Pieter Martens

Current Approach to Decongestive Therapy in Acute Heart Failure

Congestion, defined by elevated cardiac filling pressures, is the major driver of hospitalization in acute decompensated heart failure. Careful clinical assessment should allow to determine whether volume overload or volume misdistribution is the predominating mechanism of congestion. Differentiation is imperative because therapy differs. If volume overloads prevails, loop diuretics are considered the mainstay therapy. However, early use of combinational therapy with diuretics acting more proximal or distal in the nephron could allow for a more profound natriuresis and diuresis. A stepped guided pharmacological treatment should focus on achieving complete decongestion, because persistent congestion is a major driver of readmission. If diuretic strategies remain unsuccessful, ultrafiltration should be considered. Ultrafiltration should be used with caution in the setting of worsening of renal function. When volume misdistribution and impaired venous capacitance predominate the picture of congestion, unloading—more than diuretics—with arteriolar and venous vasodilators might mitigate the clinical picture of congestion. This review offers a thorough overview and practical insight in the use of current and potential decongestive therapies.

Plasma Volume Is Normal but Heterogeneously Distributed, and True Anemia Is Highly Prevalent in Patients With Stable Heart Failure

BACKGROUND Intravascular volume overload and depletion as well as anemia are associated with increased hospital admissions and mortality in patients with heart failure. This study aimed to accurately measure plasma volume and red cell mass (RCM) in stable patients with chronic heart failure with reduced ejection fraction (HFrEF) and gain more insight into plasma volume regulation and anemia in stable conditions of HFrEF. METHODS AND RESULTS Plasma volume and RCM measurement based on 99Tc-labeled red blood cells, venous blood sample,s and clinical parameters were obtained in 24 stable HFrEF patients under optimal medical therapy. Measured plasma volume values were compared with predicted values based on body surface area. Plasma volume was on average normal (99.98% of predicted) but heterogeneously distributed (variations of 81%-133%). Neurohumoral activation and medication use were not associated with plasma volume status. Furthermore, anemia based on actual measurement of RCM was present in up to 75% of subjects, but rarely hemodilutional. CONCLUSIONS In stable chronic HFrEF patients under optimal medical therapy, plasma volume is overall normal but heterogeneously distributed. Anticipated factors such as neurohumoral activation and heart failure medication were not associated with plasma volume. Furthermore, anemia is more common than as assessed by hemoglobin.

Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy

BACKGROUND Cardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. METHODS AND RESULTS Doses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316-0.913; P = .022) for ACE-I/ARB and 0.633 (0.406-0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). CONCLUSIONS After CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation.

Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction.

Abstract Background: Little information is available about the prevalence and impact on exercise capacity and outcome of iron deficiency in heart failure with mid-range (HFmrEF) and preserved (HFpEF) ejection fraction in comparison to heart failure with reduced ejection-fraction (HFrEF). Furthermore, no data is available about the progression of ID in patients without baseline anaemia. Methods: We evaluated baseline iron and haemoglobin-status in a single-centre, prospective heart failure database. Baseline functional status, VO2max, echocardiography and clinical-outcome (all-cause mortality and heart failure admissions) were evaluated. ID, anaemia, HFrEF, HFmrEF and HFpEF were defined according to established criteria. Results: A total of 1197 patients (71% male) were evaluated (HFrEF, n = 897; HFmrEF, n = 229; HFpEF, n = 72). The overall prevalence of ID was 53% (50% in HFrEF; 61% in HFmrEF; 64% in HFpEF) and 36% for anaemia. ID was associated with a lower VO2max in patients with HFrEF, HFmrEF and HFpEF (p < .001 in all). Iron status more closely related to a poor VO2max than anaemia status (p < .001). Furthermore, poor clinical-outcome was more strongly associated with iron status than anaemia status. Exposing eight patients without anaemia to iron deficiency for 39 months resulted in one patient developing new-onset anaemia (defined as progression of ID). Patients with progression of ID exhibited a significant higher risk of heart failure hospitalisation and all-cause mortality (HR = 1.4; CI = 1.01–1.94; p = .046) than patients without progression. Conclusions: Iron deficiency is common in patients with HFrEF, HFmrEF and HFpEF, and negatively affects VO2max and clinical-outcome. Progression of iron deficiency parallels an increased risk for worsening of heart failure.

Mode of Death in Octogenarians Treated With Cardiac Resynchronization Therapy

BACKGROUND Cardiac resynchronization therapy (CRT) improves morbidity and mortality in heart failure with reduced ejection fraction (HFrEF) and electrical dyssynchrony. CRT patients in clinical practice are older compared with clinical trials. OBJECTIVE To investigate clinical response, reverse remodeling, outcome, and mode of death in octogenarians receiving CRT. METHODS Baseline characteristics, change in New York Heart Association (NYHA) functional class, reverse ventricular remodeling, heart failure readmissions, all-cause mortality, and mode of death were evaluated in CRT patients with comparison between octogenarians and nonoctogenarians. In addition, annual mortality rates of octogenarians undergoing CRT were compared with age-matched control subjects from the general population with the use of national actuarial tables. RESULTS A total of 686 patients, including 178 octogenarians (26%), were followed for 38 ± 22 months. Octogenarians exhibited a similar change in NYHA functional class (P = .640), left ventricular ejection fraction increase (P = .796), and decrease in end-diastolic (P = .441) and end-systolic (P = .312) diameter compared with their younger counterparts undergoing CRT. Octogenarians had a higher all-cause mortality risk (P < .001), but heart failure readmission risk did not differ (hazard ratio 0.916, 95% confidence interval 0.638-1.313; P = .632). A higher proportion of noncardiac deaths was observed in octogenarians (74%) versus younger patients (50%; P = .022), with worsening heart failure rather than malignant tachyarrhythmia being the main cardiac cause of death. Compared with an age-matched sample from the general population, octogenarians receiving CRT had an equivalent annual mortality rate (log-rank test: P = .444). CONCLUSIONS Octogenarians retain the ability to mount a significant symptomatic and ventricular remodeling response after CRT, resulting in survival similar to the general age-matched population.

Insights into implementation of sacubitril/valsartan into clinical practice: Implementation of sacubitril/valsartan in clinical practice

Sacubitril/valsartan significantly reduced heart failure hospitalization and mortality in PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor‐Neprilysin Inhibitor With an Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). However, real‐world data from its use are lacking.

SGLT-2 Inhibitors in Heart Failure: Implications for the Kidneys

Purpose of ReviewThis review aims to summarize the renal effects of sodium-glucose transporter-2 (SGLT-2) inhibitors and their potential implications in heart failure pathophysiology.Recent FindingsIn patients with diabetes and established atherosclerosis, the SGLT-2 inhibitor empagliflozin versus placebo significantly reduced the rate of heart failure admissions with 35%. Moreover, empagliflozin slowed kidney disease progression and reduced the need for renal replacement therapy.SummarySGLT-2 inhibitors inhibit proximal tubular sodium and chloride reabsorption, leading to increased nephron flux throughout the distal renal tubules, most notably at the level of the macula densa. Afferent arteriolar vasoconstriction is promoted through tubulo-glomerular feedback and reduces glomerular capillary hydrostatic pressure, relieving podocyte stress and explaining renal preservation. Further, plasma volume is contracted and natriuresis promoted without inducing neurohumoral activation. Finally, SGLT-2 inhibitors may improve endothelial function and energy metabolism efficiency. Together, these promising features place them as a potential novel treatment for heart failure.

Value of routine investigations to predict loop diuretic down-titration success in stable heart failure

AIMS Guidelines advocate down-titration of loop diuretics in chronic heart failure (CHF) when patients have no signs of volume overload. Limited data are available on the expected success rate of this practice or how routine diagnostic tests might help steering this process. METHODS AND RESULTS Fifty ambulatory CHF-patients on stable neurohumoral blocker/diuretic therapy for at least 3months without any clinical sign of volume overload were prospectively included to undergo loop diuretic down-titration. All patients underwent a similar pre-down-titration evaluation consisting of a dyspnea scoring, physical examination, transthoracic echocardiography (diastolic function, right ventricular function, cardiac filling pressures and valvular disease), blood sample (serum creatinine, plasma NT-pro-BNP and neurohormones). Loop diuretic maintenance dose was subsequently reduced by 50% or stopped if dose was ≤40mg furosemide equivalents. Successful down-titration was defined as a persistent dose reduction after 30days without weight increase >1.5kg or new-onset symptoms of worsening heart failure. At 30-day follow-up, down-titration was successful in 62% (n=31). In 12/19 patients exhibiting down-titration failure, this occurred within the first week. Physical examination, transthoracic echocardiography and laboratory analysis had limited predictive capability to detect patients with down-titration success/failure (positive likelihood-ratios below 1.5, or area under the curve [AUC] non-statically different from AUC=0.5). CONCLUSION Loop diuretic down-titration is feasible in a majority of stable CHF patients in which the treating clinician felt continuation of loops was unnecessary to sustain euvolemia. Importantly, routine diagnostics which suggest euvolemia, have limited diagnostic impact on the post-test probability.

Limited contractile reserve contributes to poor peak exercise capacity in iron-deficient heart failure

Iron deficiency independently predicts poor exercise capacity in heart failure with reduced ejection fraction (HFrEF), objectified as a low peak maximal oxygen consumption (VO2max). 1 Yet, precise mechanisms by which iron deficiency results in limited exercise capacity remain elusive. Peak VO2max is determined by the Fick equation as the difference between arterial O2 content (CaO2) and venous O2 content (CvO2) multiplied by cardiac output (CO) [VO2max= (CaO2 − CvO2)×CO]. Iron deficiency could impact all three components of the Fick equation thereby resulting in a blunted peak VO2max. However, the precise contribution of iron deficiency to each individual component of the Fick equation remains unknown. We prospectively included HFrEF patients admitted for haemodynamic guided decongestive therapy using a pulmonary artery catheter (PAC). All patients provided written informed consent and the study was approved by the institutional review board (Ziekenhuis Oost Limburg, Belgium). On the final day of the admission to the cardiac critical care unit a complete haemodynamic profile was registered at rest. Results of the laboratory analysis were used to stratify patients into an iron-deficient group (ferritin <100 μg/L or ferritin between 100 and 300 μg/L with a transferrin saturation <20%) and a non-iron-deficient group. Arterial O2 saturation (SaO2) and partial arterial O2 pressure (PaO2) were measured from an arterial blood sample obtained from a radial artery line. Mixed venous O2 saturation (SvO2) and partial venous O2 pressure (PvO2) were measured from a mixed venous sample from the PAC. CaO2 and CvO2 were calculated using the oxygen content formula [Ca/vO2 = (Hb× 1.36× Sa/vO2)+ (0.0031× Pa/vO2) with Hb denoting haemoglobin]. Cardiac output was monitored real-time using the automatic thermodilution application of the PAC (Swan-Ganz Continuous Cardiac Output Thermodilution Catheter 744HF75, Edwards Lifesciences, Irvine, CA, USA). Afterwards patients were asked to perform a symptom-limited supine bicycle exercise test (MOTOmed®Letto2, RECKTechnik GmbH&Co, Betzenweiler, Germany) under continuous haemodynamic monitoring. Patients were instructed to achieve 55–65 r.p.m. during eight cycles of 3 min at increasing workloads. At every increase of workload, an invasive haemodynamic assessment as well as arterial and mixed venous blood gases were obtained. Afterwards the impact of iron deficiency on contractile reserve (rise in CO and cardiac index from baseline to peak exercise) and peripheral O2 extraction (CaO2 –CvO2) between

Heart Failure with Myocardial Recovery - The Patient Whose Heart Failure Has Improved: What Next?

In an important number of heart failure (HF) patients substantial or complete myocardial recovery occurs. In the strictest sense, myocardial recovery is a return to both normal structure and function of the heart. HF patients with myocardial recovery or recovered ejection fraction (EF; HFrecEF) are a distinct population of HF patients with different underlying etiologies, demographics, comorbidities, response to therapies and outcomes compared to HF patients with persistent reduced (HFrEF) or preserved ejection fraction (HFpEF). Improvement of left ventricular EF has been systematically linked to improved quality of life, lower rehospitalization rates and mortality. However, mortality and morbidity in HFrecEF patients remain higher than in the normal population. Also, persistent abnormalities in biomarker and gene expression profiles in these patients lends weight to the hypothesis that pathological processes are ongoing. Currently, there remains a lack of data to guide the management of HFrecEF patients. This review will discuss specific characteristics, pathophysiology, clinical implications and future needs for HFrecEF.