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This article discusses the role of fibrosis in heart failure (HF) and the potential impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on fibrosis. Fibrosis, the accumulation of collagen in the myocardium, is a key factor in the development and progression of HF. The article highlights a study that investigated the effects of the SGLT2 inhibitor empagliflozin on circulating biomarkers of fibrosis in patients with HF. The study found that empagliflozin reduced certain biomarkers associated with fibrosis and suggests that SGLT2 inhibition may have antifibrotic effects in HF. However, further research is needed to fully understand the mechanisms behind these effects. [Extracted from the article]

The potato cyst nematode, Globodera rostochiensis, is a quarantine pest in Australia affecting a relatively small number of properties in three different production areas in the State of Victoria. The effects of susceptible (Trent, Sebago and Coliban) and H1‐resistant potato cultivars (Atlantic, Crop 13 and Nicola) on nematode populations were compared in two trials in a naturally infested field in the 2008/09 season (Trial 1) and in the 2009/10 season (Trial 2). The latter included a bare fallow treatment. The reproduction factor Pf/Pi (final compared with initial nematode population) was used to determine treatment effects. Initial population density was very high, averaging 111 and 119 eggs g−1 soil in Trial 1 and 2, respectively. The Pf/Pi of population density (eggs g−1 soil) was greater after growing susceptible cultivars (average 1.74 and 2.92 in Trials 1 and 2, respectively) than after growing resistant cultivars (average 0.72 and 0.61 in Trials 1 and 2, respectively), or after a bare fallow (1.09) in Trial 2. This correlated with higher Pf/Pi values of cysts 500 g−1 soil and eggs cyst−1 for susceptible cultivars than for resistant cultivars. Average Pf/Pi values greater than one in both trials are consistent with more cysts and an increased population density after growing susceptible cultivars. There was a trend of population decline, that is, Pf/Pi < 1, after growing resistant cultivars (average Pf/Pi values of eggs cyst−1 of 0.77 and 0.35 and of eggs g−1 soil of 0.72 and 0.61, for Trials 1 and 2, respectively). However, Trial 2 showed that these Pf/Pi values were not significantly less than those for the bare fallow (0.68 eggs cyst−1 and 1.09 eggs g−1 soil). The susceptible cultivars Trent and Sebago produced lower yields than the resistant cultivars in both trials. In contrast, the susceptible Coliban yielded as well as the resistant cultivars, suggesting a high level of tolerance of this cultivar to infestation by the nematode. The resistant cultivar Crop 13 produced 34% and 36% greater total yields in Trials 1 and 2, respectively, than the once popular, but susceptible cultivar Sebago. This is the first report of the effects of potato cultivars on a population of the potato cyst nematode in an Australian field. The use of H1‐resistant potato cultivars can feasibly reduce populations of G. rostochiensis Ro1 on infested land and reduce PCN risk on land regulated as "linked" with infested land. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) and heart failure affect many people worldwide. Despite the availability of pharmacological treatments, both diseases remain associated with considerable morbidity and mortality. After observations that sodium-glucose co-transporter 2 (SGLT2) inhibitors - originally developed as glucose-lowering agents - improved cardiovascular and renal outcomes in patients with type 2 diabetes, dedicated trials were initiated to evaluate the cardiovascular and kidney protective effects in patients with CKD or heart failure. The results of these clinical trials and subsequent detailed analyses have shown that the benefits of SGLT2 inhibitors are consistent across many patient subgroups, including those with and without type 2 diabetes, at different stages of CKD, and in patients with heart failure with preserved or reduced ejection fraction. In addition, post-hoc analyses revealed that SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia in patients with CKD. With respect to their safety, SGLT2 inhibitors are generally well tolerated. More specifically, no increased risk of hypoglycaemia has been observed in patients with CKD or heart failure without diabetes and they do not increase the risk of acute kidney injury. SGLT2 inhibitors therefore provide clinicians with an exciting new treatment option for patients with CKD and heart failure. [ABSTRACT FROM AUTHOR]

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology‐specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three‐dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR‐Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

In the year 2021, the universal definition and classification of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with preserved ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium–glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon. [ABSTRACT FROM AUTHOR]

3 PKA (protein kinase A) is a critical signaling molecule in cardiomyocytes, involved in calcium (Ca 2+) handling, gene transcription, and metabolism. First, in contrast to previous reports, 13,14 PKARI disulfide formation did not appear to influence the catalytic activity of PKA, nor did it alter phosphorylation of established PKA targets involved in cardiac Ca 2+ handling. B, Phosphorylation of the TPC prevents Ca 2+ release and limits Ca 2+ -induced Ca 2+ release from the ryanodine receptor (RyR). First, the authors set out to determine whether PKARI oxidation occurs during I/R. Using human atrial tissue obtained before and after cardioplegic arrest, as well as murine heart samples after I/R, the authors discovered that I/R injury significantly increased PKARI oxidation and disulfide formation. [Extracted from the article]

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity. METHODS: The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment. RESULTS: Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P =0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P =0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, −6.5, 13.0; P =0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P =0.079) and 3.1 (−0.1, 5.4; P =0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, −5.9, 9.0; P =0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P =0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P =0.036) for KCCQ-PLS, and 2.5 meters (−3.5, 8.4; P =0.50) for 6MWD. CONCLUSIONS: Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224. [ABSTRACT FROM AUTHOR]

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research. [ABSTRACT FROM AUTHOR]

Aim: Traditionally, risk stratification in heart failure (HF) emphasizes assessment of high risk. We aimed to determine if biomarkers could identify patients with HF at low risk for death or HF rehospitalization.Methods and Results: This analysis was a substudy of The Coordinating Study Evaluating Outcomes of Advising and Counselling in Heart Failure (COACH) trial. Enrolment of HF patients occurred before discharge. We defined low risk as the absence of death and/or HF rehospitalizations at 180 days. We tested a diverse group of 29 biomarkers on top of a clinical risk model, with and without N-terminal pro-B-type natriuretic peptide (NT-proBNP), and defined the low risk biomarker cut-off at the 10th percentile associated with high positive predictive value. The best performing biomarkers together with NT-proBNP and cardiac troponin I (cTnI) were re-evaluated in a validation cohort of 285 HF patients. Of 592 eligible COACH patients, the mean (± SD) age was 71 (± 11) years and median (IQR) NT-proBNP was 2521 (1301-5634) pg/mL. Logistic regression analysis showed that only galectin-3, fully adjusted, was significantly associated with the absence of events at 180 days (OR 8.1, 95% confidence interval 1.06-50.0, P = 0.039). Galectin-3, showed incremental value when added to the clinical risk model without NT-proBNP (increase in area under the curve from 0.712 to 0.745, P = 0.04). However, no biomarker showed significant improvement by net reclassification improvement on top of the clinical risk model, with or without NT-proBNP. We confirmed our results regarding galectin-3, NT-proBNP, and cTnI in the independent validation cohort.Conclusion: We describe the value of various biomarkers to define low risk, and demonstrate that galectin-3 identifies HF patients at (very) low risk for 30-day and 180-day mortality and HF rehospitalizations after an episode of acute HF. Such patients might be safely discharged. [ABSTRACT FROM AUTHOR]

Aim Traditionally, risk stratification in heart failure (HF) emphasizes assessment of high risk. We aimed to determine if biomarkers could identify patients with HF at low risk for death or HF rehospitalization. Methods and results This analysis was a substudy of The Coordinating Study Evaluating Outcomes of Advising and Counselling in Heart Failure (COACH) trial. Enrolment of HF patients occurred before discharge. We defined low risk as the absence of death and/or HF rehospitalizations at 180 days. We tested a diverse group of 29 biomarkers on top of a clinical risk model, with and without N-terminal pro-B-type natriuretic peptide (NT-proBNP), and defined the low risk biomarker cut-off at the 10th percentile associated with high positive predictive value. The best performing biomarkers together with NT-proBNP and cardiac troponin I (cTnI) were re-evaluated in a validation cohort of 285 HF patients. Of 592 eligible COACH patients, the mean (' SD) age was 71 (' 11) years and median (IQR) NT-proBNP was 2521 (1301 - 5634) pg/mL. Logistic regression analysis showed that only galectin-3, fully adjusted, was significantly associated with the absence of events at 180 days (OR 8.1, 95% confidence interval 1.06 - 50.0, P = 0.039). Galectin-3, showed incremental value when added to the clinical risk model without NT-proBNP (increase in area under the curve from 0.712 to 0.745, P = 0.04). However, no biomarker showed significant improvement by net reclassification improvement on top of the clinical risk model, with or without NT-proBNP. We confirmed our results regarding galectin-3, NT-proBNP, and cTnI in the independent validation cohort. Conclusion We describe the value of various biomarkers to define low risk, and demonstrate that galectin-3 identifies HF patients at (very) low risk for 30-day and 180-day mortality and HF rehospitalizations after an episode of acute HF. Such patients might be safely discharged. [ABSTRACT FROM AUTHOR]

Since natriuretic peptides were successfully integrated into the clinical practice of heart failure ( HF), the possibility of using new biomarkers to advance the management of affected patients has been explored. While a huge number of candidate HF biomarkers have been described recently, very few have made the difficult translation from initial promise to clinical application. These markers mirror the complex pathophysiology of heart failure at various levels: cell loss (troponin), fibrosis ( ST2 and galectin-3), infection (procalcitonin), and renal disease (several renal markers). In this review, we examine the best emerging candidates for clinical assessment and management of patients with HF. [ABSTRACT FROM AUTHOR]

Guideline-directed medical therapy (GDMT) forms the cornerstone of HFrEF therapy and currently consists of four drug classes: renin-angiotensin system inhibitors (RASi), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). The "risk-treatment paradox" is notably pronounced in this subset of patients, arising from a wide range of factors attributed to the patient, healthcare system, and healthcare provider.[5] For instance, assumed intolerance or a disproportionate fear of side effects can limit GDMT implementation in frail patients who are most in need of effective medical therapy. Haemodynamic monitoring as an opportunity for tailoring diuretics and guideline-directed medical therapy in heart failure. [Extracted from the article]

Background: Ischemia-reperfusion injury (IRI) is a major cause of cardiac damage following various pathological processes. Gaseous hydrogen sulfide (H2S) is protective during IRI by inducing a hypometabolic state in mice which is associated with anti-apoptotic, anti-inflammatory and antioxidant properties. We investigated whether gaseous H2S administration is protective in cardiac IRI and whether non-hypometabolic concentrations of H2S have similar protective properties. Methods: Male C57BL/6 mice received a 0, 10, or 100 ppm H2S-N2 mixture starting 30 minutes prior to ischemia until 5 minutes pre-reperfusion. IRI was inflicted by temporary ligation of the left coronary artery for 30 minutes. High-resolution respirometry equipment was used to assess CO2-production and blood pressure was measured using internal transmitters. The effects of H2S were assessed by histological and molecular analysis. Results: Treatment with 100 ppm H2S decreased CO2-production by 72%, blood pressure by 14% and heart rate by 25%, while treatment with 10 ppm H2S had no effects. At day 1 of reperfusion 10 ppm H2S showed no effect on necrosis, while treatment with 100 ppm H2S reduced necrosis by 62% (p<0.05). Seven days post-reperfusion, both 10 ppm (p<0.01) and 100 ppm (p<0.05) H2S showed a reduction in fibrosis compared to IRI animals. Both 10 ppm and 100 ppm H2S reduced granulocyte-influx by 43% (p<0.05) and 60% (p<0.001), respectively. At 7 days post-reperfusion both 10 and 100 ppm H2S reduced expression of fibronectin by 63% (p<0.05) and 67% (p<0.01) and ANP by 84% and 63% (p<0.05), respectively. Conclusions: Gaseous administration of H2S is protective when administered during a cardiac ischemic insult. Although hypometabolism is restricted to small animals, we now showed that low non-hypometabolic concentrations of H2S also have protective properties in IRI. Since IRI is a frequent cause of myocardial damage during percutaneous coronary intervention and cardiac transplantation, H2S treatment might lead to novel therapeutical modalities. [ABSTRACT FROM AUTHOR]

Galectin-3 is a lectin involved in fibrosis, inflammation and proliferation. Increased circulating levels of galectin-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. To enhance our knowledge on galectin-3 biology we performed the first genome-wide association study (GWAS) using the Illumina HumanCytoSNP-12 array imputed with the HapMap 2 CEU panel on plasma galectin-3 levels in 3,776 subjects and follow-up genotyping in an additional 3,516 subjects. We identified 2 genome wide significant loci associated with plasma galectin-3 levels. One locus harbours the LGALS3 gene (rs2274273; P = 2.35 x 10--188) and the other locus the ABO gene (rs644234; P = 3.65 x 10--47). The variance explained by the LGALS3 locus was 25.6% and by the ABO locus 3.8% and jointly they explained 29.2%. Rs2274273 lies in high linkage disequilibrium with two non-synonymous SNPs (rs4644; r² = 1.0, and rs4652; r² = 0.91) and wet lab follow-up genotyping revealed that both are strongly associated with galectin-3 levels (rs4644; P = 4.97 x 10--465 and rs4652 P = 1.50 x 10--421) and were also associated with LGALS3 gene-expression. The origins of our associations should be further validated by means of functional experiments [ABSTRACT FROM AUTHOR]

Objective Experimental studies have shown that adrenomedullin (ADM) has an important role in circulatory homeostasis. Mid-regional pro-ADM (MRproADM) is a stable form of ADM. Observational studies found an important association with age, body mass index and kidney function. The aim of this study was to evaluate the prognostic performance of MR-proADM in the general population, controlling for these potential confounders. Methods 7903 subjects (mean age 49±13 years, 49% male) from the Prevention of REnal and Vascular ENdstage Disease (PREVEND) cohort with a median follow-up of 10.5 years were enrolled in a prospective cohort study. Results Mean baseline MR-proADM was 0.39±0.14 nmol/l. In cross-sectional analyses, age, blood pressure, C reactive protein, cystatin-C, N-terminal pro-brain type natriuretic peptide and urinary albumin excretion remained as independent determinants of MRproADM. In prospective analyses, MR-proADM was associated with the primary endpoint (combined cardiovascular mortality and cardiovascular morbidity), with event rates ranging from 8% in the lowest quintile to 45% in the highest quintile (p for trend <0.001) independent of age, sex, components of the Framingham risk score and other cardiovascular markers. Overall Net Reclassification Improvement against the Framingham risk score was 2.2%, which was non-significant. However, significant modification of the effect of MRproADM on outcome by age was observed. In subjects aged ≤70 years (N=7475), 8.8% were correctly reclassified in a higher risk category (p=0.017) and 3.4% in a lower risk category (p<0.001). In subjects aged >70 years (N=428) there was no improvement of reclassification (p=0.32). Conclusion This study gives a detailed overview of the distribution of ADM in a general population and provides evidence that it is a potent and interesting biomarker in predicting cardiovascular events. These results seem especially applicable to younger subjects. [ABSTRACT FROM AUTHOR]

Aims: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium–glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. Methods and results: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA‐HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end‐of‐study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N‐terminal pro‐B‐type natriuretic peptide [NT‐proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT‐proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37–2.17], p < 0.001; and 1.52 [1.12–2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow‐up, dapagliflozin had no effect on liver tests. Conclusion: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. Clinical Trial Registration: ClinicalTrials.gov NCT03036124. [ABSTRACT FROM AUTHOR]

Galectins are a family of soluble β-galactoside-binding lectins that play many important regulatory roles in inflammation, immunity, and cancer. Recently, a role for galectin-3 in the pathophysiology of heart failure (HF) has been suggested. Numerous studies have demonstrated the up-regulation of galectin-3 in hypertrophied hearts, its stimulatory effect on macrophage migration, fibroblast proliferation, and the development of fibrosis. The latter observation is particularly relevant as cardiac remodelling is an important determinant of the clinical outcome of HF and is linked to disease progression and poor prognosis. Because galectin-3 expression is maximal at peak fibrosis and virtually absent after recovery, routine measurement in patients with HF may prove valuable to identify those patients at highest risk for readmission or death, thus enabling physicians to tailor the level of care to individual patient needs. This review summarizes the most recent advances in galectin-3 research, with an emphasis on the role galectin-3 plays in the development and progression of HF. [ABSTRACT FROM PUBLISHER]

We investigated whether administration of estradiol to male mice augments mobilization of bone marrow-derived endothelial progenitor cells (EPC) and incorporation into foci of neovascularization after hind-limb ischemia, thereby contributing to blood flow restoration. Mice were randomized and implanted with placebo pellets or pellets containing low-dose estradiol (0.39 mg) or high-dose estradiol (1.7 mg). Hind-limb ischemia was induced by unilateral resection of the left femoral artery 1 week after pellet implantation, then EPC mobilization and functional recovery was evaluated. EPC recruitment was assessed in mice transplanted with bone marrow from transgenic donors expressing β-galactosidase driven by the Tie-2 promoter. EPC culture assay performed 2 weeks after pellet implantation revealed a significantly greater (p < 0.05) number of circulating EPCs in the high-dose estradiol group than in the low-dose estradiol and placebo groups. At 3 and 4 weeks after induction of hind-limb ischemia, perfusion was significantly greater (p < 0.05) in high-dose estradiol mice than in mice implanted with the low-dose estradiol or placebo pellets. At 1 and 4 weeks after hind-limb ischemia surgery, more bone marrow-derived EPCs, identified as β-galactosidase-positive cells, were observed in ischemic regions from high-dose estradiol animals than in low-dose (p < 0.05) or placebo groups (p < 0.05). These results indicate that estradiol dose-dependently increases the levels of EPCs in peripheral blood in male animals, improves the recovery of blood flow, and decreases limb necrosis after hind-limb ischemia, and that this enhancement occurs, in part, through augmentation of EPC mobilization and greater incorporation of bone marrow-derived EPCs into foci of neovascularization. [ABSTRACT FROM AUTHOR]

Abstract: The incidence and prevalence of cardiovascular disease increases progressively with advancing age. Cardiovascular disease is a major cause of morbidity and mortality in Western Countries. In the near future, as the population ages, it is expected that the population prevalence of cardiovascular disease will increase dramatically, imposing a major social and economical burden on society. Not only is age closely related to the development and progression of cardiovascular disease, but genetic and environmental factors also play an important role. Recently, a chromosomal mechanism, telomere shortening, has been considered a driving force by which genetic and environmental factors jointly affect biological aging, and possibly the risk for developing age-associated diseases. Telomeres are the extreme ends of chromosomes and shorten progressively during every cell cycle and therefore can be considered an indicator of biological age. In heart failure, telomere length is severely reduced. In the current review, we will discuss the emerging role of telomere biology in the pathophysiology of heart failure. [Copyright &y& Elsevier]

Abstract: Erythropoietin is a haematopoietic hormone with extensive non-haematopoietic effects. The discovery of an erythropoietin receptor outside the haematopoietic system has fuelled the research into the beneficial effects of erythropoietin for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective and angiogenic properties of erythropoietin and it seems that the erythropoietin–erythropoietin receptor system provides a powerful backbone against acute and chronic myocardial ischemia, each gaining from the different properties of erythropoietin. Clinical trials in which erythropoietin was titrated to achieve certain haematocrit levels have generated equivocal results. It has been suggested that a (too) high haematocrit is undesirable in cardiovascular disease. We have shown that intermittent (low-dose) erythropoietin administration, that does not increase haematocrit substantially, suffices to activate the beneficial downstream pathways of erythropoietin. We postulate that intermittent administration or a lower than conventional dose of erythropoietin, not only aimed at increasing haemoglobin at high levels, will provide powerful cellular protection and will improve cardiac outcome, without the side effects of erythropoietin associated with increased haematocrit. [Copyright &y& Elsevier]

The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor alpha (LXR(alpha)) and LXR(beta) in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXR(alpha) functioned as a cAMP-activated factor, LXR(beta) was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXR(alpha) was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXR(alpha) to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXR(alpha) mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXR(beta) mice exhibited reduced kidney renin mRNA levels compared with controls. LXR(alpha)LXR(beta) mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXR(alpha) and LXR(beta) regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXR(alpha) signaling pathway is required for the adrenergic control of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Current guidelines of chronic heart failure (CHF) do not recommend the use of oral anticoagulants (OAC) or antiplatelet therapy (APT). We performed a post-hoc analysis to evaluate the effect of the use of anti-thrombotic therapy with APT and OAC. Patients and methods: We examined 427 patients with advanced CHF, and assessed the effects of the use of APT or OAC at baseline on mortality. We employed a Cox-proportional hazard model to value the effects of APT or OAC use. Results: After a mean follow-up of 3.4 years (range 2.0–5.4), 214 patients died (51%). Forty-one (41) percent (95%CI: 29–53%) of the patients on APT died, and 52% (47–57%) of the patients not on APT (P=0.07). Forty-eight (48) percent (42–54%) of the patients on OAC died, and 55% (46–63%) of the patients not on OAC (P=0.20). This effect of OAC was seen both in patients in sinus rhythm and in atrial fibrillation. After adjusting for important prognostic variables, such as age, LVEF, renal function, and NYHA class, both the use of APT (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.40–0.97; P=0.04) and the use of OAC (HR 0.60, 95%–CI 0.43–0.83; P&#60;0.01) were related to an improved prognosis. Conclusion: This post-hoc analysis suggests that in CHF patients the use of APT or OAC is associated with a higher survival. [Copyright &y& Elsevier]

Background: Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used in first-world countries and are generally well tolerated. Specifically, less cardiovascular toxicity has been reported in comparison with tricyclic antidepressants. Here we report QT interval prolongation after an overdose of the SSRI sertraline. Case presentation: A previously healthy female patient presented with an attempted suicide with overdoses sertraline (2250 mg), diazepam (200 mg), and temazepam (400 mg). Routine laboratory studies were normal and her ECG upon admission showed a normal QT interval. The next day, her ECG showed prolongation of the QTc interval up to 525 ms. After discontinuation of sertraline the QT interval normalized. Echocardiography and exercise electrocardiography were normal. After hospitalization, the patient resumed sertraline in the normally recommended dose and QT interval remained within normal ranges. Conclusion: It seems that the SSRI sertraline in overdose may cause QT interval prolongation. [ABSTRACT FROM AUTHOR]

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) ß1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic dP/dt, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture. [ABSTRACT FROM AUTHOR]

Background: The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant.Aims: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers.Methods: We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes.Results: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL.Conclusion: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism. [ABSTRACT FROM AUTHOR]

In heart failure, a deficient oxygen supply often is a primary cause for myocardial dysfunction. The reverse however, may also be true; the changes that occur in the failing heart may predispose for the existence of tissue hypoxia, which further affects the function of the heart. Specifically, myocardial hypertrophy and accelerated heart rhythm enhance oxygen demand, while supply is hampered short by endothelial dysfunction and diffusion barriers (such as fibrosis, arterial hyperplasia, and myocyte hypertrophy). Another contributory factor may be deficient growth of the microvasculature that does not keep pace with the rate of myocardial hypertrophy. Fewer microvessels have been observed in many forms of cardiomyopathies. On the other hand, some distinct forms of cardiomyopathies are characterized by the compensatory growth of microvessels, or even excess angiogenesis. This review summarizes the knowledge that has been gathered on this topic thus far and discusses factors that mediate myocardial microvessel growth. Furthermore, a paradigm is presented in which the rate of microvessel growth predicts, at least in part, the degree of myocardial dysfunction. Therapies aimed at the restoration of the microcirculation are proposed to preserve and improve myocardial function.Microcirculation (2003) 10, 113-126. doi:10.1038/sj.mn.7800188 [ABSTRACT FROM AUTHOR]

Objective: To study the effects of increased levels of myocardial angiotensin II type 1 (AT1) receptor on microvascular growth following myocardial infarction (MI). Methods: MI was created in transgenic rats (TGR) with a cardioselective overexpression of the AT1 receptor. We used Sprague–Dawley (SD) rats as controls. Some of the rats were treated with the selective AT1 receptor blocker losartan (Los). Rats were sacrificed after 3 weeks. Results: MI caused left ventricular (LV) hypertrophy and LV dysfunction in both SD and TGR, which was prevented by AT1 receptor blockade. Furthermore, MI decreased microvessel density in the non-infarcted myocardium (SD MI: 1653±37/mm2, P<0.01 vs. sham-operated controls), however, microvessel density decreased significantly more in TGR with MI (1298±33/mm2, P<0.01 vs. SD MI). AT1 receptor blockade restored microvessel density (SD MI Los: 2046±195/mm2; TGR MI Los: 1742±47/mm2; P<0.01 vs. untreated). The differences in microvessel density were still present after correction for LV hypertrophy. The increase in microvessel density after AT1 receptor blockade was not accompanied by increased myocardial vascular endothelial growth factor (VEGF) levels. Microvessel density correlated with parameters of myocardial stretch, such as LV end-diastolic pressure (−0.681, P<0.001) and N-ANP (−0.424, P=0.01). Conclusions: Microvessel density after MI is decreased when the AT1 receptor is overexpressed, and this is amenable to AT1 receptor blockade. This suggests that efficacy of AT1 receptor blockers post-MI may not only be due to attenuation of LV remodeling, but also to a stimulatory effect on angiogenesis. [Copyright &y& Elsevier]

Background: Brain natriuretic peptide (BNP) levels have been used to assess clinical status and predict prognosis of patients with chronic heart failure (CHF). However, BNP levels can only be measured in specialized laboratories which has hampered its use in daily clinical practice. We compared a new, rapid, BNP assay with a conventional BNP measurement and evaluated the applicability to current practice by comparing it with standard clinical parameters. Methods: BNP levels were determined in 78 stable CHF patients and 20 controls. The severity of CHF was assessed by determination of New York Heart Association functional class (NYHA), left ventricular ejection fraction (LVEF) and peak oxygen consumption (peak Vo2), and these parameters were compared to BNP levels. Results: Overall, rapid BNP assessment was highly correlated with the conventional BNP assay (r=0.95, P<0.0001). In the higher ranges (>200 pmol/l), however, correlation was less accurate, and tended to overestimate. BNP levels also strongly correlated with both NYHA class, LVEF and peak Vo2 (all P<0.001). A cut-off value for BNP of 20 pmol/l yielded a sensitivity of 91% and a specificity of 92% to detect the presence of left ventricular systolic dysfunction. Conclusions: Rapid measurement of BNP levels is comparable to conventional BNP measurement and strongly correlated to clinical tests that are currently used to stratify CHF patients. Wider use of this method may yield a reduction of costly and time-consuming clinical tests and may reduce the medical burden of CHF. [Copyright &y& Elsevier]

Aims: Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men. Methods and results: In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over‐representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher left ventricular ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up‐regulated in women, while 21/363 and 14/363 were up‐regulated in men. In both cohorts, the strongest up‐regulated biomarkers in women were leptin and fatty acid binding protein‐4, compared to matrix metalloproteinase‐3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over‐representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuro‐inflammatory response in men (all p < 0.0001). Conclusion: In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro‐inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies. [ABSTRACT FROM AUTHOR]

Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124) [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium–glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. Methods and results: The DAPA‐HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant‐level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate‐adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02–1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72–0.96) and without previous MI (HR 0.76, 95% CI 0.68–0.85; pinteraction = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. Conclusion: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI. [ABSTRACT FROM AUTHOR]

For patients with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM), screening for pathogenic variants has become standard clinical practice. Genetic cascade screening also allows the identification of relatives that carry the same mutation as the proband, but disease onset and severity in mutation carriers often remains uncertain. Early detection of disease onset may allow timely treatment before irreversible changes are present. Although plasma biomarkers may aid in the prediction of disease onset, monitoring relies predominantly on identifying early clinical symptoms, on imaging techniques like echocardiography (Echo) and cardiac magnetic resonance imaging (CMR), and on (ambulatory) electrocardiography (electrocardiograms (ECGs)). In contrast to most other cardiac diseases, which are explained by a combination of risk factors and comorbidities, genetic cardiomyopathies have a clear primary genetically defined cardiac background. Cardiomyopathy cohorts could therefore have excellent value in biomarker studies and in distinguishing biomarkers related to the primary cardiac disease from those related to extracardiac, secondary organ dysfunction. Despite this advantage, biomarker investigations in cardiomyopathies are still limited, most likely due to the limited number of carriers in the past. Here, we discuss not only the potential use of established plasma biomarkers, including natriuretic peptides and troponins, but also the use of novel biomarkers, such as cardiac autoantibodies in genetic cardiomyopathy, and discuss how we can gauge biomarker studies in cardiomyopathy cohorts for heart failure at large. [ABSTRACT FROM AUTHOR]

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non‐coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long‐term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling. [ABSTRACT FROM AUTHOR]

The article reviews the article "Heart Failure Stimulates Tumor Growth by Circulating Factors", which appeared in an earlier issue of the journal.

The author reflects on the relevance of discoveries on telomere biology to heart failure studies. The author mentions the impact of new cellular biology discoveries on the ageing process and research for cancer cure. A historical perspective of physiological studies is given as well as major breakthroughs in telomere biology. The author concludes that new insights on cardiovascular heart failure (CHF) pathophysiology could help form new strategies for treatment.

The article presents a double-blind study on chronic heart failure (CHF) patients to determine the effects of carvedilol on plasma vascular endothelial growth factor (VEGF). It states that carvedilol or placebo were given randomly to patients, who were treated based on an uptitration schedule. Results show the benefits of beta-blockers in ischemic heart disease (IHD) and CHF. It concludes that CHF patients using carvedilol had increased VEGF.

Aim: To assess the cost‐effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). Methods and results: Patient‐level data were pooled from HF trials (DAPA‐HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N‐terminal pro‐B‐type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost‐effectiveness ratio (ICER) was £6470 per quality‐adjusted life year (QALY) gained, well below the UK willingness‐to‐pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. Conclusions: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost‐effective intervention. [ABSTRACT FROM AUTHOR]

Aim: Inhibition of microRNA (miR)‐132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR‐132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF‐REVERT (Phase 2, multicenter, randomized, parallel, 3‐arm, placebo‐controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post‐acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N‐terminal pro‐B‐type natriuretic peptide. The study consists of a 6‐month double‐blinded treatment period with the primary endpoint LV end‐systolic volume index and relevant secondary endpoints, followed by a 6‐month open‐label observation period. Conclusion: The HF‐REVERT trial may underpin the concept of miR‐132 inhibition to prevent or reverse cardiac remodelling in post‐MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF. [ABSTRACT FROM AUTHOR]

The phospholamban (PLN) pathogenic gene variant p.Arg14del causes cardiomyopathy, which is characterized by perinuclear PLN protein clustering and can lead to severe heart failure (HF). Elevated expression of dwarf open reading frame (DWORF), a protein counteracting the function of PLN in the sarcoplasmic reticulum (SR), can delay disease progression in a PLN-R14del mouse model. Here, we evaluated whether deletion of DWORF (DWORF-/-) would have an opposite effect and accelerate agedependent disease progression in wild-type (WT) mice and mice with a pathogenic PLN-R14del allele (R14Δ/+). We show that DWORF-/- mice maintained a normal left ventricular ejection fraction (LVEF) during aging and no difference with WT control mice could be observed up to 20 mo of age. R14Δ/+ mice maintained a normal cardiac function until 12 mo of age, but at 18 mo of age, LVEF was significantly reduced as compared with WT mice. Absence of DWORF did neither accelerate the R14Δ/+-induced reduction in LVEF nor enhance the increases in gene expression of markers related to cardiac remodeling and fibrosis and did not exacerbate cardiac fibrosis caused by the R14Δ/+ mutation. Together, these results demonstrate that absence of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, our data indicate that DWORF appears to be dispensable for cardiac function during aging. [ABSTRACT FROM AUTHOR]

Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/−) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8–12 weeks‐old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. Conclusions: (1) PLN R14del+/− loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a chronic and progressive syndrome associated with a poor prognosis. While it may seem intuitive that the risk of adverse outcomes varies across the different stages of HF, an overview of these risks is lacking. This study aims to determine the risk of all‐cause mortality and HF hospitalizations associated with new‐onset HF, chronic HF (CHF), worsening HF (WHF), and advanced HF. Methods and results: We performed a systematic review of observational studies from 2012 to 2022 using five different databases. The primary outcomes were 30‐day and 1‐year all‐cause mortality, as well as 1‐year HF hospitalization. Studies were pooled using random effects meta‐analysis, and mixed‐effects meta‐regression was used to compare the different HF groups. Among the 15 759 studies screened, 66 were included representing 862 046 HF patients. Pooled 30‐day mortality rates did not reveal a significant distinction between hospital‐admitted patients, with rates of 10.13% for new‐onset HF and 8.11% for WHF (p = 0.10). However, the 1‐year mortality risk differed and increased stepwise from CHF to advanced HF, with a rate of 8.47% (95% confidence interval [CI] 7.24–9.89) for CHF, 21.15% (95% CI 17.78–24.95) for new‐onset HF, 26.84% (95% CI 23.74–30.19) for WHF, and 29.74% (95% CI 24.15–36.10) for advanced HF. Readmission rates for HF at 1 year followed a similar trend. Conclusions: Our meta‐analysis of observational studies confirms the different risk for adverse outcomes across the distinct HF stages. Moreover, it emphasizes the negative prognostic value of WHF as the first progressive stage from CHF towards advanced HF. [ABSTRACT FROM AUTHOR]