosocial adjustment of young implantable cardioverter defibrillator recipients.

This article reviews the data related to psychosocial adjustment of young ICD recipients, postulates theories to explain potential adjustment difficulties to ICD therapy experienced by younger recipients, and suggests clinical management techniques for addressing the unique psychosocial concerns of young ICD recipients. Studies of young ICD recipients suggest that a wide range of psychosocial adjustment issues are prominent in the post-ICD implantation period and that the issues may be different from older ICD recipients. The disability-stress-coping model and the transactional-stress-coping model are postulated as explanations for the unique adjustment concerns of children and adolescents with ICDs. Social comparison theory is also applied to the concerns of young adults with ICDs such that they often lack same age peers to compare experiences with cardiac difficulties. Brief, clinic-based interventions by health care providers, like a screening and referral heuristic and an "ICD Buddy" system, are suggested to increase effective coping and decrease social isolation for young ICD recipients.

Weight cycling and high-density lipoprotein cholesterol in women: evidence of an adverse effect: a report from the NHLBI-sponsored WISE study. Women's Ischemia Syndrome Evaluation Study Group.

OBJECTIVES: We undertook an analysis of weight cycling, coronary risk factors and angiographic coronary artery disease (CAD) in women. BACKGROUND: The effect of weight cycling on cardiovascular mortality and morbidity is controversial, and the impact of weight cycling on cardiovascular risk factors is unclear. METHODS: This is a cross-sectional population study of 485 women with coronary risk factors undergoing coronary angiography for evaluation of suspected myocardial ischemia enrolled in the Women's Ischemia Syndrome Evaluation (WISE). Reported lifetime weight cycling-defined as voluntary weight loss of at least 10 lbs at least 3 times--coronary risk factors including core laboratory determined blood lipoproteins and CAD, as determined by a core angiographic laboratory, are the main outcome measures. RESULTS: Overall, 27% of women reported weight cycling--19% cycled 10 to 19 lbs, 6% cycled 20 to 49 lbs, and 2% cycled 50+ lbs. Reported weight cycling was associated with 7% lower high-density lipoprotein cholesterol (HDL-C) levels in women (p = 0.01). The HDL-C effect was directly related to the amount of weight cycled with women who lost > or = 50 lbs/cycle having HDL-C levels 27% lower than noncyclers (p = 0.0025). This finding was independent of other HDL-C modulators, including estrogen status, physical activity level, alcohol intake, body mass index, diabetes, beta-blocker use, cigarette smoking and race. Weight cycling was not associated with an increased prevalence of CAD in this population. CONCLUSIONS: Weight cycling is associated with lower HDL-C in women of a magnitude that is known to be associated with an increased risk of cardiac events as demonstrated in prior clinical trials.

Factors limiting the enrollment of women in a randomized coronary artery disease trial. The Asymptomatic Cardiac Ischemia Pilot Study (ACIP) Investigators.

BACKGROUND AND HYPOTHESIS: Although it is recognized that women have been underrepresented in clinical trials of cardiovascular disease, the reasons for their limited enrollment have not been elucidated. METHODS: A prospective tracking system was established in the Asymptomatic Cardiac Ischemia Pilot study (ACIP) to monitor recruitment and identify protocol issues that interfered with the recruitment of women. Patients with stress test evidence for ischemia during the course of routine clinical care were screened for asymptomatic ischemia with an ambulatory electrocardiogram (ECG). RESULTS: Those with at least one episode of asymptomatic ischemia and angiographic evidence of coronary artery disease suited for revascularization could be randomized. Women comprised only 17% of the 1,820 patients screened for asymptomatic ischemia, and only 14% of the 558 patients randomized. The limited number of women screened for ischemia was largely due to the limited number of women (25% of all patients) found to have test evidence for ischemia or coronary artery disease suited for revascularization during the course of routine clinical care. Once patients were identified as having ischemia on stress test and ambulatory ECG, the major difference in eligibility was the difference in disqualifying angiograms, occurring 21/2 times as frequently in women as in men (p < 0.001). CONCLUSION: The percentage of women recruited was lower than the prevalence of ischemic heart disease in the general population because at participating centers (1) women were found to have ischemia less often than men during the course of routine clinical care, and (2) screening tests for ischemia were less predictive of protocol-defined coronary disease in women than in men.

Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life. The Atenolol Silent Ischemia Study (ASIST)

BACKGROUND: Detection of asymptomatic ischemia in patients with coronary artery disease has been associated with increased risk for adverse outcome, but treatment of patients with asymptomatic ischemia remains controversial. Accordingly, the purpose of this study was to determine if treatment reduces adverse outcome in patients with daily life ischemia. METHODS AND RESULTS: A multicenter, randomized, double-blind, placebo-controlled study of asymptomatic or minimally symptomatic outpatients with daily life silent ischemia due to coronary artery disease was conducted. The primary outcome measure was event-free survival at 1 year by Kaplan-Meier analysis. Events were death, resuscitated ventricular tachycardia/fibrillation, myocardial infarction, hospitalization for unstable angina, aggravation of angina, or revascularization. The secondary outcome was ischemia during ambulatory ECG monitoring at 4 weeks. Three hundred six outpatients with mild or no angina (Canadian Cardiovascular Society class I or II), abnormal exercise tests, and ischemia on ambulatory monitoring were randomized to receive either atenolol (100 mg/d) or placebo. After 4 weeks of treatment, the number (mean +/- SD, 3.6 +/- 4.2 versus 1.7 +/- 4.6 episodes, P < .001) and average duration (30 +/- 3.3 versus 16.4 +/- 6.7 minutes, P < .001) of ischemic episodes per 48 hours of ambulatory monitoring decreased in atenolol- compared with placebo-assigned patients (4.4 +/- 4.6 to 3.1 +/- 6.0 episodes and 36.6 +/- 4.1 to 30 +/- 5.5 minutes). Event-free survival improved in atenolol-treated patients (P < .0066), who had an increased time to onset of first adverse event (120 versus 79 days) and fewer total first events compared with placebo (relative risk, 0.44; 95% confidence intervals, 0.26 to 0.75; P = .001). There was a nonsignificant trend for fewer serious events (death, resuscitation from ventricular tachycardia/fibrillation, nonfatal myocardial infarction, or hospitalization for unstable angina) in atenolol-treated patients (relative risk, 0.55; 95% confidence intervals, 0.22 to 1.33; P = .175). The most powerful univariate and multivariate correlate of event-free survival was absence of ischemia on ambulatory monitoring at 4 weeks. Side effects were mild and generally similar comparing atenolol- and placebo-treated patients, although bradycardia was more frequent with atenolol. CONCLUSIONS: Atenolol treatment reduced daily life ischemia and was associated with reduced risk for adverse outcome in asymptomatic and mildly symptomatic patients compared with placebo.

Characteristics of a contemporary population with angina pectoris. TIDES Investigators.

To characterize a contemporary, nonhospitalized population with angina pectoris, data were obtained from a geographically diverse cohort of 5,125 outpatients with chronic stable angina cared for by 1,266 primary care physicians between September and November of 1990. Diagnosis was based on history supported by evidence for coronary artery disease (coronary angiography, old myocardial infarction, or an abnormal stress test, either alone or in combination). The mean age of the patients was 69 years and 53% were women. Seventy percent had > 1 associated illness and 64% took > 1 cardiovascular drug. Median angina frequency was approximately 2 episodes/week and increased angina frequency (p < 0.0001) was associated with decreased overall feeling of well-being. Although effort angina was present in 90% of patients, 47% also had rest angina and 35% had mental stress-evoked angina. Female gender (relative risk [RR] 1.09; 95% confidence interval [CI] 1.02 to 1.16), concomitant illness (RR 1.17; CI 1.09 to 1.25), and pharmacotherapy (RR 1.14; CI 1.07 to 1.22) were associated with excess risk for rest angina. Younger age (RR 1.30; CI 1.20 to 1.41), female gender (RR 1.16; CI 1.07 to 1.26), concomitant illness (RR 1.13; CI 1.03 to 1.24), and pharmacotherapy (RR 1.28; CI 1.15 to 1.93) were associated with excess risk for mental stress angina. These data suggest that contemporary outpatients with angina are frequently women and elderly patients with high rates of associated illness, rest, and mental stress-related angina.

Clot busters. The future of EMS thrombolytics.

The importance of early identification and treatment of patients experiencing an AMI is clearly beneficial. Studies have shown that the time from pain onset to hospital administration of thrombolytic therapy can be reduced simply by early identification of patient eligibility by paramedics and notification of the receiving hospitals--as well as more efficient patient management after arrival at the ED. The limitations of thrombolytic therapy also may be related, in part, to patient denial of symptoms and reluctance to seek emergency assistance. To widen the net of patients who can receive thrombolytic therapy, extensive research has been and is being conducted to integrate the prehospital phase into the treatment window. The practicality of upgrading all EMS systems to provide thrombolytic therapy depends on many factors. EMS directors must accept the responsibility for the prehospital care delivered. Although the diagnostic accuracy is high and complications are relatively low when compared to the risk, the current legal environment in the United States may limit the willingness of some directors to promote a prehospital thrombolytic program. Additionally, the low yield of patients may not justify the significant capital outlay required to adequately train personnel and outfit ambulances with required telemetry systems. At a minimum, however, EMS programs can improve their ability to rapidly identify those patients who may be eligible for thrombolytic therapy.

The prognostic and economic implications of a strategy to detect and treat asymptomatic ischemia: the Atenolol Silent Ischemia Trial (ASIST) protocol.

Although silent ischemia may be linked to increases in cardiovascular morbidity and mortality, the long-term effects of a strategy aimed at the detection and treatment of this asymptomatic condition have not been fully explored. We therefore have developed the Atenolol Silent Ischemia Trial (ASIST), the first multicenter, randomized, prospective study of the prognostic implications of silent ischemia in asymptomatic and minimally symptomatic patients with coronary artery disease. Inclusion criteria for study patients were documented coronary artery disease, evidenced angiographically or by previous myocardial infarction, and transient ischemia, evidenced by abnormalities of regional wall motion, stress thallium-201, or exercise electrocardiogram. The main objective of ASIST is to assess the influence of frequency and duration of symptomatic and asymptomatic ischemic episodes on the occurrence of fatal and nonfatal cardiac events. Atenolol, a beta 1-selective adrenergic blocker, was chosen as the therapeutic intervention because of its potential benefits in treating both symptomatic and asymptomatic ischemia. Ambulatory electrocardiographic monitoring will be used to measure the frequency and duration of ischemic episodes during daily life. The predictive ability of short-term (4-week) effects on long-term (52-week) response to atenolol treatment is also being assessed, along with the economic impact of this diagnostic and therapeutic strategy. Given the current emphasis on reducing morbidity and mortality associated with coronary artery disease, ASIST results should shed light onto the long-term management and prognostic implications of this otherwise asymptomatic condition.