Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induced by aorto-caval fistula (ACF) and attenuates CKD progression. This prompted us to examine if sEH inhibitor treatment would improve the outcome if both experimental conditions are combined. Fawn-hooded hypertensive (FHH) rats, a genetic model showing early CKD development was employed, and CHF was induced by ACF. Treatment with an sEH inhibitor was initiated 4 weeks after ACF creation, in FHH and in fawn-hooded low-pressure (FHL) rats, a control strain without renal damage. The follow-up period was 20 weeks. We found that ACF FHH rats exhibited substantially lower survival rates (all the animals died by week 14) as compared with the 64% survival rate observed in ACF FHL rats. The former group showed pronounced albuminuria (almost 30-fold higher than in FHL) and reduced intrarenal EET concentrations. The sEH inhibitor treatment improved survival rate and distinctly reduced increases in albuminuria in ACF FHH and in ACF FHL rats, however, all the beneficial actions were more pronounced in the hypertensive strain. These data indicate that pharmacological blockade of sEH could be a novel therapeutic approach for the treatment of CHF, particularly under conditions when it is associated with CKD

Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA)

BACKGROUND: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. METHODS: Anemia was defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization Anemia). Adverse events reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization) and the time-updated hemoglobin relationship to outcomes. RESULTS: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo (P<0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, adverse event anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (versus placebo) on the primary outcome. In addition, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (versus placebo) on the primary outcome. CONCLUSIONS: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534

Effects of semaglutide on symptoms, function, and quality of life in patients with heart failure with preserved ejection fraction and obesity: a prespecified analysis of the STEP-HFpEF trial

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [–0.6 to 9.9] points; for body weight, –11 [–13.2 to –8.8], –9.4 [–11.5 to –7.2], and –11.8 [–14.0 to –9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction&gt;0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7–9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6–2.9 across domains; P&lt;0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains

Bioptic Study of Left and Right Atrial Interstitium in Cardiac Patients with and without Atrial Fibrillation: Interatrial but Not Rhythm-Based Differences.

One of the generally recognized factors contributing to the initiation and maintenance of atrial fibrillation (AF) is structural remodeling of the myocardium that affects both atrial cardiomyocytes as well as interstitium. The goal of this study was to characterize morphologically and functionally interstitium of atria in patients with AF or in sinus rhythm (SR) who were indicated to heart surgery. Patient population consisted of 46 subjects (19 with long-term persistent AF, and 27 in SR) undergoing coronary bypass or valve surgery. Peroperative bioptic samples of the left and the right atria were examined using immunohistochemistry to visualize and quantify collagen I, collagen III, elastin, desmin, smooth muscle actin, endothelium and Vascular Endothelial Growth Factor (VEGF). The content of interstitial elastin, collagen I, and collagen III in atrial tissue was similar in AF and SR groups. However, the right atrium was more than twofold more abundant in elastin as compared with the left atrium and similar difference was found for collagen I and III. The right atrium showed also higher VEGF expression and lower microvascular density as compared to the left atrium. No significant changes in atrial extracellular matrix fiber content, microvascular density and angiogenic signaling, attributable to AF, were found in this cohort of patients with structural heart disease. This finding suggests that interstitial fibrosis and other morphological changes in atrial tissue are rather linked to structural heart disease than to AF per se. Significant regional differences in interstitial structure between right and left atrium is a novel observation that deserves further investigation

Kidney Response to Chemotherapy-Induced Heart Failure: mRNA Analysis in Normotensive and Ren-2 Transgenic Hypertensive Rats

The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague–Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin–angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches

Attenuation of Hypocretin/Orexin Signaling Is Associated With Increased Mortality After Myocardial Infarction

Background The hypocretin/orexin system has been shown to play a role in heart failure. Whether it also influences myocardial infarction (MI) outcomes is unknown. We evaluated the effect of the rs7767652 minor allele T associated with decreased transcription of the hypocretin/orexin receptor‐2 and circulating orexin A concentrations on mortality risk after MI. Methods and Results Data from a single‐center, prospectively designed registry of consecutive patients hospitalized for MI at a large tertiary cardiology center were analyzed. Patients without previous history of MI or heart failure were included. A random population sample was used to compare allele frequencies in the general population. Out of 1009 patients (aged 64±12 years, 74.6% men) after MI, 6.1% were homozygotes (TT) and 39.4% heterozygotes (CT) for minor allele. Allele frequencies in the MI group did not differ from 1953 subjects from general population (χ2 P=0.62). At index hospitalization, MI size was the same, but ventricular fibrillation and the need for cardiopulmonary resuscitation were more prevalent in the TT allele variant. Among patients with ejection fraction ≤40% at discharge, the TT variant was associated with a lower increase in left ventricular ejection fraction during follow‐up (P=0.03). During the 27‐month follow‐up, there was a statistically significant association of the TT variant with increased mortality risk (hazard ratio [HR], 2.83; P=0.001). Higher circulating orexin A was associated with a lower mortality risk (HR, 0.41; P<0.05). Conclusions Attenuation of hypocretin/orexin signaling is associated with increased mortality risk after MI. This effect may be partially explained by the increased arrhythmic risk and the effect on the left ventricular systolic function recovery

Effects of renal sympathetic denervation on the course of congestive heart failure combined with chronic kidney disease: Insight from studies with fawn-hooded hypertensive rats with volume overload induced using aorto-caval fistula

Background: The coincidence of congestive heart failure (CHF) and chronic kidney disease (CKD) results in poor survival rate. The aim of the study was to examine if renal denervation (RDN) would improve the survival rate in CHF induced by creation of aorto-caval fistula (ACF). Methods: Fawn-hooded hypertensive rats (FHH), a genetic model of spontaneous hypertension associated with CKD development, were used. Fawn-hooded low-pressure rats (FHL), without CKD, served as controls. RDN was performed 4 weeks after creation of ACF and the follow-up period was 10 weeks. Results: We found that intact (non-denervated) ACF FHH exhibited survival rate of 58.8% (20 out of 34 rats), significantly lower than in intact ACF FHL (81.3%, 26/32 rats). In intact ACF FHL albuminuria remained stable throughout the study, whereas in ACF FHH it increased significantly, up to a level 40-fold higher than the basal values. ACF FHL did not show increases in renal glomerular and tubulointerstitial injury as compared with FHL, while ACF FHH exhibited marked increases in kidney injury as compared with FHH. RDN did not improve the survival rate in either ACF FHL or ACF FHH and did not alter the course of albuminuria in ACF FHL. RDN attenuated the albuminuria, but did not reduce the kidney injury in ACF FHH. Conclusions: Our present results support the notion that even modest CKD increases CHF-related mortality. RDN did not attenuate CHF-dependent mortality in ACF FHH, it delayed the progressive rise in albuminuria, but it did not reduce the degree of kidney injury