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Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension ( p  = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

The impact of serum uric acid on cardiovascular outcomes in the LIFE study. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the superiority of a losartan-based regimen over atenolol-based regimen for reduction of cardiovascular (CV) morbidity and mortality. It has been suggested that the LIFE study results may be related to the effects of losartan on serum uric acid (SUA). SUA has been proposed as an independent risk factor for CV morbidity and death. Cox regression analysis was used to assess relationship of SUA and treatment regimens with the LIFE primary composite outcome (CV death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke). Baseline SUA was significantly associated with increased CV events [hazard ratio (HR) 1.024 (95% CI 1.017–1.032) per 10 μmol/L, P < 0.0001] in the entire study population. The association was significant in women [HR = 1.025 (1.013–1.037), P < 0.0001], but not in men [HR = 1.009 (0.998–1.019), P = 0.108]. After adjustment for Framingham risk score (FRS), SUA was no longer significant in the entire study population [HR = 1.006 (0.998–1.014), P = 0.122] or in men [HR = 1.006 (0.995–1.017), P = 0.291], but was significant in women [HR = 1.013 (1–1.025), P = 0.0457]. The baseline-to-end-of-study increase in SUA (standard deviation, SD) was greater (P < 0.0001) in atenolol-treated subjects (44.4 ± 72.5 μmol/L) than in losartan-treated subjects (17.0 ± 69.8 μmol/L). SUA as a time-varying covariate was strongly associated with events (P < 0.0001) in the entire population. The contribution of SUA to the treatment effect of losartan on the primary composite end point was 29% (14%-107%), P = 0.004. The association between time-varying SUA and increased CV risk tended to be stronger in women (P < 0.0001) than in men (P = 0.0658), although the gender-outcome interaction was not significant (P = 0.079). The increase in SUA over 4.8years in the LIFE study was attenuated by losartan compared with atenolol treatment, appearing to explain 29% of the treatment effect on the primary composite end point. The association between SUA and events was stronger in women than in men with or without adjustment of FRS.

Telomere shortening, along with various other endogenous and environmental factors, can drive cells into senescence, which is involved in the complex process of biological ageing. In this Review, Fyhrquist and colleagues discuss the associations between cardiovascular risk factors and telomere shortening, and whether cellular senescence has a causal role in conditions such as atherosclerosis, heart failure, and hypertension. Cellular senescence, defined as arrest during the cell cycle (G 0 ), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed. Key Points Cellular senescence—arrest during the cell cycle (G 0 )—is involved in the ageing process, and driven by oxidative stress, DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening Cellular senescence parallels the development of atherosclerosis and other pathologies in the vasculature and heart and is, therefore, likely to have a pivotal role in cardiovascular disease Telomere length, usually measured as leucocyte telomere length, is widely considered a marker of biological ageing, is largely inherited, and is modulated by various intrinsic and environmental factors throughout life Endogenous factors causing telomere attrition include ageing, cell division, genetic factors, DNA damage, inflammation, and oxidative stress; telomere attrition can be retarded by genetic factors, telomerase, oestrogen, and antioxidants Environmental factors associated with telomere shortening include poor lifestyle (smoking, excess calories, sedentary lifestyle, alcohol abuse), and severe mental stress, whereas healthy lifestyle is associated with maintenance of long telomeres Telomere length seems to have a key role in cardiovascular disease by driving cells into cell-cycle arrest, senescence, and ultimately apoptosis

Background Telomeres are short segments in chromosome ends, the length of which is reduced during cell life-cycles. We examined the association of leukocyte telomere length and short telomere proportion with hemodynamic variables. Methods Altogether 566 subjects (279 women and 287 men) without cardiovascular disease and medications with direct cardiovascular influences were subjected supine recordings for 5 minutes. Haemodynamics were captured using continuous tonometric pulse wave analysis and whole-body impedance cardiography. The analyses were adjusted for age, body mass index (BMI), alcohol use, smoking, plasma chemistry, and estimated glomerular filtration rate (eGFR). Results In univariate analyses, leukocyte telomere length correlated with age, BMI, eGFR, aortic blood pressure, augmentation index, pulse wave velocity, and systemic vascular resistance ( p < 0.05 for all). Short telomere proportion correlated with age, BMI, eGFR, aortic systolic blood pressure, augmentation index, and pulse wave velocity ( p < 0.05 for all). In linear regression analyses of all hemodynamic variables, leukocyte telomere length was only an independent explanatory factor for augmentation index (Beta −0.006, p = 0.032), while short telomere proportion was not an explanatory factor for any of the hemodynamic variables, in contrast to age, BMI and several cardiovascular risk factors. Conclusion Augmentation index was predominantly related with chronological aging, but also with leukocyte telomere length, suggesting that this variable of central wave reflection is a moderate marker of vascular biological aging.

The prognostic importance of hemoglobin is controversial. We investigated the prognostic importance of baseline and in-treatment hemoglobin in the LIFE study. Eight thousand one hundred ninety-four LIFE patients with hypertension and left ventricular hypertrophy with available baseline hemoglobin measurements were randomized to losartan- or atenolol-based treatment and followed for 4.8 years for end points of all-cause mortality and composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. U-shaped relations were observed between deciles of baseline hemoglobin and all-cause mortality and the composite end point. In univariate Cox models, baseline hemoglobin in the lowest gender-specific decile (women/men: <12.5/13.4 g/dL) was associated with all-cause mortality (hazard ratio [HR] 2.01, 95% CI 1.64-2.64) and the composite end point (HR 1.53, 95% CI 1.27-1.85, both P < .001), whereas hemoglobin in the highest gender-specific decile (women/men: ≥15.0/16.2 g/dL) was not. The decrease in hemoglobin was higher ( P < .001) in patients allocated to losartan- (14.3-13.8 g/dL) versus atenolol-based treatment (14.3-14.0 g/dL). In Cox models with the same gender-specific definitions for high and low hemoglobin as time-varying covariates with adjustment for treatment allocation and established risk factors and diseases, hemoglobin in the lowest decile was associated with higher rates of all-cause mortality (HR 3.03, 95% CI 1.89-4.85, P < .001) and the composite end point (HR 1.36, 95% CI 1.08-1.71, P < .01), whereas hemoglobin in the highest decile was not. After adjusting for other risk factors, relatively low, but not high, hemoglobin during antihypertensive treatment was associated with higher incidence of all-cause mortality and the composite end point.

Blood pressure reduction achieved with β-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension. Left ventricular hypertrophy (LVH) is a strong independent indicator of risk of cardiovascular morbidity and death. We aimed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death. We did a double-masked, randomised, parallel-group trial in 9193 participants aged 55–80 years with essential hypertension (sitting blood pressure 160–200/95–115 mm Hg) and LVH ascertained by electrocardiography (ECG). We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event (death, myocardial infarction, or stroke). We used Cox regression analysis to compare regimens. Blood pressure fell by 30·2/16·6 (SD 18·5/10·1) and 29·1/16·8 mm Hg (19·2/10·1) in the losartan and atenolol groups, respectively. The primary composite endpoint occurred in 508 losartan (23·8 per 1000 patient-years) and 588 atenolol patients (27·9 per 1000 patient-years; relative risk 0·87, 95% Cl 0·77–0·98, p=0·021). 204 losartan and 234 atenolol patients died from cardiovascular disease (0·89, 0·73–1·07, p=0·206); 232 and 309, respectively, had fatal or non-fatal stroke (0·75, 0·63–0·89, p=0·001); and myocardial infarction (non-fatal and fatal) occurred in 198 and 188, respectively (1·07, 0·88–1·31, p=0·491). New-onset diabetes was less frequent with losartan. Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure.

The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients. As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4·7 years [1·1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction). Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0·76 (95% CI 0·58–0·98), p=0·031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0·63 (0·42–0·95), p=0·028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0·61 (0·45–0·84), p=0·002. Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.

There are scarce data of alcohol consumption and telomere length, an indicator of biological age. In 1974, detailed alcohol consumption was available for a socioeconomically homogenous cohort of middle-aged men (The Helsinki Businessmen Study). Their alcohol use, divided into 5 groups (zero, 1—98, 99—196, 197—490, >490 g/week) has been repeatedly assessed until old age. In 2002/2003, leukocyte telomere length (LTL) and the proportion of short telomeres (less than 5 kilobases) were measured in a random subcohort of 499 men (mean age 76 years) using the Southern blot. Age-adjusted mean LTL in the 5 midlife alcohol consumption groups were 8.33, 8.24, 8.12, 8.13, and 7.87 kilobases, respectively (P < 0.001). The respective proportions (%) for short telomeres were 11.24, 11.52, 11.89, 12.08, and 13.47 (P = 0.004). The differences remained after further adjustments (ever smoking, body mass index, cholesterol, perceived fitness) for LTL (P = 0.03) and tended to remain for proportion of short telomeres (P = 0.07). Neither LTL, nor proportion of short telomeres, were associated with contemporary alcohol consumption groups in old age. Even minor alcohol consumption in midlife was significantly associated with shorter telomere length in old age. The differences represent an up to 10 year gap in biological age between zero and highest consumption.

Plasma was acidified with a mixture of hydrochloric acid and the enzyme inhibitor hydroxyquinoline, to ensure optimal incubation pH (6.0) (1) and sufficient inhibition of proteolytic breakdown of generated angiotensin I (Ang I). The later development of immunoradiometric assays of plasma renin concentration and direct assays of prorenin provided complementary information to PRA determinations, but these assays have not replaced adequate PRA assays, which are still needed for both clinical and research purposes.

Several studies have shown that albuminuria is associated with increased risk for fatal and nonfatal cardiovascular events, independent of conventional risk factors. The partition values for urine albumin-creatinine ratio (UACR) used to identify microalbuminuria have been based on studies that predicted risk in diabetic patients. To determine whether the relation between albuminuria and cardiovascular risk can be used to predict cardiovascular morbidity and mortality in hypertensive patients. Multicenter cohort study derived from a randomized, controlled trial. 8206 patients with stage II or III hypertension randomly assigned to double-blind therapy with losartan or atenolol. Follow-up was 39 122 patient-years. Renal glomerular permeability evaluated by UACR. In nondiabetic hypertensive patients with left ventricular hypertrophy, the risk for the composite cardiovascular end point increased continuously as albuminuria increased (P < 0.001 for trend). There was no specific threshold for increased risk. For every 10-fold increase in UACR, hazard ratios in nondiabetic patients increased as follows: composite end point, by 57% (95% CI, 40.6% to 75.0%); cardiovascular mortality, by 97.7% (CI, 66.5% to 235%); all-cause mortality, by 75.2% (CI, 54.0% to 99.4%); stroke, by 51.0% (CI, 28.8% to 76.9%); and myocardial infarction, by 45% (CI, 19.9% to 75.4%) (P < 0.001 for all comparisons). Values were similar in diabetic patients, although for myocardial infarction the trend was weaker and not significant. Increased UACR resulted in increasing risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy. We found no thresholds or plateaus. Risk increases at much lower UACR values than has been reported among diabetic patients.