Matthias Dupont

Abdominal Contributions to Cardiorenal Dysfunction in Congestive Heart Failure

Current pathophysiological models of congestive heart failure unsatisfactorily explain the detrimental link between congestion and cardiorenal function. Abdominal congestion (i.e., splanchnic venous and interstitial congestion) manifests in a substantial number of patients with advanced congestive heart failure, yet is poorly defined. Compromised capacitance function of the splanchnic vasculature and deficient abdominal lymph flow resulting in interstitial edema might both be implied in the occurrence of increased cardiac filling pressures and renal dysfunction. Indeed, increased intra-abdominal pressure, as an extreme marker of abdominal congestion, is correlated with renal dysfunction in advanced congestive heart failure. Intriguing findings provide preliminary evidence that alterations in the liver and spleen contribute to systemic congestion in heart failure. Finally, gut-derived hormones might influence sodium homeostasis, whereas entrance of bowel toxins into the circulatory system, as a result of impaired intestinal barrier function secondary to congestion, might further depress cardiac as well as renal function. Those toxins are mainly produced by micro-organisms in the gut lumen, with presumably important alterations in advanced heart failure, especially when renal function is depressed. Therefore, in this state-of-the-art review, we explore the crosstalk between the abdomen, heart, and kidneys in congestive heart failure. This might offer new diagnostic opportunities as well as treatment strategies to achieve decongestion in heart failure, especially when abdominal congestion is present. Among those currently under investigation are paracentesis, ultrafiltration, peritoneal dialysis, oral sodium binders, vasodilator therapy, renal sympathetic denervation and agents targeting the gut microbiota.

Differential Response to Cardiac Resynchronization Therapy and Clinical Outcomes According to QRS Morphology and QRS Duration

OBJECTIVES The goal of this study was to examine the relative impact of QRS morphology and duration in echocardiographic responses to cardiac resynchronization therapy (CRT) and clinical outcomes. BACKGROUND At least one-third of all patients treated with CRT fail to derive benefit. Patients without left bundle branch block (LBBB) or patients with smaller QRS duration (QRSd) respond less or not at all to CRT. METHODS We retrospectively assessed baseline characteristics, clinical and echocardiographic response, and outcomes of all patients who received CRT at our institution between December 2003 and July 2007. Patients were stratified into 4 groups according to their baseline QRS morphology and QRSd. RESULTS A total of 496 patients were included in the study; 216 (43.5%) had LBBB and a QRSd ≥150 ms, 85 (17.1%) had LBBB and QRSd <150 ms, 92 (18.5%) had non-LBBB and a QRSd ≥150 ms, and 103 (20.8%) had non-LBBB and QRSd <150 ms. Echocardiographic response (change in ejection fraction) was better in patients with LBBB and QRSd ≥150 ms (12 ± 12%) than in those with LBBB and QRSd <150 ms (8 ± 10%), non-LBBB and QRSd ≥150 ms (5 ± 9%), and non-LBBB and QRSd <150 ms (3 ± 11%) (p < 0.0001). In a multivariate stepwise model with change in ejection fraction as the dependent variable, the presented classification was the most important independent variable (p = 0.0003). Long-term survival was better in LBBB patients with QRSd ≥150 ms (p = 0.02), but this difference was not significant after adjustment for other baseline characteristics (p = 0.15). CONCLUSIONS QRS morphology is a more important baseline electrocardiographic determinant of CRT response than QRSd.

Prognostic Role of Pulmonary Arterial Capacitance in Advanced Heart Failure

Background—Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure. Methods and Results—We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (r=−0.64) and wedge pressure (r=−0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively, P=0.003). During a mean follow-up of 3.2±2.2 years, both lower PAC (P<0.0001) and higher PVR (P<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84–1.0, P=0.037]). Treatment of heart failure resulted in a decrease in PVR (270±165 to 211±88 dynes·s–1·cm–5, P=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 mL/mm Hg, P<0.0001), leading to an increase in pulmonary arterial time constant (PVR×PAC) (0.29±0.12 to 0.37±0.15 second, P<0.0001). Conclusions—PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy.

Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment

‘Worsening renal function’ (WRF) and ‘improvement in renal function’ (IRF) monitored by changes in serum creatinine are frequently encountered during treatment of acute decompensated heart failure (ADHF). We sought to establish the important haemodynamic determinants of alterations in serum creatinine.

Lack of significant renal tubular injury despite acute kidney injury in acute decompensated heart failure

Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase‐associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury.

Relation of systemic and urinary neutrophil gelatinase-associated lipocalin levels to different aspects of impaired renal function in patients with acute decompensated heart failure

Both urine and serum neutrophil gelatinase-associated lipocalin (NGAL) reflect active chronic kidney disease and predict acute kidney injury. However, a direct comparison of these markers in acute decompensated heart failure has not been performed. We prospectively evaluated 93 patients admitted with acute decompensated heart failure and treated with intravenous furosemide and measured both systemic (serum) and urine NGAL levels and their corresponding markers of estimated glomerular filtration rate, natriuresis (urine sodium), and diuretic response (net output, urine sodium/furosemide ratio). In our study cohort, the median urine and serum NGAL level was 34 ng/ml (interquartile range 24 to 86) and 252 ng/ml (interquartile range 175 to 350), respectively. The urine and serum NGAL levels correlated modestly (r = 0.37, p <0.001). Higher urine (but not systemic) NGAL correlated with the markers of impaired natriuresis and reduced diuresis (p <0.005 for all). In contrast, higher serum NGAL demonstrated a stronger relation with reduced glomerular filtration function (p <0.0001). Both markers predicted acute kidney injury (urine NGAL, odds ratio 1.7, p = 0.035; serum NGAL, odds ratio 1.9, p = 0.009). In conclusion, in patients with acute decompensated heart failure, urine NGAL levels reflect renal distal tubular injury with impaired natriuresis and diuresis, and systemic NGAL levels demonstrate a stronger association with glomerular filtration function. Both systemic and urine NGAL predict worsening renal function.

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 nephrons 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.

Cystatin C Identifies Patients with Stable Chronic Heart Failure at Increased Risk for Adverse Cardiovascular Events

Background—Renal function is a strong predictor of adverse events in heart failure. Current renal function measures are imperfect, and cystatin C (CysC) is promoted as a better marker of glomerular filtration rate. This study compares the prognostic use of CysC and derived glomerular filtration rate estimates with other measures of renal function in patients with chronic heart failure. Methods and Results—We measured serum CysC levels in 823 patients with heart failure undergoing coronary angiography with follow-up of major adverse cardiovascular events (death, myocardial infarction, stroke). CysC levels strongly correlated with creatinine (r=0.73), blood urea nitrogen (r=0.70), and estimated glomerular filtration rate by the 4-variable modification of diet in renal disease equation (r=−0.62) (all P<0.001). However, the correlation was lower in estimated glomerular filtration rate ≥60 mL/min per 1.73 m2. CysC-based measures significantly improved areas under the receiver operating characteristic curve for the prediction of major adverse cardiovascular events, especially in estimated glomerular filtration rate ≥60 mL/min per 1.73 m2 (P<0.01). Net reclassification improvement was 22.2% (P<0.001) in this group. CysC remained an independent predictor of major adverse cardiovascular events (P<0.001) after adjustment for traditional risk factors and brain natriuretic peptide. Conclusions—CysC is an independent predictor of adverse events in chronic heart failure. It adds prognostic value to creatinine, particularly in patients with preserved renal function.

Impact of Systemic Venous Congestion in Heart Failure

Systemic venous congestion is one of the hallmarks of the syndrome of heart failure that results from activation of different deleterious neurohormonal pathways. Apart from contributing to patients’ symptoms and hospital admissions, growing evidence suggests that congestion itself drives further heart failure progression. In addition, systemic venous congestion exerts detrimental effects on other organs (such as kidneys and liver) due to ineffective organ perfusion. Endothelial cell activation, altered ventricular geometry, and functional mitral insufficiency are among the proposed mechanisms. Diuretics and vasodilators remain the mainstay of treatment options, mostly because of poor understanding of the underlying cardiorenal mechanisms involved. Recently, ultrafiltration has emerged as an invasive treatment option in the setting of diuretic resistance. Congestion ideally should be prevented, often initially through water and salt restriction. Early detection, possibly with the help of novel implantable sensor technology, may allow for early detection and intervention long before overt congestion is established.

Response to cardiac resynchronization therapy in elderly patients (≥70 years) and octogenarians

Cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling, improved functional capacity, and better clinical outcome in patients with advanced chronic heart failure, reduced ejection fraction, and evidence of ventricular conduction delay, who are under optimal medical therapy. This study investigated whether these benefits can be extrapolated to older patients, typically not included in randomized clinical trials.