Cholesterol in end-stage renal disease: the good, the bad or the ugly?

The incidence of cardiovascular disease is markedly increased in patients with end-stage renal disease (ESRD). High serum cholesterol is widely recognised as a cardiovascular risk factor in the general population. However, in patients with ESRD high concentrations of cholesterol are associated with a better survival. This reverse epidemiology is, amongst others, caused by confounding due to malnutrition and chronic inflammation. In this population, treatment with statins to lower the serum cholesterol remains a matter of debate. In ESRD, LDL cholesterol is modified by increased oxidative stress. These altered LDL particles play a pivotal role in the development of atherosclerosis. Treatment with the antioxidant vitamin E has not equivocally been shown to be beneficial in this population. This review tries to put data from literature on dyslipidaemia and oxidative stress in ESRD in perspective.     

Are thiazolidinediones good or bad for the heart?

Type 2 diabetes is a global epidemic contributing to significant cardiovascular morbidity and mortality. The high prevalence of cardiovascular disease can largely be attributed to the metabolic syndrome with its multiple cardiovascular risk factors, including central obesity, hypertension, glucose intolerance, chronic inflammation, and dyslipidemia. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, may potentially correct the inflammatory disarray, endothelial dysfunction, dyslipidemia, and plaque vulnerability associated with diabetic cardiovascular disease through their effects on insulin resistance and fat metabolism, yet they can also exacerbate congestive heart failure. This review summarizes basic science, animal, and human data on the effects of thiazolidinediones on cardiovascular disease.     

The kidney in congestive heart failure: ‘are natriuresis,sodium, and diuretics really the good,the bad and the ugly?’

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy‐refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter‐regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction—although not by conventional GFR measurements—is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.     

Heart failure: the electrophysiological connection. Myocardial stunning and heart failure: mechanisms in common?

The delayed recovery of function after brief episodes of ischemia is known as stunning. Myocardial stunning and heart failure would, at first glance, appear to have little in common other than the obvious contractile dysfunction in both settings. Here I describe studies which shed new light on the underlying mechanisms of these two forms of contractile dysfunction, revealing unexpected fundamental similarities.     

HDL cholesterol in cardiovascular diseases: The good,the bad,and the ugly?

Atherosclerotic cardiovascular diseases are the leading cause of death in developed and developing countries. HDL-raising therapeutic modalities (such as cholesterol ester transferase protein (CETP) inhibitors) are being developed to combat these diseases. However, recent setback of two CETP inhibitors (Torcetrapib and Dalcetrapib) has highlighted the importance of measuring qualitative functionality of HDL particles, rather than focusing quantitatively on HDL cholesterol serum concentrations. It has been known that, HDL from patients with coronary artery disease (CAD) (i.e., HDL^CAD) limits the anti-inflammatory and endothelial repair properties of normal HDL, due to the activation of lectin-like oxidized LDL receptor-1 (LOX-1), thereby causing failure in endothelial nitric oxide (NO) production. A more recent study (Immunity 2013; 38: 754–768) also demonstrates that HDL from patients with chronic kidney dysfunction (CKD) (i.e., HDL^CKD), unlike its healthy counterpart (i.e., HDL^Healthy), promotes superoxide production, reduces NO bioavailability and raises blood pressure via toll-like receptor-2 (TLR-2) activation. This study provides novel insights into understanding why HDL-raising agents failed to demonstrate beneficial effects on cardiovascular mortality in large clinical trials and why CKD accelerates the development of atherosclerosis in CAD patients. Further research is warranted to elucidate whether HDL^CKD and HDL^CAD participate in other cellular processes in atherosclerosis, such as foam cell formation, the proliferation and migration of smooth muscle cells, and most importantly, plaque destabilization.     

Measuring plasma B-type natriuretic peptide in heart failure: good to go in 2004?

Elevated plasma brain natriuretic (BNP) concentrations correlate with increased cardiac filling pressures. Therefore, increased BNP has been proposed as a marker for asymptomatic ventricular dysfunction, as an aid in the diagnosis of cardiac dyspnea, as an end point to assess the efficacy of heart failure therapy, and as a prognostic marker in heart failure. An understanding of the utility of BNP requires an appreciation of the sensitivity, specificity, and diagnostic accuracy of BNP in each of these clinical situations. At this time, there is strong evidence for the value of BNP in the evaluation of dyspnea of uncertain cause. Further population studies will need to be performed to refine the application of BNP to community cohorts and to determine its clinical value and cost-effectiveness as a screening tool in the early diagnosis of ventricular dysfunction. To make optimal use of BNP for the assessment of heart failure therapy and prognosis in individual patients, physicians will require additional information on the biological variability of BNP. Studies comparing the sensitivity, specificity, and predictive value of the available BNP and N-terminal pro-BNP assays need to be conducted in each of these clinical settings.     

Why is depression bad for the failing heart? A review of the mechanistic relationship between depression and heart failure

BACKGROUND: Depression is 4 to 5 times as common in heart failure (HF) patients as in the general population, might confer a higher risk of developing HF, and negatively affects prognosis in established HF. METHODS AND RESULTS: A review was undertaken via Medline (1966-2003) and PsycINFO (1872-2003) searches using the subject headings "depressive disorder" and "heart failure, congestive." Our findings suggest that the link between depression and HF may be due to shared pathophysiology. Depression may augment catecholamine release, arrhythmias, elaboration of proinflammatory cytokines, and platelet activation--processes that may influence prognosis in HF. Depression is also associated with a higher risk of noncompliance and lower levels of social support, which have been shown to worsen prognosis in HF. The impact of pharmacologic or behavioral treatment for depression on physiologic parameters or clinical outcomes in HF remains unclear. Inherent difficulties in recognition of depression in the setting of HF may decrease the likelihood that depressed patients receive the treatment they need. CONCLUSIONS: Depression is common in HF, may contribute to the development of HF in susceptible populations, and is independently predictive of poor clinical outcomes. Pathophysiologic pathways and psychosocial issues that are shared between the 2 conditions might explain these observations and represent potential therapeutic targets. Vigilant attention to the recognition and treatment of depression in HF patients is warranted.     

Atrial fibrillation in heart failure: the chicken or the egg?

Atrial fibrillation (AF) and heart failure (HF) are the emerging epidemics of cardiovascular disease in the new millennium. Both are responsible for considerable morbidity and mortality and health budget expenditure. The advent of catheter ablation for patients with AF has provided important new insights into the relative contribution of AF to left ventricular dysfunction. The aim of this review is to discuss the complex interplay in the pathophysiology of AF and HF to improve our understanding of the basis for current treatment strategies and guide future research direction.     

Perceived overprotection: support gone bad?

OBJECTIVE: This article focuses on the effects of perceived overprotection, a potentially problematic aspect of receiving support, on the ability to adjust to a chronic impairment, specifically, age-related vision loss. Perceived overprotection is an especially critical issue in this population of chronically ill older adults because of the safety issues associated with vision impairment and because perceptions on the part of the older adult that the support providers are overprotective may lead to excess disability. METHODS: Participants were 584 older men and women with age-related vision impairment who applied for services at a vision rehabilitation agency. Path analysis was used to examine the effects of perceived overprotection on two positive indicators of adjustment: vision-specific adaptation and environmental mastery. Moreover, antecedents of perceived overprotection were examined. RESULT: Higher levels of perceived overprotection were associated with less optimal adjustment to age-related vision loss, with lower scores on measures of vision-specific adaptation and environmental mastery. Higher levels of functional disability and instrumental support received were associated with higher levels of perceived overprotection. DISCUSSION: Findings indicate that support providers of older adults with visual impairment as well as vision rehabilitation service providers need to be aware of the detrimental impact of perceived overprotection.     

Diastolic and systolic heart failure: Different stages or distinct phenotypes of the heart failure syndrome?

It remains uncertain if diastolic heart failure (DHF) is a distinct HF phenotype or a precursor stage of systolic HF (SHF). The unimodal distribution of left ventricular ejection fraction (LVEF) in HF, depressed LV long-axis shortening in DHF, and progression to eccentric LV remodeling in hypertension favor DHF and SHF as successive stages. These arguments are countered by the bimodal distribution of LVEF after correction for gender, by the preserved LV twist in DHF and by the low incidence of eccentric LV remodeling in hypertension. Clinical features, LV anatomy and histology, cardiomyocyte stiffness, myocardial effects of diabetes, and the response to HF therapy support DHF and SHF as distinct phenotypes. Comparison of the myocardial signal transduction cascades that drive LV remodeling in DHF and SHF may solve the controversy. This review analyzes arguments supporting DHF and SHF as successive stages or distinct phenotypes of the HF syndrome.