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Background: Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. Methods: Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety. Results: Firibastat lowered systolic AOBP by 9.5 mm Hg ( P P P P P Conclusions: Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.

Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population.Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP)140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety.Firibastat lowered systolic AOBP by 9.5 mm Hg ( P0.0001) and diastolic AOBP by 4.2 mm Hg ( P0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg ( P0.0001) in obese patients, by 10.5 mm Hg ( P0.0001) in blacks, and 8.9 mm Hg ( P0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed.Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension.URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03198793.

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: ● What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients at high risk of developing CAD or in those with established CAD? ● Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? ● Are there antihypertensive drugs that have shown particular efficacy in the primary and secondary prevention of IHD? ● Which antihypertensive drugs should be used in patients who have established CAD with stable or unstable angina pectoris, in those with non–ST-elevation myocardial infarction (NSTEMI), and in those with ST-elevation myocardial infarction (STEMI)?

Background— Prehypertension is common and is associated with increased vascular mortality. The extent to which it increases risk of nonfatal myocardial infarction, stroke, and congestive heart failure is less clear. Methods and Results— We determined the prevalence of prehypertension, its association with other coronary risk factors, and the risk for incident cardiovascular disease events in 60 785 postmenopausal women during 7.7 years of follow-up using Cox regression models that included covariates as time-dependent variables. Prehypertension was present at baseline in 39.5%, 32.1%, 42.6%, 38.7%, and 40.3% of white, black, Hispanic, American Indian, and Asian women, respectively ( P P P =0.71 for interaction), although the numbers of events among Hispanic and Asian women were small. Conclusions— Prehypertension is common and was associated with increased risk of myocardial infarction, stroke, heart failure, and cardiovascular death in white and nonwhite postmenopausal women. Risk factor clustering was conspicuous, emphasizing the need for trials evaluating the efficacy of global cardiovascular risk reduction through primordial prevention.

Fifteen years ago, a panel of experts representing the full spectrum of cardiovascular disease (CVD) research and practice assembled at a workshop to examine the state of knowledge about CVD. The leaders of the workshop generated a hypothesis that framed CVD as a chain of events, initiated by a myriad of related and unrelated risk factors and progressing through numerous physiological pathways and processes to the development of end-stage heart disease (Figure 1). 1 They further hypothesized that intervention anywhere along the chain of events leading to CVD could disrupt the pathophysiological process and confer cardioprotection. The workshop participants endorsed this paradigm but also identified the unresolved issues relating to the concept of a CVD continuum. There was limited availability of clinical trial data and pathobiological evidence at that time, and the experts recognized that critical studies at both the mechanistic level and the clinical level were needed to validate the concept of a chain of events leading to end-stage CVD. In the intervening 15 years, new evidence for underlying pathophysiological mechanisms, the development of novel therapeutic agents, and the release of additional landmark clinical trial data have confirmed the concept of a CVD continuum and reinforced the notion that intervention at any point along this chain can modify CVD progression. In addition, the accumulated evidence indicates that the events leading to disease progression overlap and intertwine and do not always occur as a sequence of discrete, tandem incidents. Furthermore, although the original concept focused on risk factors for coronary artery disease (CAD) and its sequelae, the CVD continuum has expanded to include other areas such as cerebrovascular disease, peripheral vascular disease, and renal disease. Since its conception 15 years ago, the CVD continuum has become much in need of an update. Accordingly, this 2-part article will present a critical and comprehensive update of the current evidence for a CVD continuum based on the results of pathophysiological studies and the outcome of a broad range of clinical trials that have been performed in the past 15 years. It is not the intent of the article to include a comprehensive listing of all trials performed as part of the CVD continuum; instead, we have sought to include only those trials that have had the greatest impact. Part I briefly reviews the current understanding of the pathophysiology of CVD and discusses clinical trial data from risk factors for disease through stable CAD. Part II continues the review of clinical trial data beginning with acute coronary syndromes and continuing through extension of the CVD continuum to stroke and renal disease. The article concludes with a discussion of areas in which future research might further clarify our understanding of the CVD continuum.

Whether certain classes of antihypertensive drugs confer benefits beyond those associated with lowering blood pressure remains a highly controversial issue. Data from several meta-analyses have been used to support the notion that most, if not all, of the cardiovascular benefits reported with the use of different classes of antihypertensive drugs are simply a consequence of the extent to which they lower blood pressure. However, we submit evidence in this review that the diverse pharmacological actions of several antihypertensive medications may have benefits beyond their blood pressure–lowering effects and that, in the case of certain classes of drugs, notably β-blockers, adverse metabolic effects of these drugs may actually mitigate the potential benefits of blood pressure lowering. The early placebo-controlled trials of the treatment of hypertension, several of which were undertaken in high-risk patient populations, provided convincing evidence for substantial reductions in the risk of stroke but little or no evidence for benefits on coronary heart disease (CHD) events.1–6 However, the design, numbers of patients recruited, and event rates in individual trials provided inadequate power to evaluate the impact of treatment on CHD events. In only 1 trial, the Hypertension Detection and Follow-up Programme (HDFP),7 was a reduction in CHD events observed in those assigned “special care” compared with those assigned “usual care.” The conduct of this particular trial, however, differed from the other early trials in that those in the special care group would have been likely to benefit from more comprehensive intervention on other cardiovascular risk factors. In the first meta-analysis of the placebo-controlled trials of antihypertensive drug therapy,8 HDFP was excluded, presumably because the authors of the meta-analysis considered that outcome benefits could have occurred independently of blood pressure reduction. In subsequent meta-analyses, however, for reasons that are unclear, HDFP was included.9 From observational studies …

Background— The definition of a normal heart rate (HR) response to exercise stress testing in women is poorly understood, given that most studies describing a normative response were predominately based on male data. Measures of an attenuated HR response (chronotropic incompetence) and age-predicted HR have not been validated in asymptomatic women. We investigated the association between HR response to exercise testing and age with prognosis in 5437 asymptomatic women. Methods and Results— Participants underwent a symptom-limited maximal stress test in 1992. HR reserve (change in HR from rest to peak), chronotropic index, and age-predicted peak HR were calculated. Deaths were identified to December 31, 2008. Mean age at baseline was 52±11 years, with 549 deaths (10%) over 15.9±2.2 years. Mean peak HR was inversely associated with age; mean peak HR=206–0.88(age). After adjusting for exercise capacity and traditional cardiac risk factors, risk of death was reduced by 3% for every 1–beat-per-minute increase in peak HR, and by 2% for every 1–beat-per-minute increase in HR reserve ( P P P =0.023, respectively). Conclusions— Chronotropic incompetence is associated with an increased risk of death in asymptomatic women; however, the traditional male-based calculation overestimates the maximum HR for age in women. Sex-specific parameters of physiological HR response to exercise should be incorporated into clinical practice.

The mission of many organizations is the optimal care to those with or at risk for developing CVD (primary and secondary prevention). Over the past two decades, there have been dramatic increases in knowledge concerning specific risk factors in atherosclerosis, hypertension, thrombosis, and other forms of vascular dysfunction. Clinical trials have proven that strategies aimed at the appropriate detection and modification of risk factors can slow progression of atherosclerosis, diabetes mellitus, and hypertension and reduce the occurrence of clinical cardiovascular events in both primary and secondary prevention settings. More recently, it has been shown that atherosclerosis can be stabilized or even modestly reversed. Finally, a new and growing knowledge base of molecular genetics applied to the study of the cardiovascular system has potential relevance to the clinical practice of preventive cardiovascular medicine. Despite the fact that clinical outcomes can be improved by promotion of favorable life habits and behaviors and by the proper use of drug treatment, the application of primary and secondary preventive interventions in clinical practice is not optimal. Prevention of CVD in both the primary and secondary prevention setting, while dominantly the responsibility of the primary care provider, is increasingly challenged given this ever expanding new knowledge as well as the ongoing problems related to adherence to recommendations. New knowledge in the area of pre-clinical disease detection has presented increasingly challenging scenarios to primary care healthcare providers relative to the decisions regarding the need for further risk stratification and aggressive medical regimens. Furthermore, increasingly complex patients are surviving with CVD, many of whom can benefit from advanced knowledge and expertise with regard to risk factor management and rehabilitation that is beyond traditional general primary and cardiology practitioner's scope of practice. The prevention of cardiovascular morbidity and mortality is a shared responsibility among all health professionals involved in the care of people at risk of developing cardiovascular disease. This document is directed at those individuals seeking expertise at a leadership level in this field, and includes opportunities for formal training and alternative routes to competence and maintenance of competence in prevention of cardiovascular disease (Table 2), and educational resources for acquisition and maintenance of competence in the prevention of cardiovascular disease (Table 3). To address the expanding fund of knowledge in the area and to ensure that an adequately trained force of preventive cardiovascular leaders will be available to primary care providers, as well as provide a pool of providers with expertise in running rehabilitation and other programs designed to address the ongoing issue of adherence, the formulation of clinical competency criteria for the cardiovascular preventive specialist is needed. These competency criteria are expected to address issues of expert clinical and scientific leadership, specialty patient care and consultation, and directorship of primary and secondary preventive cardiac programs. Of note and similar to other subspecialty areas of medicine, cardiovascular preventive specialists will have varying areas of expertise and will not necessarily achieve all the outlined areas of competencies. These clinical competency criteria in the area of specialty treatment and prevention of CVD are needed given the current setting of a rapidly growing field of knowledge ranging from molecular and cellular mechanisms to clinical outcomes in order to translate into improved patient care. Table 2 Opportunities for Formal Training and Alternative Routes to Competence and Maintenance of Competence in Prevention of Cardiovascular Disease Table 3 Educational Resources for Acquisition and Maintenance of Competence in the Prevention of Cardiovascular Disease C. Noel Bairey Merz, MD, FACC, FAHA Chair, ACCF/AHA/ACP Clinical Competence Statement on Prevention of CVD

This is the second part of a 2-part article that presents a critical and comprehensive update of the current evidence for a cardiovascular disease (CVD) continuum based on the results of pathophysiological studies and the outcome of a broad range of clinical trials that have been performed in the past 15 years. In part I, we reviewed the current understanding of CVD pathophysiology and discussed data from clinical trials on subjects ranging from risk factors for disease through stable coronary artery disease (CAD). The present article continues the review of clinical trials, beginning with acute coronary syndromes (ACS) and continuing through extension of the concept of the CVD continuum to include stroke and renal disease. The article concludes with a discussion of areas in which future research might further clarify our understanding of the CVD continuum. ACS represent a spectrum of events ranging from unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) to ST-segment elevation myocardial infarction (STEMI). ACS events are frequently the consequence of thrombotic occlusion of a coronary artery. Intervention at this point in the CVD continuum clearly interrupts disease progression by preventing cardiac muscle death, decreasing the risk of a recurrent ischemic event, slowing progression to heart failure, and reducing mortality. Patients presenting with an ACS must receive prompt treatment to prevent ischemic complications; optimal management includes anti-ischemic therapy (eg, supplemental oxygen, nitroglycerin, and β-blocker), antiplatelet agents (eg, aspirin, clopidogrel, or platelet glycoprotein [GP] IIb/IIIa inhibitor), antithrombotic therapy (unfractionated heparin, low-molecular-weight heparin [LMWH]), and the use of invasive reperfusion procedures (ie, percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]). For STEMI patients, optimal therapy also includes fibrinolytic agents to restore blood flow in the occluded coronary artery. ### Treatment of UA/NSTEMI UA and NSTEMI are considered closely related conditions and may be indistinguishable in their early stages in …

Background— Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. Methods and Results— We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives ≥55 years of age with ≥1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata. Conclusions— ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response.

Background— Cardiovascular disease is the leading cause of death among women and accounts for more than half of their deaths. Women have been underrepresented in most studies of cardiovascular disease. Reduced physical fitness has been shown to increase the risk of death in men. Exercise capacity measured by exercise stress test is an objective measure of physical fitness. The hypothesis that reduced exercise capacity is associated with an increased risk of death was investigated in a cohort of 5721 asymptomatic women who underwent baseline examinations in 1992. Methods and Results— Information collected at baseline included medical and family history, demographic characteristics, physical examination, and symptom-limited stress ECG, using the Bruce protocol. Exercise capacity was measured in metabolic equivalents (MET). Nonfasting blood was analyzed at baseline. A National Death Index search was performed to identify all-cause death and date of death up to the end of 2000. The mean age of participants at baseline was 52±11 years. Framingham Risk Score–adjusted hazards ratios (with 95% CI) of death associated with MET levels of 8 were 3.1 (2.0 to 4.7), 1.9 (1.3 to 2.9), and 1.00, respectively. The Framingham Risk Score–adjusted mortality risk decreased by 17% for every 1-MET increase. Conclusions— This is the largest cohort of asymptomatic women studied in this context over the longest period of follow-up. This study confirms that exercise capacity is an independent predictor of death in asymptomatic women, greater than what has been previously established among men. The implications for clinical practice and health care policy are far reaching.