Insulin sensitization therapy and the heart: focus on metformin and thiazolidinediones.

Chronic heart failure (CHF) is an insulin-resistant (IR) state and the degree of IR is related to disease severity and poor clinical outcome in CHF. IR may be pathophysiologically linked with CHF. Therefore, IR may represent a new target for treatment in CHF. Metformin and thiazolidinediones (TZDs) are effective diabetic therapies that are insulin sensitizers. TZDs are contraindicated in CHF because their use is associated with increased incidence of CHF as a result of their effects on renal sodium reabsorption and vascular permeability. There is evidence to suggest that metformin may be both safe and useful in CHF.

Dapagliflozin Versus Placebo on Left Ventricular Remodeling in Patients With Diabetes and Heart Failure: The REFORM Trial.

OBJECTIVE: To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI. RESEARCH DESIGN AND METHODS: We randomized 56 patients with T2DM and HF with LV systolic dysfunction to dapagliflozin 10 mg daily or placebo for 1 year, on top of usual therapy. The primary end point was difference in LV end-systolic volume (LVESV) using cardiac MRI. Key secondary end points included other measures of LV remodeling and clinical and biochemical parameters. RESULTS: In our cohort, dapagliflozin had no effect on LVESV or any other parameter of LV remodeling. However, it reduced diastolic blood pressure and loop diuretic requirements while increasing hemoglobin, hematocrit, and ketone bodies. There was a trend toward lower weight. CONCLUSIONS: We were unable to determine with certainty whether dapagliflozin in patients with T2DM and HF had any effect on LV remodeling. Whether the benefits of dapagliflozin in HF are due to remodeling or other mechanisms remains unknown.

The APEX trial: Effects of allopurinol on exercise capacity, coronary and peripheral endothelial function, and natriuretic peptides in patients with cardiac syndrome X.

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognized. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden, and improve myocardial efficiency. In this "proof of concept" study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischemia) in patients with cardiac syndrome X. METHODS AND RESULTS: This study was a randomized, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59 ± 10 years, 11 women and 8 men) with cardiac syndrome X were randomized to a 6-week treatment with either allopurinol (600 mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring the response of flow velocity in the left anterior descending artery to adenosine, and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (-48 ± 24% vs 1.9 ± 11%, P < .001). There was no significant difference in maximum ET, CFR, and FMD between allopurinol and placebo. However, there was a trend that allopurinol reduced serum BNP when compared to placebo (-8% [interquartile range -22% to 65%] vs 44% [interquartile range -18% to 140%]; P = .07). CONCLUSION: In patients with cardiac syndrome X, high-dose allopurinol did not improve exercise capacity, and coronary or peripheral endothelial function.

Ethnicity and drug therapy for hypertension.

Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic factors, environmental factors and/or their interaction. This review is divided into 2 parts. Firstly, there will be overview of ethnicity as a determinant of drug metabolism and response with reference to antihypertensive agents. The concept of ethnicity has been applied extensively to the study of hypertension especially in American blacks in whom the hypertension is more common and more aggressive. Thus, the second part of this review will then focus on examining the black-white differences in physiological responses to pharmacological challenge that may provide a link between these models and known ethnic differences in drug responses. We will discuss the hypertension studies that have examined the relative effectiveness of different classes of antihypertensive agents including several recent cardiovascular outcome trials that either have a high proportion of blacks or were conducted entirely in black subjects.

Combination of drugs acting on the natriuretic system and the renin-angiotensin system in heart failure.

Conventional diuretic agents are very effective agents in relieving volume overload and congestive symptoms in chronic heart failure (CHF). However, they are associated with activation of the renin-angiotensin system (RAS) and the sympathetic nervous system and a reduction in glomerular filtration rate, all of which have been associated with adverse outcomes in CHF. Therefore, there is an increasing interest in drugs that target the natriuretic system without neurohormonal activation and deterioration of renal function. In this review, we will discuss the underlying rationale and evidence behind currently pursued strategies that target the natriuretic system. This includes the administration of natriuretic peptides (NPs) and strategies that potentiate the NP system, such as neutral endopeptidase inhibition. We will also highlight some potentially important interactions of these strategies with drugs that target the RAS.

Pulmonary hypertension predicts all-cause mortality in patients with heart failure: a retrospective cohort study.

AIMS: The presence of pulmonary hypertension (PH) in left ventricular systolic dysfunction (LVSD) and symptomatic heart failure is an ominous sign. There are insufficient data regarding the risk conferred by increasing severity of PH in patients with heart failure. METHODS AND RESULTS: We performed a record linkage study in Tayside, Scotland (population ∼400,000) utilizing the Tayside echocardiogram database (>50,000 echocardiograms) maintained by the Health Informatics Centre (HIC). Data sets from the HIC include mortality data, cardiovascular medications, and other healthcare activities linked anonymously by the community health index (CHI) number. Patients were included in the analysis if they had LVSD, had a valid right ventricular systolic pressure (RVSP) measurement, and had a loop diuretic prescription (provided not more than 1 year prior to echocardiogram). A Cox proportional hazard model was used to examine the effects of RVSP on all-cause mortality. A total of 1612 patients [mean age, 75.2 ± 10.9 (SD) years; 57.4% male] met the entry criteria. Mean RVSP for the cohort was 44.9 ± 13.1 mmHg and mean follow-up was 2.8 ± 2.5 years. For each 5 mmHg stepwise increase in RVSP, after adjustment for confounding factors including the degree of LVSD and the presence of chronic obstructive pulmonary disease, the hazard ratio (HR) for all-cause mortality was 1.06 (1.03-1.08, P < 0.001). CONCLUSIONS: Pulmonary hypertension predicted all-cause mortality in a heterogeneous group of patients with heart failure. Each 5 mmHg rise in RVSP was associated with a 6% increased risk of death.

Insulin resistance: a potential new target for therapy in patients with heart failure.

There is increasing evidence to suggest that chronic heart failure (CHF) is an insulin resistant (IR) state and that the degree of IR correlates with the severity and mortality of CHF. The pathophysiology of IR in CHF has yet to be fully defined. Additionally, it remains to be determined if IR is merely a marker reflecting the severity of CHF or whether it contributes to the disease in CHF. If IR is truly a culprit that worsens CHF, it will potentially be a new target for therapy as strategies that can reverse IR in CHF may potentially result in an improvement in symptoms and even mortality in these patients. However, there are concerns regarding the use of certain insulin sensitizers, most notably, the thiazolidinediones (TZDs) which have been associated with increased risk of hospitalizations for CHF. Despite previous concerns of lactic acidosis (LA), there is now evidence that metformin may not only be safe but could potentially be useful in the setting of CHF. There are now ongoing prospective studies, including the TAYSIDE study, to determine if reversing IR with metformin will have beneficial effects in patients with CHF.

Differential effects of carvedilol and atenolol on plasma noradrenaline during exercise in humans.

AIMS: Evidence of long-term beneficial effects of beta-blockers on mortality and morbidity in patients with heart failure has been demonstrated in recent randomized trials. However, not all beta-blockers are identical. Carvedilol, a nonselective beta- and alpha-adrenergic blocker, can potentially blunt the release of noradrenaline by blocking presynaptic beta2-adrenergic receptors. To test this hypothesis, we have compared the effects of carvedilol and atenolol on plasma noradrenaline during exercise in healthy young volunteers. METHODS: This study investigated the differential effects of 2 weeks pretreatment with carvedilol 25 mg day(-1) and atenolol 50 mg day(-1) on plasma noradrenaline at rest and during exercise on a treadmill in a double-blind randomized crossover study, involving 12 healthy male volunteers (mean age 21.6 +/- 0.3 years). RESULTS: Haemodynamic parameters at rest and during exercise were not significantly different in either carvedilol or atenolol pretreatment groups. However, carvedilol pretreatment significantly blunted the increase in plasma noradrenaline during exercise [393.8 +/- 51.7 pg ml(-1) (pretreatment) to 259.7 +/- 21.2 pg ml(-1) (post-treatment)], when compared with atenolol [340.4 +/- 54.6 pg ml(-1) (pretreatment) to 396.2 +/- 32.0 pg ml(-1) (post-treatment)]. The difference between carvedilol and atenolol (95% confidence interval) was -145.2, -351.0, P < 0.05. CONCLUSIONS: We have demonstrated that carvedilol but not atenolol significantly blunted the increase in plasma noradrenaline during exercise. These findings may suggest a sympathoinhibitory effect of carvedilol that may enhance its ability to attenuate the cardiotoxicity associated with adrenergic stimulation in patients with heart failure.