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Although metabolic, renal, and cardiovascular disorders frequently coexist, little is known about how illness combinations affect prognosis. Cardiovascular disease (CVD), which can manifest as coronary artery disease (CAD), stroke, heart failure (HF), arrhythmias, and sudden cardiac death, is more likely to develop in patients with chronic kidney disease (CKD). This link is closer with regard of heart failure (HF) and renal dysfunction, in which a reciprocal relationship has been demonstrated, with the initial illness of one organ causing the progressive dysfunction of the other system. Common risk factors for both illnesses include obesity, diabetes, metabolic disorders, hypertension, and dyslipemia. Theoretically, each of these factors accelerates the atherosclerotic process or directly damages the endothelium through inflammatory, oxidative, and pro-thrombotic pathways, which in turn causes the beginning of heart dysfunction and renal function deterioration. Although the mechanisms and causes have been identified, there are still a number of unanswered questions regarding classification, development, monitoring, and preventive aspects. Furthermore, the absence of reliable data on cardiac and renal outcomes across different stages contributes to creating confusion in CKM classification and management. This paper discusses the current challenges and perspectives in CKM definition and assessment proposing a specific diagnostic and laboratory fingerprint.

Although congestion is considered to be the main reason for hospital admission in patients with acute heart failure, a simplistic view considering idro saline retention and total body volume accumulation did not provide convincing data. Clinical congestion occurrence is often the tip of the iceberg of several different mechanisms ranging from increased filling pressure to extravascular fluid accumulation and blood flow redistribution. Therefore, the clinical evaluation is often restricted to a simple physical examination including few and inaccurate signs and symptoms. This superficial approach has led to contradictory data and patients have not been evaluated according to a more realistic clinical scenario. The integration with new diagnostic ultrasonographic and laboratory tools would substantially improve these weaknesses. Indeed, congestion could be assessed by following the most recognized HF subtypes including primitive cardiac defect, presence of right ventricular dysfunction, and organ perfusion. Moreover, there is a tremendous gap regarding the interchangeable concept of fluid retention and redistribution used with a univocal meaning. Overall, congestion assessment should be revised, considering it as either central, peripheral, or both. In this review, we aim to provide different evidence regarding the concept of congestion starting from the most recognized pathophysiological mechanisms of AHF decompensation. We highlight the fact that a better knowledge of congestion is a challenge for future investigation and it could lead to significant advances in HF treatment.

Diabetic cardiomyopathy (DCM) is a diabetes mellitus–induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Renal dysfunction affects approximately 30 to 50% of heart failure (HF) patients. The unfavourable relationship between heart and kidney dysfunction contributes to worse outcomes through several mechanisms such as inflammation, oxidative stress, impaired hydrosaline homeostasis, and diuretic resistance. Renal dysfunction not only carries important prognostic value both in acute and in chronic HF, but also is a potential precipitating factor after the first diagnosis. Because renal dysfunction encompasses different etiologies, a better understanding of its definition, incidence, and pathophysiology provides additional information. Although old and novel available biomarkers for the detection of renal dysfunction have been recently proposed, there is no general consensus regarding the terminology and definition of renal dysfunction in HF. Due to some specific pathophysiological mechanisms, renal impairment seems to be different on an individual patient level and, recognizing it in acute and chronic settings, could be useful to optimize decongestive treatment. For these reasons, in this review, we aim to describe and evaluate different phenotypes of renal dysfunction in acute and chronic HF and the possible management in these settings.Key messages• Chronic kidney dysfunction and worsening renal function are highly prevalent in acute heart failure and chronic heart failure and associated with poor outcomes.• This association is modified by the context in which it occurs, i.e. worsening renal function in the context of adequate decongestion in acute heart failure, or worsening renal function after initiation of neurohormonal blockers in chronic heart failure.• Future research should be aimed at elucidating the mechanisms involved in these differenct contexts, as well as alternative treatment approaches in the case of true worsening renal function.

Uric acid, the metabolic mediator of gout and urate renal stones, is associated with increased cardiovascular risk burden. Hyperuricemia is an old emerging metabolic disorder, and interaction among uric acid and cardiovascular diseases has been clearly described. Several illness including hypertension, myocardial infarction, metabolic syndrome, and heart failure, are related with uric acid levels increase. In this review, we will discuss the pathophysiology of hyperuricemia and describe the biological plausibility for this metabolite to participate in the pathogenesis of cardiovascular disorders. In particular, we will focus on the implications of hyperuricemia in the onset and progression of heart failure, paying special attention to the pathophysiology and the possible clinical implications. We will conclude by discussing the effects of lowering plasma uric acid concentration on the prognosis of heart failure by reviewing most of available data on the different classes of drugs directly or indirectly involved in the hyperuricemia management.

Heart failure is associated with a range of comorbidities that have the potential to impair both quality of life and clinical outcome. Unfortunately, noncardiac diseases are underrepresented in large randomized clinical trials, and their management remains poorly understood. In clinical practice, the prevalence of comorbidities in heart failure is high. Although the prognostic impact of comorbidities is well known, their prevalence and impact in specific heart failure settings have been overlooked. Many studies have described specific single noncardiac conditions, but few have examined their overall burden and grading in patients with multiple comorbidities. The risk of comorbidities in patients with heart failure rises with more advanced disease, older age, and increased frailty—three conditions that are poorly represented in clinical trials. The pathogenic links between comorbidities and heart failure involve many pathways and include neurohormonal overdrive, inflammatory activation, oxidative stress, and endothelial dysfunction. Such interactions may worsen prognoses, but details of these relationships are still under investigation. We propose a shift from cardiac-focused care to a more systemic approach that considers all noncardiac diseases and related medications. Some new drugs class such as ARNI or SGLT2 inhibitors could change prognosis by acting directly or indirectly on metabolic disorders and related vascular consequences.

Right heart failure (RHF) is a clinical syndrome in which symptoms and signs are caused by dysfunction and/or overload of the right heart structures, predominantly the right ventricle (RV), resulting in systemic venous hypertension, peripheral oedema and finally, the impaired ability of the right heart to provide tissue perfusion. Pathogenesis of RHF includes the incompetence of the right heart to maintain systemic venous pressure sufficiently low to guarantee an optimal venous return and to preserve renal function. Virtually, all myocardial diseases involving the left heart may be responsible for RHF. This may result from coronary artery disease, hypertension, valvular heart disease, cardiomyopathies and myocarditis. The most prominent clinical signs of RHF comprise swelling of the neck veins with an elevation of jugular venous pressure and ankle oedema. As the situation worsens, fluid accumulation becomes generalised with extensive oedema of the legs, congestive hepatomegaly and eventually ascites. Diagnosis of RHF requires the presence of signs of elevated right atrial and venous pressures, including dilation of neck veins, with at least one of the following criteria: (1) compromised RV function; (2) pulmonary hypertension; (3) peripheral oedema and congestive hepatomegaly. Early recognition of RHF and identifying the underlying aetiology as well as triggering factors are crucial to treating patients and possibly reversing the clinical manifestations effectively and improving prognosis.

Despite recent advances in heart failure (HF) management, the risk of death and hospitalizations remains high in the long term. HF is characterized by endothelial dysfunction, inflammation and increased oxidative stress, due to a reduction in the activity of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. All these factors contribute to direct damage at the myocardial, vascular and renal level. Vericiguat restores the deficiency in this signaling pathway, through stimulation and activation of sGC, aiming to increase cGMP levels, with a reduction in HF-related oxidative stress and endothelial dysfunction. Two main clinical trials were developed in this setting: the SOCRATES-REDUCED phase II study and the VICTORIA phase III study. They found that vericiguat is safe, well tolerated and effective with an absolute event-rate reduction in patients affected by HF with reduced ejection fraction (HFrEF) and recent cardiac decompensation. In patients with HF with preserved ejection fraction (HfpEF), the SOCRATES-PRESERVED trial demonstrated an improvement in quality of life and health status, but the proven beneficial effects with vericiguat are still limited. Further studies are needed to correctly define the role of this drug in heart failure syndromes. Our paper reviews the potential applications and pharmacological characteristics of vericiguat in HFrEF and HFpEF.

BackgroundRight ventricular (RV) dysfunction and RV–pulmonary artery (PA) uncoupling are associated with the development of pulmonary congestion during exercise. However, there is limited information regarding the association between these right-sided cardiac parameters and pulmonary congestion in acutely decompensated heart failure (HF).MethodsWe performed an individual patient meta-analysis from four cohort studies of hospitalized patients with HF who had available lung ultrasound (B-lines) data on admission and/or at discharge. RV function was assessed by tricuspid annular plane systolic excursion (TAPSE), RV–PA coupling was defined as the ratio of TAPSE to PA systolic pressure (PASP).ResultsAdmission and discharge cohort included 319 patients (75.8 ± 10.1 years, 46% women) and 221 patients (77.9 ± 9.0 years, 47% women), respectively. Overall, higher TAPSE was associated with higher ejection fraction, lower PASP, b-type natriuretic peptide and B-line counts. By multivariable analysis, worse RV function or RV–PA coupling was associated with higher B-line counts on admission and at discharge, and with a less reduction in B-line counts from admission to discharge. Higher B-line counts at discharge were associated with a higher risk of the composite of all-cause mortality and/or HF re-hospitalization [adjusted-HR 1.13 (1.09–1.16), p < 0.001]. Furthermore, the absolute risk increase related to high B-line counts at discharge was higher in patients with lower TAPSE.ConclusionsIn patients with acutely decompensated HF, impaired RV function and RV–PA coupling were associated with severe pulmonary congestion on admission, and less resolution of pulmonary congestion during hospital stay. Worse prognosis related to residual pulmonary congestion was enhanced in patients with RV dysfunction.Graphic abstract TAPSE, tricuspid annular plane systolic excursion; PASP, pulmonary artery systolic pressure.