Lars Grieten

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.

Nanocrystalline diamond impedimetric aptasensor for the label-free detection of human IgE

Like antibodies, aptamers are highly valuable as bioreceptor molecules for protein biomarkers because of their excellent selectivity, specificity and stability. The integration of aptamers with semiconducting materials offers great potential for the development of reliable aptasensors. In this paper we present an aptamer-based impedimetric biosensor using a nanocrystalline diamond (NCD) film as a working electrode for the direct and label-free detection of human immunoglobulin E (IgE). Amino (NH(2))-terminated IgE aptamers were covalently attached to carboxyl (COOH)-modified NCD surfaces using carbodiimide chemistry. Electrochemical impedance spectroscopy (EIS) was applied to measure the changes in interfacial electrical properties that arise when the aptamer-functionalized diamond surface was exposed to IgE solutions. During incubation, the formation of aptamer-IgE complexes caused a significant change in the capacitance of the double-layer, in good correspondence with the IgE concentration. The linear dynamic range of IgE detection was from 0.03 μg/mL to 42.8 μg/mL. The detection limit of the aptasensor reached physiologically relevant concentrations (0.03 μg/mL). The NCD-based aptasensor was demonstrated to be highly selective even in the presence of a large excess of IgG. In addition, the aptasensor provided reproducible signals during six regeneration cycles. The impedimetric aptasensor was successfully tested on human serum samples, which opens up the potential of using EIS for direct and label-free detection of IgE levels in blood serum.

Hyponatremia in acute decompensated heart failure: depletion versus dilution.

Hyponatremia frequently poses a therapeutic challenge in acute decompensated heart failure (ADHF). Treating physicians should differentiate between depletional versus dilutional hyponatremia. The former is caused by diuretic agents, which enhance sodium excretion, often with concomitant potassium/magnesium losses. This can be treated with isotonic saline, whereas potassium/magnesium administration may be helpful if plasma concentrations are low. In contrast, as impaired water excretion, rather than sodium deficiency, is the culprit in dilutional hyponatremia, isotonic saline administration may further depress the serum sodium concentration. Because free water excretion is achieved by continuous sodium reabsorption in distal nephron segments with low water permeability, diuretic agents that impair this mechanism (e.g., thiazide-type diuretic agents and mineralocorticoid receptor antagonists) should be avoided, and proximally acting agents (e.g., acetazolamide and loop diuretic agents) are preferred. Vasopressin antagonists, which promote low water permeability in the collecting ducts and, hence, free water excretion, remain under investigation for dilutional hyponatremia in ADHF.

Heat-Transfer Resistance at Solid–Liquid Interfaces: A Tool for the Detection of Single-Nucleotide Polymorphisms in DNA

In this article, we report on the heat-transfer resistance at interfaces as a novel, denaturation-based method to detect single-nucleotide polymorphisms in DNA. We observed that a molecular brush of double-stranded DNA grafted onto synthetic diamond surfaces does not notably affect the heat-transfer resistance at the solid-to-liquid interface. In contrast to this, molecular brushes of single-stranded DNA cause, surprisingly, a substantially higher heat-transfer resistance and behave like a thermally insulating layer. This effect can be utilized to identify ds-DNA melting temperatures via the switching from low- to high heat-transfer resistance. The melting temperatures identified with this method for different DNA duplexes (29 base pairs without and with built-in mutations) correlate nicely with data calculated by modeling. The method is fast, label-free (without the need for fluorescent or radioactive markers), allows for repetitive measurements, and can also be extended toward array formats. Reference measurements by confocal fluorescence microscopy and impedance spectroscopy confirm that the switching of heat-transfer resistance upon denaturation is indeed related to the thermal on-chip denaturation of DNA.

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.

Management of the Cardiorenal Syndrome in Decompensated Heart Failure

Background: The management of the cardiorenal syndrome (CRS) in decompensated heart failure (HF) is challenging, with high-quality evidence lacking. Summary: The pathophysiology of CRS in decompensated HF is complex, with glomerular filtration rate (GFR) and urine output representing different aspects of kidney function. GFR depends on structural factors (number of functional nephrons and integrity of the glomerular membrane) versus hemodynamic alterations (volume status, renal perfusion, arterial blood pressure, central venous pressure or intra-abdominal pressure) and neurohumoral activation. In contrast, urine output and volume homeostasis are mainly a function of the renal tubules. Treatment of CRS in decompensated HF patients should be individualized based on the underlying pathophysiological processes. Key Messages: Congestion, defined as elevated cardiac filling pressures, is not a surrogate for volume overload. Transient decreases in GFR might be accepted during decongestion, but hypotension must be avoided. Paracentesis and compression therapy are essential to remove fluid overload from third spaces. Increasing the effective circulatory volume improves renal function when cardiac output is depressed. As mechanical support is invasive and inotropes are related to increased mortality, afterload reduction through vasodilator therapy remains the preferred strategy in patients who are normo- or hypertensive. Specific therapies to augment renal perfusion (rolofylline, dopamine or nesiritide) have rendered disappointing results, but recently, serelaxin has been shown to improve renal function, even with a trend towards reduced all-cause mortality in selected patients. Diuretic resistance is associated with worse outcomes, independent of the underlying GFR. Combinational diuretic therapy, with ultrafiltration as a bail-out strategy, is indicated in case of diuretic resistance. i 2014 S. Karger AG, Basel

Mitral valve area during exercise after restrictive mitral valve annuloplasty: importance of diastolic anterior leaflet tethering.

BACKGROUND Restrictive mitral valve annuloplasty (RMA) for secondary mitral regurgitation might cause functional mitral stenosis, yet its clinical impact and underlying pathophysiological mechanisms remain debated. OBJECTIVES The purpose of our study was to assess the hemodynamic and clinical impact of effective orifice area (EOA) after RMA and its relationship with diastolic anterior leaflet (AL) tethering at rest and during exercise. METHODS Consecutive RMA patients (n = 39) underwent a symptom-limited supine bicycle exercise test with Doppler echocardiography and respiratory gas analysis. EOA, transmitral flow rate, mean transmitral gradient, and systolic pulmonary arterial pressure were assessed at different stages of exercise. AL opening angles were measured at rest and peak exercise. Mortality and heart failure readmission data were collected for at least 20 months after surgery. RESULTS EOA and AL opening angle were 1.5 ± 0.4 cm(2) and 68 ± 10°, respectively, at rest (r = 0.4; p = 0.014). EOA increased significantly to 2.0 ± 0.5 cm(2) at peak exercise (p < 0.001), showing an improved correlation with AL opening angle (r = 0.6; p < 0.001). Indexed EOA (EOAi) at peak exercise was an independent predictor of exercise capacity (maximal oxygen uptake, p = 0.004) and was independently associated with freedom from all-cause mortality or hospital admission for heart failure (p = 0.034). Patients with exercise EOAi <0.9 cm(2)/m(2) (n = 14) compared with ≥0.9 cm(2)/m(2) (n = 25) had a significantly worse outcome (p = 0.048). In multivariate analysis, AL opening angle at peak exercise (p = 0.037) was the strongest predictor of exercise EOAi. CONCLUSIONS In RMA patients, EOA increases during exercise despite fixed annular size. Diastolic AL tethering plays a key role in this dynamic process, with increasing AL opening during exercise being associated with higher exercise EOA. EOAi at peak exercise is a strong and independent predictor of exercise capacity and is associated with clinical outcome. Our findings stress the importance of maximizing AL opening by targeting the subvalvular apparatus in future repair algorithms for secondary mitral regurgitation.

Non-invasive assessment of gestational hemodynamics: benefits and limitations of impedance cardiography versus other techniques

To obtain data for maternal stroke volume and cardiac output during pregnancy, it is preferable to use a non-invasive, accurate and reproducible method. In this aspect, impedance cardiography is an excellent technique which is also highly accessible and easy to perform. This paper is a comprehensive review on the published literature about impedance cardiography and highlights the strengths and limitations of its applications in obstetrics.

Revisiting diastolic filling time as mechanistic insight for response to cardiac resynchronization therapy

AIMS Intraventricular dyssynchrony and commonly associated prolonged atrioventricular conduction both reduce diastolic filling time (DFT), which can be improved by cardiac resynchronization therapy (CRT). Our aim was to investigate whether change in DFT corrected for RR interval (DFTC) after CRT might serve to assess the mechanistic response to CRT. METHODS AND RESULTS Echocardiography data of consecutive patients in sinus rhythm (n = 91) were studied before and 6 months after implantation. Mortality and heart failure hospitalization data were collected. Patients with vs. without DFTC increase after 6 months were compared. The programmed atrioventricular delay, percentage of biventricular pacing, and change in PR interval were similar in both groups. DFTC increase after 6 months reflected favourable reverse left ventricular remodelling and was significantly associated with freedom from death or heart failure admission (P = 0.008). In multivariate analysis including guideline criteria for CRT (i.e. QRS width, presence of left bundle branch block, and ejection fraction), interventricular mechanical delay, and Tei index, baseline DFTC was the strongest predictor of adverse outcome. Notably, while patients with impaired relaxation had a large and highly significant reduction in all-cause mortality and heart failure admissions when DFTC increased [hazard ratio (HR), 95% confidence interval (CI) = 0.24, 0.08-0.73; P = 0.012], this benefit was less pronounced and did not reach statistical significance in patients with pseudonormal or restrictive filling (HR, 95% CI = 0.64, 0.23-1.77; P = 0.388). CONCLUSION DFTC increase after CRT reflects favourable reverse remodelling and is associated with better clinical outcome.

New Insights into Combinational Drug Therapy to Manage Congestion in Heart Failure

Congestion is the most important contributor to morbidity and mortality in heart failure. In patients without congestion, maintaining a neutral sodium balance is imperative to prevent evolving volume overload. Adequate use of neurohumoral blockers, in combination with dietary sodium restriction, is essential and may preclude the need for maintenance diuretic therapy. If volume overload still prevails, loop diuretics remain the mainstay treatment to reduce excessive extracellular volume. However, combinational drug therapy might offer a more attractive alternative to achieve a balanced natriuresis, instead of further uptitration of loop diuretics. Importantly, elevated cardiac filling pressures may be caused by volume misdistribution and impaired venous capacitance, rather than absolute volume overload. Vasodilator therapy to unload the heart, increase venous capacitance, and lower arterial impedance might be interesting in such cases. This review offers a practical approach into current and potential future pharmacologic therapies for managing congestion, focusing on combinational and targeted therapy.