Despite therapeutic advances, chronic heart failure (HF) is still associated with significant risk of morbidity and mortality. The course of disease and responses to therapies vary widely among ...individuals with HF, highlighting the need for precision medicine approaches. Gut microbiome stands to be an important aspect of precision medicine in HF. Exploratory clinical studies have revealed shared patterns of gut microbiome dysregulation in this disease, with mechanistic animal studies providing evidence for active involvement of the gut microbiome in development and pathophysiology of HF. Deeper insights into gut microbiome-host interactions in patients with HF promise to deliver novel disease biomarkers, preventative and therapeutic targets, and improve disease risk stratification. This knowledge may enable a paradigm shift in how we care for patients with HF, and pave the path toward improved clinical outcomes through personalized HF care.
Appropriate interpretation of changes in markers of kidney function is essential during the treatment of acute and chronic heart failure. Historically, kidney function was primarily assessed by serum ...creatinine and the calculation of estimated glomerular filtration rate. An increase in serum creatinine, also termed worsening renal function, commonly occurs in patients with heart failure, especially during acute heart failure episodes. Even though worsening renal function is associated with worse outcome on a population level, the interpretation of such changes within the appropriate clinical context helps to correctly assess risk and determine further treatment strategies. Additionally, it is becoming increasingly recognized that assessment of kidney function is more than just glomerular filtration rate alone. As such, a better evaluation of sodium and water handling by the renal tubules allows to determine the efficiency of loop diuretics (loop diuretic response and efficiency). Also, though neurohumoral blockers may induce modest deteriorations in glomerular filtration rate, their use is associated with improved long‐term outcome. Therefore, a better understanding of the role of cardio–renal interactions in heart failure in symptom development, disease progression and prognosis is essential. Indeed, perhaps even misinterpretation of kidney function is a leading cause of not attaining decongestion in acute heart failure and insufficient dosing of guideline‐directed medical therapy in general. This position paper of the Heart Failure Association Working Group on Cardio‐Renal Dysfunction aims at improving insights into the interpretation of renal function assessment in the different heart failure states, with the goal of improving heart failure care.
Abstract Lower serum chloride (Cl) levels are strongly associated with increased long-term mortality after admission for acute heart failure (AHF). However, the therapeutic implications of serum Cl ...levels during AHF are unknown. We sought to determine the short-term clinical response and post-discharge outcomes associated with serum Cl levels in AHF. Serum Cl was measured at randomization (N=358) and during hospitalization from patients with AHF in the in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial. Outcomes included diuretic response and renal function at 72 hours and death and rehospitalization at 60 and 180-days. Baseline Cl tertiles were: 84-98 meq/L; 99-102 meq/L; and 103-117 meq/L. Baseline Cl level was associated with diuretic efficiency (P<.001), but not change in cystatin C (P=0.30) at 72 hours; and was associated with 60-day death (HR 0.86, P=0.029), 60-day death and rehospitalization (HR 0.90, P=0.01), and 180-day death (HR 0.91, P=0.049). These associations were attenuated with additional adjustment for loop diuretic dose (P>0.05). Chloride change correlated with weight change (rho 0.18, P=0.001), cystatin C change (rho -0.35, P<.001), and cumulative sodium excretion (rho -0.21, P<.001), but was not associated with any clinical outcomes (P>0.05 for all). In conclusion, serum Cl levels in AHF were inversely associated with loop diuretic response and were prognostic. However, changes in Cl levels were associated with parameters of decongestion, but not with clinical outcomes.
There is increasing appreciation that changes in microbiome composition and function can promote long-term susceptibility for cardiometabolic risk. Gut microbe-derived metabolites that are ...biologically active, such as trimethylamine N -oxide (TMAO), are now recognized as contributors to atherogenesis. This review summarizes our current understanding of the role of TMAO in the pathogenesis of cardiometabolic diseases and will discuss current findings, controversies, and further perspectives in this new area of investigation. Better appreciation of the interactions between dietary nutrient intake with gut microbiota-mediated metabolism may provide clinical insights into defining individuals at risk for disease progression in cardiometabolic diseases, as well as additional potential therapeutic targets for reducing risks for cardiometabolic disease progression.
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear
. Here we show that mtDNA mutations ...are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
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