Loop diuretics for chronic heart failure: a foe in disguise of a friend?

Loop diuretics are recommended for relieving symptoms and signs of congestion in patients with chronic heart failure and are administered to more than 80% of them. However, several of their effects have not systematically been studied. Numerous cohort and four interventional studies have addressed the effect of diuretics on renal function; apart from one prospective study, which showed that diuretics withdrawal is accompanied by increase in some markers of early-detected renal injury, all others converge to the conclusion that diuretics receipt, especially in high doses is associated with increased rates of renal dysfunction. Although a long standing perception has attributed a beneficial effect to diuretics in the setting of chronic heart failure, many cohort studies support that their use, especially in high doses is associated with adverse outcome. Several studies have used propensity scores in order to match diuretic and non-diuretic receiving patients; their results reinforce the notion that diuretics use and high diuretics dose are true risk factors and not disease severity markers, as some have suggested. One small, randomized study has demonstrated that diuretics decrease is feasible and safe and accompanied by a better prognosis. In conclusion, until elegantly designed, randomized trials, powered for clinical endpoints answer the unsettled issues in the field, the use of diuretics in chronic heart failure will remain subject to physicians' preferences and biases and not evidence based.

Cardioprotective effects of intracoronary administration of 4-chlorodiazepam in small and large animal models of ischemia-reperfusion.

BACKGROUND: The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. In the present study we investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion. METHODS: Acute myocardial infarction was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2µM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1h of reperfusion (for histological assessment of the "no reflow" area) or after 60days (for serial evaluation of cardiac function and structure by echocardiography and assessment of infarct size). Infarcted pigs were euthanized after 2h of reperfusion for histological assessment of infarct size and "no reflow" area. RESULTS: In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the "no reflow" area and conferred durable long-term structural and functional benefits (reduction in infarct size, attenuation of adverse remodeling, improvement in global systolic function). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size, reduction in "no reflow" area and more rapid resolution of ST-segment elevation. CONCLUSIONS: In a rat model of myocardial infarction, intracoronary administration of 4-CLD attenuated the "no reflow" phenomenon and produced long-term structural and functional benefits. In a porcine model of myocardial infarction intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.

Bone mass loss in chronic heart failure is associated with secondary hyperparathyroidism and has prognostic significance.

AIMS: Chronic heart failure (CHF) is associated with increased risk of osteoporosis. We investigated the relationship between severity of CHF and bone loss, underlying pathophysiological mechanisms, and the prognostic significance of bone mass changes in heart failure. METHODS AND RESULTS: Total body (TB) and femoral (F) bone mineral density (BMD), and T- and Z-scores in the femur were measured in 60 men with CHF (56 ± 11 years) and 13 age-matched men free from CHF. The composite study endpoint was death, implantation of a left ventricular assist device (LVAD), or inotrope dependency during a median 2-year follow-up. Parathyroid hormone (PTH) and vitamin D were measured in all subjects. TBBMD, FBMD, T-score, and Z-score were significantly lower in men with CHF. Their PTH levels were also significantly increased (111 ± 59 vs. 39 ± 14; P < 0.001). Patients in New York Heart Association classes III-IV compared with those in classes I-II demonstrated significantly lower TBBMD, FBMD, T-score, and Z-score, and higher PTH (136 ± 69 vs. 86 ± 31; P= 0.001). Increased PTH levels were correlated with reduced TBBMD (P = 0.003), FBMD (P = 0.002), and femur T-score (P = 0.001), reduced cardiac index (P = 0.01) and VO(2) peak (P < 0.0001), and increased wedge pressure (P = 0.001). Low TBBMD [hazard ratio (HR) 0.003, 95% confidence interval (CI) 0.00-0.58; P = 0.03] and Z-score (HR 0.56, 95% CI 0.35-0.90; P = 0.017) were associated with adverse outcome. CONCLUSIONS: Secondary hyperparathyroidism and reduction in bone density occur in CHF patients and are associated with disease severity. Increased bone mass loss in CHF has prognostic significance.

Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure.

BACKGROUND: Several skeletal muscle abnormalities have been identified in patients with chronic heart failure (CHF), including endothelial dysfunction. We hypothesized that skeletal muscle microcirculation, assessed by near-infrared spectroscopy (NIRS), is impaired in CHF patients and is associated with disease severity. METHODS: Eighty-three stable patients with mild-moderate CHF (72 males, mean age 54 ± 14 years, body mass index 26.7 ± 3.4 kg/m(2)) and 8 healthy subjects, matched for age, gender and body mass index, underwent NIRS with the vascular occlusion technique and cardiopulmonary exercise testing (CPET) evaluation on the same day. Tissue oxygen saturation (StO(2), %), defined as the percentage of hemoglobin saturation in the microvasculature compartments, was measured in the thenar muscle by NIRS before, during and after 3-minute occlusion of the brachial artery. Measurements included StO(2), oxygen consumption rate (OCR, %/min) and reperfusion rate (RR, %/min). All subjects underwent a symptom-limited CPET on a cycle ergometer. Measurements included VO(2) at peak exercise (VO(2)peak, ml/kg/min) and anaerobic threshold (VO(2)AT, ml/kg/min), VE/VCO(2) slope, chronotropic reserve (CR, %) and heart rate recovery (HRR(1), bpm). RESULTS: CHF patients had significantly lower StO(2) (75 ± 8.2 vs 80.3 ± 6, p < 0.05), lower OCR (32.3 ± 10.4 vs 37.7 ± 5.5, p < 0.05) and lower RR (10 ± 2.8 vs 15.7 ± 6.3, p < 0.05) compared with healthy controls. CHF patients with RR ≥9.5 had a significantly greater VO(2)peak (p < 0.001), VO(2)AT (p < 0.01), CR (p = 0.01) and HRR(1) (p = 0.01), and lower VE/VCO(2) slope (p = 0.001), compared to those with RR <9.5. In a multivariate analysis, RR was identified as an independent predictor of VO(2)peak, VE/VCO(2) slope and HRR(1). CONCLUSIONS: Peripheral muscle microcirculation, as assessed by NIRS, is significantly impaired in CHF patients and is associated with disease severity.