John M. Flack

Prevalence of Hypertrophic Cardiomyopathy in a General Population of Young Adults Echocardiographic Analysis of 4111 Subjects in the CARDIA Study

BACKGROUND Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes. At present, however, few data exist to estimate the prevalence of this disease in large populations. METHODS AND RESULTS As part of the Coronary Artery Risk Development in (Young) Adults (CARDIA) Study, an epidemiological study of coronary risk factors, 4111 men and women 23 to 35 years of age selected from the general population of four urban centers had technically satisfactory echocardiographic studies during 1987 through 1988. Probable or definite echocardiographic evidence of HCM was present in 7 subjects (0.17%) on the basis of identification of a hypertrophied, nondilated left ventricle and maximal wall thickness > or = 15 mm that were not associated with systemic hypertension. Prevalence in men and women was 0.26:0.09%; in blacks and whites, 0.24:0.10%. Ventricular septal thickness was 15 to 21 mm (mean, 17 mm) in the 7 subjects. Only 1 of the 7 subjects had ever experienced important cardiac symptoms attributable to HCM, had previously been suspected of having cardiovascular disease, or had obstruction to left ventricular outflow; 4 other subjects had relatively mild systolic anterior motion of the mitral valve that was insufficient to produce dynamic basal outflow obstruction. ECGs were abnormal in 5 of the 7 subjects. Five other study subjects had left ventricular wall thicknesses of 15 to 21 mm that were a consequence of systemic hypertension. CONCLUSIONS HCM was present in about 2 of 1000 young adults. These unique population-based data will aid in assessments of the impact of HCM-related mortality and morbidity in the general population and the practicality of screening large populations for HCM, including those comprising competitive athletes.

Human blood pressure determination by sphygmomanometry.

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A controlled trial of renal denervation for resistant hypertension.

BACKGROUND Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension. METHODS We designed a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. RESULTS A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was -6.75±15.11 mm Hg in the denervation group and -4.79±17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95% CI, -4.97 to 1.06; P=0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. CONCLUSIONS This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.).

Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension.

Clinical Practice Guidelines for the Management of Hypertension in the Community A Statement by the American Society of Hypertension and the International Society of Hypertension

Long-term Effects on Sexual Function of Five Antihypertensive Drugs and Nutritional Hygienic Treatment in Hypertensive Men and Women: Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension.

Michael A. Weber, MD; Ernesto L. Schiffrin, MD; William B. White, MD; Samuel Mann, MD; Lars H. Lindholm, MD; John G. Kenerson, MD; John M. Flack, MD; Barry L. Carter, Pharm D; Barry J. Materson, MD; C. Venkata S. Ram, MD; Debbie L. Cohen, MD; Jean-Claude Cadet, MD; Roger R. Jean-Charles, MD; Sandra Taler, MD; David Kountz, MD; Raymond R. Townsend, MD; John Chalmers, MD; Agustin J. Ramirez, MD; George L. Bakris, MD; Jiguang Wang, MD; Aletta E. Schutte, MD; John D. Bisognano, MD; Rhian M. Touyz, MD; Dominic Sica, MD; Stephen B. Harrap, MD

Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A Mendelian Randomization Analysis

OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). BACKGROUND LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. RESULTS All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)). CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Relationship of Cardiovascular Risk Factors to Echocardiographic Left Ventricular Mass in Healthy Young Black and White Adult Men and Women: The CARDIA Study

BACKGROUND The objective of this study was to describe the distribution of echo left ventricular (LV) mass and its association with demographic and cardiovascular risk factors in a large race- and sex-balanced cohort of young adults. Recent epidemiological data have suggested that M-mode echocardiographically determined LV hypertrophy is an independent predictor of mortality and morbidity from coronary heart disease (CHD) in older adults. Echocardiographic LV mass has been associated in middle-aged and older adults with multiple factors including age, arterial blood pressure, body mass, and sex. However, there are few data describing the distribution of echo LV mass among black and white young adult men and women and relating LV mass to cardiovascular disease risk factors within race-sex subgroups. METHODS AND RESULTS CARDIA (Coronary Artery Risk Development in Young Adults) is a multicenter study of young adults, including approximately equal proportions of black and white men and women aged 23 to 35 years at the time of echo examination (1990 through 1991). Two-dimensionally guided M-mode echocardiograms were attempted in 4243 participants with recordings deemed acceptable for calculation of LV mass, that is, of at least fair quality score, obtained in 3840 (90.5% of the 1990-1991 cohort). M-mode LV mass was calculated from the formula of Devereux and Reicheck, adapted for use with measurements made according to the American Society of Echocardiography Standards. LV mass was greater in men than in women and greater in blacks than in whites (P < .001) (mean +/- SD): black men, 176 +/- 42 g; white men, 169 +/- 40 g; black women, 135 +/- 38 g; and white women, 125 +/- 33 g. In all race-sex groups, LV mass was positively correlated (P < .0001) in bivariate analyses with body weight, subcapular skinfold thickness, height, and systolic blood pressure. In multivariate analyses, LV mass remained independently and positively related to body weight and systolic blood pressure and, when body weight was not considered, with subcapular skinfold thickness and height. In addition, the multivariate models allowed us to infer a direct relation between LV mass and both fatness and lean body mass. Weaker positive associations were noted of LV mass with pulse pressure in white participants and with physical activity in men. After adjustment for subscapular skinfold thickness, height, systolic and diastolic blood pressures, alcohol consumption, pulmonary function, smoking history, physical activity, total serum cholesterol, and family history of hypertension, LV mass remained higher in men than in women (P < .0001), in black men (167 +/- 43 g) than in white men (156 +/- 50 g, P < .0001), and in black women (142 +/- 49 g) than in white women (137 +/- 43 g, P < .002). CONCLUSIONS In the healthy young adults of the CARDIA cohort, LV mass was highly correlated with body weight, subscapular skinfold thickness, height, and systolic blood pressure across race and sex subgroups. Furthermore, after adjustment for anthropometric, blood pressure, and other covariates, LV mass remained higher in men than in women and in blacks than in whites. Longitudinal studies are necessary to delineate the possible roles of these factors in the genesis of LV hypertrophy.

Predictors of blood pressure response in the SYMPLICITY HTN-3 trial

AIMS The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results. METHODS AND RESULTS Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥ 180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; -15.2 ± 23.5 vs. -8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern. CONCLUSIONS Post hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension. CLINICALTRIALS.GOV IDENTIFIER: NCT01418261.

Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial.

Hypertension represents a significant global public health concern, contributing to vascular and renal morbidity, cardiovascular mortality, and economic burden. The opportunity to influence clinical outcomes through hypertension management is therefore paramount. Despite adherence to multiple available medical therapies, a significant proportion of patients have persistent blood pressure elevation, a condition termed resistant hypertension. Recent recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure that selectively removes these contributors to resistant hypertension represents an opportunity to provide clinically meaningful benefit across wide and varied patient populations. Early clinical evaluation with catheter‐based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN‐3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single‐blind trial evaluating the safety and effectiveness of catheter‐based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is measured as the change in office‐based systolic blood pressure from baseline to 6 months. This manuscript describes the design and methodology of a regulatory trial of selective renal denervation for the treatment of hypertension among patients who have failed pharmacologic therapy. Clin. Cardiol. 2012. doi: 10.1002/clc.22008