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Cardiovascular disease (CVD) and chronic kidney disease (CKD) often coexist and have a major impact on patient prognosis. Organ fibrosis plays a significant role in the pathogenesis of cardio-renal syndrome (CRS), explaining the high incidence of heart failure and sudden cardiac death in these patients. Various mediators and mechanisms have been proposed as contributors to the alteration of fibroblasts and collagen turnover, varying from hemodynamic changes to the activation of the renin–angiotensin system, involvement of FGF 23, and Klotho protein or collagen deposition. A better understanding of all the mechanisms involved has prompted the search for alternative therapeutic targets, such as novel inhibitors of the renin–angiotensin–aldosterone system (RAAS), serelaxin, and neutralizing interleukin-11 (IL-11) antibodies. This review focuses on the molecular mechanisms of cardiac and renal fibrosis in the CKD and heart failure (HF) population and highlights the therapeutic alternatives designed to target the responsible pathways.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic disorder, most often caused by sarcomeric gene mutations, with a small proportion due to variants in non-sarcomeric loci. Phospholamban (PLN) is a phosphoprotein associated with the cardiac sarcoplasmic reticulum, a major determinant of cardiac contractility and relaxation. We conducted a retrospective study to determine the prevalence, phenotypical spectrum and clinical course of patients carrying the PLN p.Leu39* variant. A cohort including 11 PLN patients was identified among all patients with HCM (9/189, 4.8%) and DCM (2/62, 3.2%) who underwent genetic testing from two tertiary centers and five more were detected through cascade screening. Complete phenotyping was performed. PLN p.Leu39* variant-driven cardiomyopathy presented mostly as hypertrophic, with frequent progression to end-stage dilated HCM. We proceeded to compare these results to a similar analysis of a control cohort consisting of age-matched individuals that inherited pathogenic or likely pathogenic variants in common sarcomeric genes (MYBPC3/MYH7). Overall, the clinical characteristics and examination findings of patients carrying PLN p.Leu39* were not different from patients with cardiomyopathy related to sarcomeric mutations except for the presence of pathological Q waves and the incidence of non-sustained ventricular arrhythmias, which were higher in PLN patients than in those with MYBPC3/MYH7-related diseases.