Frans H. H. Leenen

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trials recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Results of the Ontario Survey on the Prevalence and Control of Hypertension

Background: Available information on the prevalence and management of hypertension in the Canadian population dates back to 1986–1992 and probably does not reflect the current status of this major risk factor for cardiovascular disease. We sought to evaluate the current prevalence and management of hypertension among adults in the province of Ontario. Methods: Potential respondents from randomly selected dwellings within target neighbourhoods in 16 municipalities were contacted at their homes to request participation in the study. For potential respondents who agreed to participate, blood pressure was measured with an automated device. Estimation weights were used to obtain representative estimates of population parameters. Responses were weighted to the total adult population in Ontario of 7 996 653. Results: From 6436 eligible dwellings, contact was made with 4559 potential participants, of whom 2992 agreed to participate. Blood pressure measurements were obtained for 2551 of these respondents (age 20–79 years). Hypertension, defined as systolic blood pressure of 140 mm Hg or more, diastolic blood pressure of 90 mm Hg or more, or treatment with an antihypertensive medication, was identified in 21.3% of the population overall (23.8% of men and 19.0% of women). Prevalence increased with age, from 3.4% among participants 20–39 years of age to 51.6% among those 60–79 years of age. Hypertension was more common among black people and people of South Asian background than among white people; hypertension was also associated with higher body mass index. Among participants with hypertension, 65.7% were undergoing treatment with control of hypertension, 14.7% were undergoing treatment but the hypertension was not controlled, and 19.5% were not receiving any treatment (including 13.7% who were unaware of their hypertension). The extent of control of hypertension did not differ significantly by age, sex, ethnic background or comorbidities. Interpretation: In Ontario, the overall prevalence of hypertension is high in the older population but appears not to have increased in recent decades. Hypertension management has improved markedly among all age groups and for both sexes.

Changes in the rates of awareness, treatment and control of hypertension in Canada over the past two decades.

Background Analyses of medication databases indicate marked increases in prescribing of antihypertensive drugs in Canada over the past decade. This study was done to examine the trends in the prevalence of hypertension and in control rates in Canada between 1992 and 2009. Methods Three population-based surveys, the 1986–1992 Canadian Heart Health Surveys, the 2006 Ontario Survey on the Prevalence and Control of Hypertension and the 2007–2009 Canadian Health Measures Survey, collected self-reported health information from, and measured blood pressure among, community-dwelling adults. Results The population prevalence of hypertension was stable between 1992 and 2009 at 19.7%–21.6%. Hypertension control improved from 13.2% (95% confidence interval [CI] 10.7%–15.7%) in 1992 to 64.6% (95% CI 60.0%–69.2%) in 2009, reflecting improvements in awareness (from 56.9% [95% CI 53.1%–60.5%] in 1992 to 82.5% [95% CI 78.5%–86.0%] in 2009) and treatment (from 34.6% [95% CI 29.2%–40.0%] in 1992 to 79.0% [95% CI 71.3%–86.7%] in 2009) among people with hypertension. The size of improvements in awareness, treatment and control were similar among people who had or did not have cardiovascular comorbidities Although systolic blood pressures among patients with untreated hypertension were similar between 1992 and 2009 (ranging from 146 [95% CI 145–147] mm Hg to 148 [95% CI 144–151] mm Hg), people who did not have hypertension and patients with hypertension that was being treated showed substantially lower systolic pressures in 2009 than in 1992 (113 [95% CI 112–114] v. 117 [95% CI 117–117] mm Hg and 128 [95% CI 126–130] v. 145 [95% CI 143–147] mm Hg). Interpretation The prevalence of hypertension has remained stable among community-dwelling adults in Canada over the past two decades, but the rates for treatment and control of hypertension have improved markedly during this time.

How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.

Clinical Events in High-Risk Hypertensive Patients Randomly Assigned to Calcium Channel Blocker Versus Angiotensin-Converting Enzyme Inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker–initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

Role of Diuretics in the Prevention of Heart Failure The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Background— Hypertension is a major cause of heart failure (HF) and is antecedent in 91% of cases. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) stipulated assessment of the relative effect of chlorthalidone, lisinopril, and amlodipine in preventing HF. Methods and Results— ALLHAT was a double-blind, randomized, clinical trial in 33 357 high-risk hypertensive patients aged ≥55 years. Hospitalized/fatal HF outcomes were examined with proportional-hazards models. Relative risks (95% confidence intervals; P values) of amlodipine or lisinopril versus chlorthalidone were 1.35 (1.21 to 1.50; <0.001) and 1.11 (0.99 to 1.24; 0.09). The proportional hazards assumption of constant relative risk over time was not valid. A more appropriate model showed relative risks of amlodipine or lisinopril versus chlorthalidone during year 1 were 2.22 (1.69 to 2.91; <0.001) and 2.08 (1.58 to 2.74; <0.001), and after year 1, 1.22 (1.08 to 1.38; P=0.001) and 0.96 (0.85 to 1.10; 0.58). There was no significant interaction between prior medication use and treatment. Baseline blood pressures were equivalent (146/84 mm Hg) and at year 1 were 137/79, 139/79, and 140/80 mm Hg in those given chlorthalidone, amlodipine, and lisinopril. At 1 year, use of added open-label atenolol, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers in the treatment groups was similar. Conclusions— HF risk decreased with chlorthalidone versus amlodipine or lisinopril use during year 1. Subsequently, risk for those individuals taking chlorthalidone versus amlodipine remained decreased but less so, whereas it was equivalent to those given lisinopril. Prior medication use, follow-up blood pressures, and concomitant medications are unlikely to explain most of the HF differences. Diuretics are superior to calcium channel blockers and, at least in the short term, angiotensin-converting enzyme inhibitors in preventing HF in hypertensive individuals.

The renin-angiotensin system and volume overload-induced cardiac hypertrophy in rats. Effects of angiotensin converting enzyme inhibitor versus angiotensin II receptor blocker.

BackgroundThe degree of cardiac hypertrophy is not only load dependent: Among other factors, the renin-angiotensin system may play a role in the regulation of cardiac myocyte growth. Methods and ResultsTo evaluate the role of the renin-angiotensin system in volume overload-induced cardiac hypertrophy, we assessed 1) the time course of changes in cardiac hemodynamics, cardiac anatomy, and plasma and cardiac renin activity in response to volume overload induced by two sizes abdominal aortocaval shunt and 2) the effects of chronic treatment with an angiotensin converting enzyme inhibitor (ACEI) versus an angiotensin H receptor blocker on hemodynamics and cardiac hypertrophy. Drug treatment started 3 days before shunt surgery. An increase in left ventricular end-diastolic pressure (LVEDP) and the development of right ventricular (RV) and left ventricular (LV) eccentric hypertrophy in response to volume overload occurred within the first week after induction of the shunt. Plasma renin activity (PRA) and cardiac renin activity peaked shortly after induction of the shunt. During the chronic phase, LVEDP and PRA decreased somewhat but remained significantly elevated up to 7 weeks after shunt surgery. Cardiac renin activity returned toward normal within 4 weeks after surgery. Treatment with the ACEI enalapril caused only a modest decrease in LV internal diameter but did not affect increases in LV and RV weights in response to volume overload despite a major decrease in LVEDP after chronic treatment. In contrast, treatment with the angiotensin II receptor blocker losartan, which had similar effects on cardiac and peripheral hemodynamics, prevented dilation of the LV after 7 days and attenuated the dilation of the LV after 28 days. Moreover, increases in LV and RV weights were significantly attenuated by losartan. ConclusionsThe development of volume overload-induced cardiac hypertrophy is associated with significant increases in PRA and cardiac renin activity shortly after induction of an aortocaval shunt. Whereas the two blockers of the renin-angiotensin system decreased LVEDP to a similar extent, only the angiotensin II receptor blocker blunted the hypertrophic response of the heart to volume overload, which is indicative for other than hemodynamic determinants of the cardiac hypertrophic response. One trophic factor may be cardiac angiotensin H generated via an angiotensin lI-forming enzyme resistant to ACEI and possibly activated by cardiac volume overload.

Prevention of Sympathetic and Cardiac Dysfunction After Myocardial Infarction in Transgenic Rats Deficient in Brain Angiotensinogen

Abstract— To provide evidence for the role of angiotensin II locally produced in the brain in the development of sympathetic hyperactivity and heart failure after myocardial infarction (MI), transgenic rats (TGR) were used, which express an antisense RNA against angiotensinogen. In TGR and control Sprague-Dawley (SD) rats, an MI was induced by acute coronary artery ligation. At 8 weeks after MI, MI sizes were similar in TGR and SD rats. In the groups with MI ≥25% of left ventricle (LV), LV peak systolic pressure decreased in SD rats but not in TGR. LV end-diastolic pressure increased substantially more in SD-MI than TGR-MI rats (from 2±1 to 15±2 mm Hg, and 2±1 to 8±1 mm Hg, respectively; P <0.05). LV dP/dtmax decreased from ≈5400 to 3573±187 in SD-MI rats, but only to 4353±180 mm Hg/sec in TGR-MI (P <0.05). LV pressure volume curves in vitro showed a marked shift to the right in SD-MI rats. This shift was significantly attenuated by −70% in TGR versus SD rats with MI. Both RV weight and interstitial fibrosis in the LV increased clearly in the SD-MI rats, but not or significantly less in the TGR-MI rats. In SD-MI rats, arterial baroreflex control of heart rate and renal sympathetic nerve activity was markedly impaired but was not affected in the TGR-MI. Plasma angiotensin II levels tended to be higher in SD versus TGR rats, both in sham and MI-groups. This study provides the major new finding that in rats after MI, angiotensin II locally produced in the brain plays a dominant role in the development of LV dysfunction after MI, possibly through its effects on sympathetic function and on circulatory/cardiac renin-angiotensin system.

Brain Ouabain mediates the sympathoexcitatory and hypertensive effects of high sodium intake in Dahl salt-sensitive rats

To assess whether brain ouabain-like activity (OLA) mediates the hypertensive effects of high sodium intake in Dahl salt-sensitive (Dahl S) rats, the effects of blockade of brain OLA on mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were evaluated in conscious Dahl salt-resistant (Dahl R) and Dahl S rats on a regular (120 mumol/g) or high sodium (1370 mumol/g) diet from 4 to 7 weeks of age. Dahl S rats given high sodium showed higher basal MAP and augmented responses of MAP and RSNA to air stress and to intracerebroventricular injection of the alpha 2-adrenergic receptor agonist guanabenz as compared with Dahl R rats or Dahl S rats given regular sodium. In contrast, the sympathoexcitatory and pressor responses to intracerebroventricular injection of ouabain (0.3 and 1.0 microgram) were markedly attenuated in Dahl S rats given high sodium. Intracerebroventricular preinjection of 0.3 microgram ouabain significantly enhanced blood pressure and RSNA responses to air stress and intracerebroventricular guanabenz in Dahl S rats given regular sodium to the levels observed in Dahl S rats given high sodium. Intracerebroventricular digoxin-specific antibody Fab (DAF) fragments (132 micrograms/8 microL for 5 minutes) did not change basal MAP and RSNA during the first 4 hours after administration in Dahl S rats on a high sodium diet for 3 weeks. However, 18 hours after the injection of DAF fragments, basal MAP and RSNA were significantly decreased, reaching values for Dahl S rats on a regular sodium diet. The magnitude of increases or decreases in MAP and RSNA to air stress or intracerebroventricular guanabenz were significantly attenuated by the DAF fragments in Dahl S rats on a high sodium but not regular sodium diet. Concomitant intracerebroventricular infusion of DAF fragments (200 micrograms per day) prevented the development of hypertension after a high sodium diet in Dahl S rats and prevented an augmentation in pressor and sympathoexcitatory responses to air stress. After discontinuing the infusion of DAF fragments, resting MAP gradually increased to the high levels found in Dahl S rats given high sodium treated with gamma-globulins. These results support the concept that high sodium intake may cause hypertension in Dahl S rats by increasing endogenous brain OLA, thereby enhancing sympathetic outflow and basal blood pressure as well as sympathoexcitatory and pressor responses to stress.

Effects of ACE Inhibitors on Circulating Versus Cardiac Angiotensin II in Volume OverloadInduced Cardiac Hypertrophy in Rats

BACKGROUND Cardiac volume overload by an aortocaval shunt increases left ventricular end-diastolic pressure (LVEDP) and plasma and cardiac renin activity and results in LV hypertrophy. To a similar extent, the angiotensin-converting enzyme (ACE) inhibitors enalapril and quinapril prevent the increase in LVEDP. However, only quinapril attenuates the development of LV hypertrophy. We hypothesize that a low affinity of enalapril for cardiac ACE results in continuing generation of cardiac angiotensin II and thus hypertrophic growth of cardiomyocytes. METHODS AND RESULTS In the present study, we assessed plasma and cardiac angiotensins I and II 1 and 7 days after aortocaval shunt and the effects of enalapril and quinapril started 3 days before surgery on plasma and cardiac angiotensin I and II at the same time points. Aortocaval shunt increased plasma angiotensin II at 1 day by 180%, but only a small increase (by 40%) persisted at 7 days. Aortocaval shunt increased LV angiotensin II by 100% and 65% at 1 and 7 days, respectively. Both blockers similarly prevented the increase in plasma angiotensin II by aortocaval shunt at both time points. In contrast, only quinapril prevented the rise in LV angiotensin II induced by shunt at 1 and 7 days. CONCLUSIONS Aortocaval shunt increases LVEDP and plasma and cardiac angiotensin II and results in LV hypertrophy. Only prevention of the increase in LVEDP and in plasma and cardiac angiotensin II attenuates the development of LV hypertrophy, consistent with the concept that angiotensin II is involved in the development of cardiac hypertrophy by aortocaval shunt by both hemodynamic and cardiac trophic effects. This study is the first to show that differences in affinity for cardiac ACE may determine the effect of ACE inhibitors on cardiac angiotensin II and therefore cardiac hypertrophy.