Predictors of cardiac morbidity in diabetic, new-onset diabetic and non-diabetic high-risk hypertensive patients: The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.

Diabetic and new-onset diabetic patients with hypertension have higher cardiac morbidity than patients without diabetes. We aimed to investigate whether baseline predictors of cardiac morbidity, the major constituent of the primary endpoint in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, were different in patients with diabetes and new-onset diabetes compared to patients without diabetes. In total, 15,245 high-risk hypertensive patients in the VALUE trial were followed for an average of 4.2 years. At baseline, 5250 patients were diabetic by the 1999 World Health Organization criteria, 1298 patients developed new-onset diabetes and 8697 patients stayed non-diabetic during follow-up. Cardiac morbidity was defined as a composite of myocardial infarction and heart failure requiring hospitalization, and baseline predictors were identified by univariate and multivariate stepwise Cox regression analyses. History of coronary heart disease (CHD) and age were the most important predictors of cardiac morbidity in both diabetic and non-diabetic patients. History of CHD, history of stroke and age were the only significant predictors of cardiac morbidity in patients with new-onset diabetes. Predictors of cardiac morbidity, in particular history of CHD and age, were essentially the same in high-risk hypertensive patients with diabetes, new-onset diabetes and without diabetes who participated in the VALUE trial.

Markers of remodeling in subcutaneous adipose tissue are strongly associated with overweight and insulin sensitivity in healthy non-obese men.

Alteration in extracellular matrix (ECM) in adipose tissues (AT) has been associated with insulin resistance, diabetes and obesity. We investigated whether selected biomarkers of ECM remodeling in AT in healthy subjects associated with the amount and distribution of AT and with glucometabolic variables. Subcutaneous AT and fasting blood samples from 103 middle-aged healthy non-obese men were used. AT gene expression and circulating levels of the biomarkers were quantified. Distribution of AT was assessed by computed tomography, separated into subcutaneous, deep subcutaneous and visceral AT. Insulin sensitivity was measured by glucose clamp technique. Metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 expression in AT correlated significantly to the amount of AT in all compartments (rs = 0.41-0.53, all p ≤ 0.01), and to insulin sensitivity, insulin, C-peptide, waist circumference and body mass index (BMI) (rs = 0.25-0.57, all p ≤ 0.05). MMP-9 was 5.3 fold higher in subjects with insulin sensitivity below median (p = 0.002) and 3.1 fold higher in subjects with BMI above median level (p = 0.013). In our healthy non-obese middle-aged population AT-expressed genes, central in remodeling of ECM, associated strongly with the amount of abdominal AT, overweight and insulin sensitivity, indicating AT-remodeling to play a role also in non-obese individuals. The remodeling process seems furthermore to associate significantly with glucometabolic disturbances.Trial registration: ClinicalTrials.gov, NCT01412554. Registered 9 August 2011, https://clinicaltrials.gov/ct2/show/NCT01412554?term=NCT01412554 .

Prevention of atrial fibrillation in hypertension.

Hypertensive patients have an increased risk of developing atrial fibrillation (AF), which increases cardiovascular morbidity and mortality in this population. Primary prevention is a new strategy in treating AF; previously, it was more common to focus on preventing adverse outcomes and controlling the arrhythmia's rate and rhythm. In this review, we consider the possible preventive effects of antihypertensive treatment on new-onset AF seen in recent trials, especially with blockers of the renin-angiotensin system (RAS). Several secondary analyses of large, randomized trials regarding hypertension and heart failure have shown promising results with benefits beyond the expected blood pressure-lowering effect. A few prospective studies on prevention of AF recurrence with RAS blockade have been published, and more studies are expected to be published in the near future.

Interleukin-18 and the NLR family pyrin domain containing-3 inflammasome in adipose tissue are strongly associated with glucometabolic variables in a cohort of middle-aged men.

BACKGROUND: Previous studies have indicated an association between interleukin-18 and glucose. Interleukin-18 becomes active when cleaved by caspase-1, activated by the NLR family pyrin domain containing-3 inflammasome. AIM: To investigate associations between glucometabolic variables and serum levels of interleukin-18 and genetic expression of interleukin-18, caspase-1 and NLR family pyrin domain containing-3 in adipose tissue and circulating leukocytes, and whether these mediators are related to the amount of abdominal adipose tissue . MATERIALS AND METHODS: Fasting blood samples and subcutaneous adipose tissue were collected in a cohort of 103 middle-aged men. Serum levels of interleukin-18 were determined by enzyme-linked immunosorbent assay, gene expression by real-time polymerase chain reaction and insulin sensitivity by glucose clamp. The distribution of abdominal adipose tissue, separated into superficial- and deep subcutaneous, and visceral adipose tissue, was assessed by computed tomography scan. RESULTS: Glucometabolic variables correlated significantly to serum levels of interleukin-18, and to the expression of interleukin-18 and NLR family pyrin domain containing-3 in subcutaneous adipose tissue ( p < 0.05). Significant correlations were further observed between the amount of fat in the different compartments of abdominal adipose tissue and both serum levels of interleukin-18 and genetic expression of interleukin-18 and NLR family pyrin domain containing-3 in adipose tissue. CONCLUSION: The results implicate that the glucometabolic state is of importance for the inflammasome-related inflammation expressed both circulatory and genetically in subcutaneous adipose tissue, the latter highly reflected in the amount of abdominal adipose tissue.

Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure.

Atrial fibrillation is the most frequent occurring sustained cardiac arrhythmia and it is related to common cardiac disease conditions. Hypertension increases the risk of atrial fibrillation by approximately two-fold and, because of the high prevalence of hypertension, it accounts for more cases of atrial fibrillation than any other risk factor. In recent years, there are two large hypertension trials (LIFE and VALUE) and two large heart failure trials (CHARM and Val-HeFT) reporting the beneficial effect of angiotensin II-receptor blockers (ARBs) on new-onset atrial fibrillation, beyond the blood pressure-lowering effect. Blockade of the renin-angiotensin system may prevent left atrial dilatation, atrial fibrosis, dysfunction and conduction velocity slowing. Some studies also indicate direct anti-arrhythmic properties. This review aims to consider the preventive effect of ARBs on new-onset atrial fibrillation observed in recent reports from these trials, and to discuss possible mechanisms of the beneficial effect of angiotensin II-receptor blockade.

Clinical implications of the 2013 ESH/ESC hypertension guidelines: targets, choice of therapy, and blood pressure monitoring.

The European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2013 guidelines for the management of arterial hypertension included simplified blood pressure (BP) targets across patient groups, more balanced discussion on monotherapy vs. combination therapy, as well as reconfirmation of the importance of out-of-office BP measurements. In light of these updates, we wished to review some issues raised and take a fresh look at the role of calcium channel blocker (CCB) therapy; an established antihypertensive class that appears to be a favorable choice in many patients. Relaxed BP targets for high-risk hypertensive patients in the 2013 ESH/ESC guidelines were driven by a lack of commanding evidence for an aggressive approach. However, substantial evidence demonstrates cardiovascular benefits from more intensive BP lowering across patient groups. Individualized treatment of high-risk patients may be prudent until more solid evidence is available. Individual patient profiles and preferences and evidence for preferential therapy benefits should be considered when deciding upon the optimal antihypertensive regimen. CCBs appear to be a positive choice for monotherapy, and in combination with other agent classes, and may provide specific benefits beyond BP lowering. Ambulatory and home BP monitoring have an increasing role in defining the diagnosis and prognosis of hypertension (especially non-sustained); however, their value for comprehensive diagnosis and appropriate treatment selection should be more widely acknowledged. In conclusion, further evidence may be required on BP targets in high-risk patients, and optimal treatment selection based upon individual patient profiles and comprehensive diagnosis using out-of-office BP measurements may improve patient management.

Treatment of hypertension in diabetes: what is the best therapeutic option?

Patients with diabetes mellitus have a high risk of cardiovascular disease, and the latter is the leading cause of premature mortality in diabetic patients. Treatment of risk factors and comorbidities, such as hypertension, is very important and may effectively prevent cardiovascular events. The blood pressure goal in diabetic patients should be below 140/90 mmHg, probably down to 130-135/85 mmHg, although the evidence for this is scarce. To reach this blood pressure goal, intensive lifestyle intervention and often combinations of different antihypertensive drugs must be initiated. In combination treatment, a blocker of the renin-angiotensin system should be included, and according to the results of the ACCOMPLISH trial, a combination of a renin-angiotensin system blocker and a calcium channel blocker should probably be the first choice.

A link between hypertension and atrial fibrillation: methods of treatment and prevention.

Atrial fibrillation is the most common clinically significant cardiac arrhythmia and is associated with markedly increased risks of cardiovascular diseases. Atrial fibrillation and hypertension often coexist and are both responsible for considerable morbidity and mortality. Aggressive treatment of hypertension, especially with a blocker of the reninangiotensin system, may postpone or prevent development of atrial fibrillation and reduce thromboembolic complications. Awareness of the risk of developing atrial fibrillation in hypertensives may be of great importance and focus on prevention of atrial fibrillation development with optimal antihypertensive treatment may reduce morbidity, mortality and health care expenditures.

Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study.

Insulin resistance and sympathetic activity are related by a positive feedback system. However, which precedes the other still remains unclear. The present study aimed to investigate the predictive role of sympathoadrenal activity in the development of insulin resistance in an 18-year follow-up study. We also examined whether reactivity to 2 different stress tests, a cold pressor test and a mental stress test, would differ in their predictive power. The 2 tests are supposed to represent different reactivity mechanisms: alpha- and beta-adrenergic responses, respectively. At entry, arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age, 19.3 +/- 0.4 years, mean +/- SD) during rest, a mental stress test, and a cold pressor test. Fasting plasma glucose concentration was measured at entry and at follow-up. Insulin resistance at follow-up was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). Eighty subjects (81%) were eligible for follow-up after 18.0 +/- 0.9 years (mean +/- SD). The norepinephrine responses to cold pressor test at entry predicted plasma glucose concentration (r = 0.301, P = .010) and HOMA-IR (r = 0.383, P = .004) at follow-up in univariate analyses. In multiple regression analyses, corrected for fasting glucose at entry, family history of diabetes, blood pressure-lowering medication, body mass index at entry, and level of exercise, norepinephrine response to cold pressor test was found to be a positive predictor of future HOMA-IR (P = .010). This is the first long-term follow-up study in white subjects showing that sympathetic reactivity predicts future insulin resistance 18 years later. These findings may provide further insights into the pathophysiologic mechanisms of insulin resistance.

Impact of new-onset diabetes mellitus on cardiac outcomes in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial population.

There has been a lot of interest about new-onset diabetes mellitus in recent hypertension trials, but the implications of diabetes development on cardiac outcomes have not been known. In the Valsartan Antihypertensive Long-Term Use Evaluation trial, 15 245 high-risk patients were followed for an average of 4.2 years. At baseline, 5250 patients were diabetic by the 1999 World Health Organization criteria, and among the 9995 nondiabetic patients, 1298 patients developed diabetes during follow-up. We have investigated the influence of diabetes development on outcomes in the Valsartan Antihypertensive Long-Term Use Evaluation trial. The patients with diabetes at baseline and new-onset diabetes were compared with patients who did not develop diabetes by a Cox regression model with adjustment for prespecified covariates (age, diabetes status, left ventricular hypertrophy, baseline coronary heart disease, and randomized study treatment). Patients with diabetes at baseline had the highest cardiac morbidity defined as myocardial infarction and heart failure with a hazard ratio of 2.20 (95% CI: 1.95 to 2.49). The patients with new-onset diabetes had significantly higher cardiac morbidity, especially more congestive heart failure, than those without diabetes, with a hazard ratio of 1.43 (95% CI: 1.16 to 1.77). This indicates that patients who develop diabetes during antihypertensive treatment have cardiac morbidity intermediate between diabetic subjects and those subjects who never had diabetes and that it is of importance to find these patients at risk of diabetes development and optimize lifestyle and medical treatment.