Determinants Of Cardiovascular Disease Risk Research Articles

Physical activity parameters as determinants of cardiovascular disease risk in kidney transplant recipients: an accelerometer-based study

Physical activity parameters as determinants of cardiovascular disease risk in kidney transplant recipients: an accelerometer-based study

The heart of Detroit study: a window into urban middle-aged and older African Americans’ daily lives to understand psychosocial determinants of cardiovascular disease risk

BackgroundCardiovascular disease disproportionately affects African Americans. Psychosocial factors, including the experience of and emotional reactivity to racism and interpersonal stressors, contribute to the etiology and progression of cardiovascular disease through effects on health behaviors, stress-responsive neuroendocrine axes, and immune processes. The full pathway and complexities of these associations remain underexamined in African Americans. The Heart of Detroit Study aims to identify and model the biopsychosocial pathways that influence cardiovascular disease risk in a sample of urban middle-aged and older African American adults.MethodsThe proposed sample will be composed of 500 African American adults between the ages of 55 and 75 from the Detroit urban area. This longitudinal study will consist of two waves of data collection, two years apart. Biomarkers of stress, inflammation, and cardiovascular surrogate endpoints (i.e., heart rate variability and blood pressure) will be collected at each wave. Ecological momentary assessments will characterize momentary and daily experiences of stress, affect, and health behaviors during the first wave. A proposed subsample of 60 individuals will also complete an in-depth qualitative interview to contextualize quantitative results. The central hypothesis of this project is that interpersonal stressors predict poor cardiovascular outcomes, cumulative physiological stress, poor sleep, and inflammation by altering daily affect, daily health behaviors, and daily physiological stress.DiscussionThis study will provide insight into the biopsychosocial pathways through which experiences of stress and discrimination increase cardiovascular disease risk over micro and macro time scales among urban African American adults. Its discoveries will guide the design of future contextualized, time-sensitive, and culturally tailored behavioral interventions to reduce racial disparities in cardiovascular disease risk.

Abstract 13588: Association of Longitudinal Trajectories of Branched Chain Amino Acids Through Young Adulthood With Diabetes in Later Life: The CARDIA Study

Introduction: Branched chain amino acids (BCAA), measured at a single timepoint in midlife, are directly associated with risk for incident type 2 diabetes mellitus (DM), a strong determinant of cardiovascular disease risk. However, the trajectories (traj) of BCAAs through young adulthood and their associations with DM in midlife are unknown. Methods: We used NMR spectroscopy to measure serum BCAA levels from up to 3,081 Coronary Artery Risk Development in Young Adults (CARDIA) participants who attended the Year(Y) 2, 7, 15, 20, and 30 exams. We used latent class modeling to generate BCAA traj groups. To quantify associations between BCAA traj and prevalent DM* at the Y30 exam, we excluded participants with DM at Y2, and modeled traj groups from Y2 to Y30. To quantify associations between BCAA traj and incident DM by the Y30 exam, we excluded participants who developed DM by the Y20 exam and modeled traj from Y2 to Y20. We used adjusted** logistic regression to quantify the associations between traj group and prevalent and incident DM (at Y30), separately. Results: Among 3,081 participants (mean age at Y2: 27y), there were 3 BCAA traj groups: 1,427 participants in the low-stable group, 1,384 in the moderate-stable group, and 270 in the high-increasing group. Male sex, Black race, and higher body mass index were more common in the higher BCAA traj groups. Compared with the low-stable BCAA traj group (reference), the moderate-stable and high-increasing BCAA traj groups were associated with prevalent DM at Y30 (OR [95 th CI]: moderate-stable, 2.59 [1.90-3.55]; high-increasing, 6.03 [3.86-9.43]). Moderate-stable and high-increasing traj groups were associated with incident DM at Y30 (OR [95 th CI]: moderate-stable, 1.56 [1.02-2.39]; high-increasing, 2.20 [1.25-3.87]; low-stable, reference). Conclusions: BCAA levels track, on average, over a 28-year span in most young adults, but serial measurements identify subpopulations with rising levels and high risk of DM in later life.

Central Versus Peripheral Artery Stiffening and Cardiovascular Risk.

The large elastic arteries fulfill an important role in buffering the cyclical changes in blood pressure, which result from intermittent ventricular ejection. With aging and accrual of cardiovascular risk factors, the elastic arteries stiffen, and this process holds a number of deleterious consequences for the cardiovascular system and major organs. Indeed, arterial stiffness is now recognized as an important, independent determinant of cardiovascular disease risk. Additional, important information concerning the mechanisms underlying arterial stiffening has come from longitudinal studies of arterial stiffness. More recently, attention has focused on the role of peripheral, muscular arteries in cardiovascular disease risk prediction and, in particular, the clinical consequences of reversal of the normal gradient of arterial stiffness between central and peripheral arteries, with aging and disease.

Childhood Adversities as Determinants of Cardiovascular Disease Risk and Perceived Illness Burden in Adulthood: Comparing Retrospective and Prospective Self-Report Measures in a Longitudinal Sample of African Americans.

A large body of evidence suggests that exposure to childhood adversities increases risk for poor quality physical health in adulthood. Much of this evidence is based on retrospective measures which are believed to be contaminated by the limitations and biases of autobiographical memory. Using longitudinal data on 454 African Americans (61 percent female) this study examines the corroboration between prospective and retrospective measures of childhood adversities gathered approximately two decades apart, and the relative ability of the measures to predict self-reported illnesses and a biomarker of 30-year cardiovascular disease risk. Comparisons indicated that the retrospective and prospective measures demonstrated weak convergence and did not provide completely equivalent information about self-reported adverse childhood experiences. A series of regression models indicated that the two measures of adversities exhibited similar associations with the cardiovascular disease biomarker but divergent associations with self-reported illnesses. Furthermore, both the prospective and retrospective measures simultaneously predicted cardiovascular disease risk in adulthood. That the prospective measure did not significantly predict perceived illnesses after adjusting for the retrospective measure is evidence that childhood adversities predict self-reported health burden insofar as respondents remember those adversities as adults. The findings provide evidence that retrospective self-report measures of childhood adversities do not closely converge with prospective measures, and that retrospective measures may not provide valid estimates of the association between childhood adversities and perceived illnesses in adulthood.

Associations Between Objective Sleep and Ambulatory Blood Pressure in a Community Sample.

Epidemiologic data increasingly support sleep as a determinant of cardiovascular disease risk. Fewer studies have investigated the mechanisms underlying this relationship using objective sleep assessment approaches. Therefore, the aim of this study was to examine associations between daily blood pressure (BP) and both objectively assessed sleep duration and efficiency. A diverse community sample of 300 men and women aged 21 to 70 years, enrolled in the North Texas Heart Study, participated in the study. Actigraphy-assessed sleep was monitored for two consecutive nights with ambulatory BP sampled randomly within 45-minute blocks on the first and second day as well as the second night. Overall, sleep duration results paralleled those of sleep efficiency. Individuals with lower sleep efficiency had higher daytime systolic (B = -0.35, SE = 0.11, p = .0018, R = 0.26) but not diastolic BP (B = -0.043, SE = 0.068, p = .52, R = 0.17) and higher nighttime BP (systolic: B = -0.37, SE = 0.10, p < .001, R = .15; diastolic: B = -0.20, SE = 0.059, p < .001, R = .14). Moreover, lower sleep efficiency on one night was associated with higher systolic (B = -0.51, SE = 0.11, p < .001, R = 0.23) and diastolic BP (B = -0.17, SE = 0.065, p = .012, R = .16) the following day. When 'asleep' BP was taken into account instead of nighttime BP, the associations between sleep and BP disappeared. When both sleep duration and efficiency were assessed together, sleep efficiency was associated with daytime systolic BP, whereas sleep duration was associated with nighttime BP. Lower sleep duration and efficiency are associated with higher daytime systolic BP and higher nighttime BP when assessed separately. When assessed together, sleep duration and efficiency diverge in their associations with BP at different times of day. These results warrant further investigation of these possible pathways to disease.

Dietary intakes and prevalence of overweight/obesity in male non-dysvascular lower limb amputees.

Lower limb amputees are at higher risk of cardiovascular disease compared to non-amputees. Dietary intake, a major determinant of cardiovascular disease risk, has not previously been studied in this group. The aim of this study was to investigate dietary intakes and prevalence of overweight/obesity in adult lower limb amputees. A cross-sectional survey was used to investigate the dietary intake and prevalence of overweight/obesity in adults with lower limb amputations living in the United Kingdom. Dietary intakes of male adult lower limb amputees ( n = 46, non-dysvascular) were assessed using food frequency questionnaires and results were compared to dietary reference values in the United Kingdom. Prevalence of overweight/obesity was assessed through body mass index and waist-to-hip ratio and compared to the general population according to the Health Survey for England 2011. Dietary intake risk factors for cardiovascular disease such as sugars (22.01%), total fat (34.87%), saturated fat (12.72%) and sodium (2660.10 mg/day) were significantly higher ( p < 0.001, p < 0.001, p = 0.043, p < 0.001; p < 0.001; respectively) than the dietary reference values. A high prevalence (82.8%) of overweight/obesity was found with a significantly higher body mass index and waist-to-hip ratio ( p = 0.027; p = 0.001; respectively) compared to the Health Survey for England 2011. High intakes of sugars, dietary fats, sugars and salts, combined with high prevalence of overweight/obesity observed in lower limb amputees are concerning. These findings suggest that greater emphasis on dietary intakes should be considered for rehabilitation programmes. Findings highlight poor dietary habits in lower limb amputees with respect to fat, sugar and salt intake, also high levels of overweight/obesity. Considering greater emphasis on dietary intake and including lifestyle changing interventions in rehabilitation programmes for lower limb amputees may lower the risk of obesity and CVD.

Ethnicity and arterial stiffness in children and adolescents from a Brazilian population

Increased stiffness of large arteries is an important determinant of cardiovascular disease risk. Higher values of arterial stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) have been measured in adult African-Americans compared with whites. Studies assessing ethnic differences in cf-PWV among children and adolescents are scarce. This study sought to evaluate the association between ethnicity and cf-PWV in Brazilian children and adolescents. Seven hundred and seventy-one children and adolescents (211 blacks and 560 nonblacks, 11.3 ± 2.7 years) were included. Arterial stiffness was evaluated by cf-PWV. The ethnic classification was obtained by a single interviewer according to general phenotypes such as skin color, hair shape and facial traces. Blood pressure was similar in blacks and nonblacks across all pubertal stages. Differently, cf-PWV was higher in blacks than nonblacks pubescent (5.9 ± 0.7 vs. 5.6 ± 0.8 m/s, P = 0.001) and postpubescent (6.1 ± 0.7 vs. 5.7 ± 0.7 m/s, P = 0.042), whereas no difference was detected between blacks and nonblacks prepubescent. These analyses were adjusted for sex, age, height, BMI, SBP and heart rate. Our study showed that higher cf-PWV values in blacks appear in adolescence and are independent of blood pressure values. Therefore, our data suggest adolescence as the key phase for the appearance of the vascular profile found in adults black individuals.

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans.

Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis. Cholesterol metabolism and carotid intima-media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d5 and the nonabsorbable stool marker sitostanol-d4. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima-media thickness was negatively correlated with fecal excretion of endogenous cholesterol (r=-0.426; P<0.0001), total cholesterol (r=-0.472; P≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (r=-0.343; P=0.0012) and was positively correlated with percent cholesterol absorption (r=+0.279; P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008). Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima-media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.

Evaluating the longitudinal risk of social vigilance on atherosclerosis: study protocol for the North Texas Heart Study

IntroductionPsychosocial factors are increasingly recognised as important determinants of cardiovascular disease risk. The North Texas Heart Study aims to understand the mechanisms responsible for this association with a focus on...

Early life programming and the risk of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease and can be considered the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of disease, from the relatively benign simple steatosis to the more serious non-alcoholic steatohepatitis, which can progress to liver cirrhosis, hepatocellular carcinoma and end-stage liver failure, necessitating liver transplantation. Although the increasing prevalence of NAFLD in developed countries has substantial implications for public health, many of the precise mechanisms accounting for the development and progression of NAFLD are unclear. The environment in early life is an important determinant of cardiovascular disease risk in later life and studies suggest this also extends to NAFLD. Here we review data from animal models and human studies which suggest that fetal and early life exposure to maternal under- and overnutrition, excess glucocorticoids and environmental pollutants may confer an increased susceptibility to NAFLD development and progression in offspring and that such effects may be sex-specific. We also consider studies aimed at identifying potential dietary and pharmacological interventions aimed at reducing this risk. We suggest that further human epidemiological studies are needed to ensure that data from animal models are relevant to human health.

Heritability of arterial stiffness in a Brazilian population: Baependi Heart Study.

Increased arterial stiffness is an important determinant of cardiovascular disease risk. In addition, it has been recognized that arterial stiffness has familial aggregation; however, there are no studies involving Brazilian families. Thus, the aim of this study was to evaluate the heritability of arterial stiffness in a Brazilian population. In this study, 1675 eligible individuals (both sexes and aged 18-102 years) were distributed in 125 families resident in the municipality of Baependi, a city located in the southeast of Brazil. Carotid-femoral pulse wave velocity (PWV) was measured with a noninvasive automatic device (Complior; Artech Medical, Pantin, France). Variance component approaches, implemented in the SOLAR computer package (San Antonio, Texas, USA), were applied to estimate the heritability of the studied phenotype under different statistical models. Heritability estimates for carotid-femoral PWV stratified by age ranging from 11 to 35% (higher in individuals aged ≤45 years and lower in individuals aged 18-102 years). Age and hypertension showed significant effects on the PWV trait and significantly affect heritability estimates in all models. We conclude that the heritability of carotid-femoral PWV in a Brazilian population is intermediate, and therefore genetic studies evolving arterial stiffness phenotypes should be encouraged.

Blood Pressure and Left Ventricular Hypertrophy During American-Style Football Participation

Hypertension, a strong determinant of cardiovascular disease risk, has been documented among elite, professional American-style football (ASF) players. The risk of increased blood pressure (BP) and early adulthood hypertension among the substantially larger population of collegiate ASF athletes is not known. We conducted a prospective, longitudinal study to examine BP, the incidence of hypertension, and left ventricular remodeling among collegiate ASF athletes. Resting BP and left ventricular structure were assessed before and after a single season of competitive ASF participation in 6 consecutive groups of first-year university athletes (n=113). ASF participation was associated with significant increases in systolic BP (116±8 versus 125±13 mm Hg; P<0.001) and diastolic BP (64±8 mm Hg versus 66±10 mm Hg; P<0.001). At the postseason assessment, the majority of athletes met criteria for Joint National Commission (seventh report) prehypertension (53 of 113, 47%) or stage 1 hypertension (16 of 113, 14%). Among measured characteristics, lineman field position, intraseason weight gain, and family history of hypertension were the strongest independent predictors of postseason BP. Among linemen, there was a significant increase in the prevalence of concentric left ventricular hypertrophy (2 of 64 [3%] versus 20 of 64 [31%]; P<0.001) and change in left ventricular mass correlated with intraseason change in systolic BP (R=0.46, P<0.001). Collegiate ASF athletes may be at risk for clinically relevant increases in BP and the development of hypertension. Enhanced surveillance and carefully selected interventions may represent important opportunities to improve later-life cardiovascular health outcomes in this population.

The leptin receptor Gln223Arg polymorphism (rs1137101) mediates the postprandial lipaemic response, but only in males

ObjectiveAn exaggerated postprandial triacylglycerol (TAG) response is an important determinant of cardiovascular disease risk. With increased recognition of the role of leptin in systemic macronutrient metabolism, we used a candidate gene approach to examine the impact of the common leptin receptor (LEPR) Gln223Arg polymorphism (rs1137101) on postprandial lipaemia. Methods and resultsHealthy adults (n = 251) underwent a sequential meal postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (t = 0) and lunch (t = 330 min). Fasting total- and low-density lipoprotein cholesterol were 9% lower in the ArgArg than GlnArg group (P < 0.04), whereas fasting TAG was 27% lower in the ArgArg than GlnGln group (P < 0.02). The magnitude of the postprandial TAG response was also significantly lower in the ArgArg compared with the GlnArg and GlnGln genotypes, with a 26% lower area under the curve (AUC) and incremental AUC in the ArgArg individuals (P ≤ 0.023). Genotype*gender interactions were evident for fasting and postprandial TAG responses (P < 0.05), with the genotype effect only evident in males. Regression analysis indicated that the LEPR genotype and genotype*gender interactions were independent predictors of the TAG AUC, accounting for 6.3% of the variance. Our main findings were replicated in the independent LIPGENE-Cordoba postprandial cohort of metabolic syndrome subjects (n = 75), with a 52% lower TAG AUC in the ArgArg than GlnGln male subjects (P = 0.018). ConclusionWe report for the first time that the common LEPR Gln223Arg genotype is an important predictor of postprandial TAG in males. The mechanistic basis of these associations remains to be determined.

On- and Off-Target Pharmacology of Torcetrapib

Lowering of serum low-density lipoprotein cholesterol (LDL-C) levels remains the primary aim of lipid management. Much progress has been made in reducing rates of cardiovascular disease morbidity and mortality, largely through increased awareness of lipid-lowering therapies and particularly through the use of high-efficacy LDL-C-lowering HMG-CoA reductase inhibitors (statins). While statins have been effective in reducing cardiovascular disease risk, many patients do not adequately achieve guideline-recommended LDL-C goals and may benefit from additional cholesterol management therapies. Low serum levels of high-density lipoprotein cholesterol (HDL-C) are considered another important determinant of cardiovascular disease risk, and increased serum HDL-C levels have been shown to be associated with reductions in the incidence of cardiovascular disease. One approach toward raising serum HDL-C levels is the inhibition of cholesteryl ester-transfer protein (CETP), a plasma protein that promotes the transfer of cholesteryl ester from HDL particles and other lipoprotein fractions to pro-atherogenic apolipoprotein B-containing lipoproteins. The inhibition of this protein raises HDL-C levels and also reduces LDL-C levels. The concept of raising HDL-C levels through pharmacological intervention of this target was validated in preclinical and clinical studies with torcetrapib, the first CETP inhibitor to be assessed in late-stage clinical trials. The large clinical outcomes trial, ILLUMINATE, was prematurely terminated due to other unexpected pharmacological effects of torcetrapib that led to an increased risk of cardiovascular events and deaths. Thus, the ultimate effect of CETP inhibition on cardiovascular disease outcomes remains to be determined. Other CETP inhibitors currently in development do not have the adverse effects of increased blood pressure and circulating levels of aldosterone shown to be structurally related to torcetrapib. Preclinical and pharmacology studies have shown that these CETP inhibitors are distinct compared with torcetrapib and lack the features related to its off-target pharmacology. These findings indicate that the off-target activities of torcetrapib are not necessarily class effects of CETP inhibitors. Recent clinical trials have shown that dalcetrapib, anacetrapib and evacetrapib, the most advanced of these compounds in development, effectively raise HDL-C levels and lower LDL-C in the absence of off-target activities. The results of these trials are encouraging within the limits of study size and duration and provide a rationale for conducting further studies, including large clinical outcomes trials to assess whether CETP inhibition can lead to cardioprotective effects. This review summarizes the data supporting the development of CETP inhibitors as HDL-C-raising therapy, including structure-activity relationships and preclinical and clinical pharmacology studies of known CETP inhibitors.

Sortilin: An unusual suspect in cholesterol metabolism

The concentration of low-density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome-wide association studies (GWASs) of common genetic variation associated with LDL-C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 - the first gene identified by GWAS as a determinant of plasma LDL-C to be evaluated mechanistically.

Pharmacogenomic application of the haptoglobin genotype in the treatment of HDL dysfunction

An emerging paradigm of research has suggested that in the setting of diabetes mellitus (DM) the quality or function of high-density lipoprotein (HDL) may be a determinant of cardiovascular disease risk. Specific structural modifications of HDL protein and lipid components, resulting from oxidative modification, have been proposed to mediate HDL's loss of the ability to promote cholesterol efflux (reverse cholesterol transport), serve as an antioxidant and anti-inflammatory agent. Therefore, inhibiting HDL oxidative modification would be expected to improve its function and provide cardioprotection. Nevertheless, antioxidant strategies to reduce cardiovascular events from atherosclerosis in DM have failed. It has been proposed that this failure may have been due to the inadequate nature of patient selection. High dose antioxidant therapy may only provide benefit to a subset of DM individuals with oxidatively modified HDL. We will review evidence that haptoglobin (Hp) identifies such individuals who can be successfully treated with vitamin E. These data will suggest that a pharmacogenomic approach utilizing the Hp genotype may be useful in identifying individuals who will benefit from antioxidant therapy.

Strengthening causal inference in cardiovascular epidemiology through Mendelian randomization

Observational studies have contributed in a major way to understanding modifiable determinants of cardiovascular disease risk, but several examples exist of factors that were identified in observational studies as potentially protecting against coronary heart disease, that in randomized controlled trials had no such effect. The likely reason for misleading findings from observational epidemiological studies is that associations are influenced by confounding, bias, and reverse causation—where disease influences a risk factor, rather than vice versa. Mendelian randomization utilizes genetic variants that serve as proxy measures for modifiable risk factors to allow estimation of the causal influence of the modifiable risk factor in question. We present examples of the use of the Mendelian randomization approach and discuss both the limitations and potentials of this strategy.

Pharmacogenomics of statin response

Although statin therapy has been shown to reduce substantially the risk for cardiovascular disease in multiple patient subgroups, there is wide inter-individual variation in statin efficacy, in terms of both plasma lipoprotein response and clinical outcome. A number of studies have reported that polymorphisms in genes affecting statin pharmacodynamics and pharmacokinetics are associated with measures of statin efficacy, but the magnitude of variation in statin response that could be explained by these associations is small. Genome-wide association studies may yield a more comprehensive set of markers for predicting statin efficacy and muscle toxicity. For the results of these analyses to have clinical value, however, there remains a need to replicate findings in multiple populations, to connect effects on LDL and other biomarkers with clinical outcomes, and to determine whether the associations apply to each individual statin. Satisfying these requirements for clinical applicability will be challenging, but discovery of specific genotypes that influence statin efficacy and characterization of their functional effects in cellular or animal model systems may enhance our understanding of determinants of cardiovascular disease risk. They may also allow us to identify pathways that may be targeted to yield effective prevention and treatment.

Does the aldosterone: renin ratio predict the efficacy of spironolactone over bendroflumethiazide in hypertension? A clinical trial protocol for RENALDO (RENin-ALDOsterone) study

BackgroundHigh blood pressure is an important determinant of cardiovascular disease risk. Treated hypertensives do not attain a risk level equivalent to normotensives. This may be a consequence of suboptimal blood pressure control to which indiscriminate use of antihypertensive drugs may contribute. Indeed the recent ALLHAT[1]study suggests that thiazides should be given first to virtually all hypertensives. Whether this is correct or whether different antihypertensive therapies should be targeted towards different patients is a major unresolved issue, which we address in this study.The measurement of the ratio of aldosterone: renin is used to identify hypertensive subjects who may respond well to treatment with the aldosterone antagonist spironolactone. It is not known if subjects with a high ratio have aldosteronism or aldosterone-sensitive hypertension is debated but it is important to know whether spironolactone is superior to other diuretics such as bendroflumethiazide in this setting.Methods/designThe study is a double-blind, randomised, crossover, controlled trial that will randomise 120 hypertensive subjects to 12 weeks treatment with spironolactone 50 mg once daily and 12 weeks treatment with bendroflumethiazide 2.5 mg once daily. The 2 treatment periods are separated by a 2-week washout period. Randomisation is stratified by aldosterone: renin ratio to include equal numbers of subjects with high and low aldosterone: renin ratios.Primary Objective – To test the hypothesis that the aldosterone: renin ratio predicts the antihypertensive response to spironolactone, specifically that the effect of spironolactone 50 mg is greater than that of bendroflumethiazide 2.5 mg in hypertensive subjects with high aldosterone: renin ratios.Secondary Objectives – To determine whether bendroflumethiazide induces adverse metabolic abnormalities, especially in subjects with high aldosterone: renin ratios and if baseline renin measurement predicts the antihypertensive response to spironolactone and/or bendrofluazideDiscussionThe numerous deleterious effects of hypertension dictate the need for a systematic approach for its treatment. In spite of various therapies, resistant hypertension is widely prevalent. Among various factors, primary aldosteronism is an important cause of resistant hypertension and is now more commonly recognised. More significantly, hypertensives with primary aldosteronism are also exposed to various other deleterious effects of excess aldosterone. Hence treating hypertension with specific aldosterone antagonists may be a better approach in this group of patients. It may lead on to better blood pressures with fewer medications.