Cardiac and Renal Fibrosis, the Silent Killer in the Cardiovascular Continuum: An Up-to-Date.

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.

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM's morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin-proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

Connection between Cardiac Fibrosis Biomarkers and Echocardiography Parameters in Advanced Chronic Kidney Disease Patients.

BACKGROUND: Myocardial fibrosis represents a mainstay pathway in the pathophysiology of uremic cardiomyopathy. This process leads to structural and functional changes in the heart, which can be detected by echocardiography. The purpose of our study was to determine the association between four echocardiographic parameters (ejection fraction (EF), global longitudinal strain (GLS), mean E/e' ratio, and left atrial volume indexed) and biomarkers associated with cardiac fibrosis, such as procollagen type I carboxy-terminal propeptide (PICP), procollagen type III N-terminal peptide (P3NP), and galectin-3 (Gal-3) in patients with end-stage renal disease (ESRD). METHODS: 140 patients with ESRD were enrolled and investigated by echocardiography and the serum levels of the aforementioned biomarkers were determined at baseline. RESULTS: The mean EF was 53.63 ± 8%, the mean GLS was -10.2 ± 5.3%, the mean E/e' ratio was 9.8 ± 4.3, and the mean left atrial volume indexed (LAVI) was 45.8 ± 14.2 mL/m2. The average levels for PICP, P3NP, and Gal-3 were 457.2 ± 240 µg/L, 242 ± 199.9 µg/L, and 10.7 ± 3.7 ng/mL, respectively. In regression analysis, PICP was strongly associated with all four echocardiographic parameters (EF: p = 0.0002, R2 = 0.69; GLS: p = 0.00001, R2 = 0.81; mean E/e': p = 0.00002; R2 = 0.89; LAVI: p = 0.003; R2 = 0.73). P3NP and Gal-3 were only associated with the EF (p = 0.01, R2 = 0.31 and p = 0.02; R2 = 0.35, respectively). CONCLUSION: Our study evidenced that PICP, a collagen-derived biomarker, is associated with important echocardiography parameters, suggesting that it can serve as an indicator of the presence of subclinical systolic and diastolic dysfunction in patients with advanced CKD.

Kidney transplantation: a possible solution to obstructive sleep apnea in patients with end-stage kidney disease.

INTRODUCTION: Obstructive sleep apnea (OSA) is frequently reported among patients with chronic kidney disease resulting in considerable morbidity and mortality. OSA may cause repetitive stimulation of the sympathetic nervous system and elevations in pulmonary artery pressure leading to an elevated risk of cardiac and vascular complications in patients with chronic kidney disease. Furthermore, OSA is associated with progressive worsening of kidney injury and loss of renal function. METHODS: In this systematic review and meta-analysis, we evaluated the effect of renal transplantation on the progression of OSA in patients with end-stage kidney disease. RESULTS: The meta-analysis included eight studies with a total of 401 patients. Findings showed that kidney transplantation does not lead to a statistically significant effect on the apnea-hypopnea index (MD 2.6 events/hr, 95% CI -3.2 to 8.3, p = 0.21), total sleep time (MD 14.7 min/night, 95% CI -8.4 to 37.8, p = 0.76), sleep efficiency (MD 2.5%, 95% CI -1.4 to 6.3, p = 0.57), slow wave sleep (MD 0.4% of total sleep time, 95% CI -7.5 to 8.4, p = 0.05), and rapid eye movement sleep (MD 0.6% of total sleep time, 95% CI -2.2 to 3.3, p = 0.98). There was no statistically significant effect of kidney transplantation on OSA in patients with chronic renal disease.

Predictive Value of Collagen Biomarkers in Advanced Chronic Kidney Disease Patients.

Patients with chronic kidney disease have an increased risk of all-cause death. The value of collagen biomarkers such as procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III N-terminal peptide (P3NP), in end-stage renal disease (ESRD), has not yet been defined (in the literature and in clinics). The purpose of this study was to determine the potential value of these new biomarkers in the prediction of mortality in this population. Plasma PICP and P3NP levels were determined in 140 patients with ESRD, not yet on dialysis, who were followed up for 36 ± 5.3 months. During follow-up, 58 deaths were recorded (41.4%), with the majority of them being cardiovascular deaths (43, 74.13%). Using the ROC curve, the cut-off value for the prediction of mortality for PICP was 297.31 µg/L, while for P3NP, the cut-off value was 126.67 µg/L. In univariate analysis, a value of PICP above the cut-off point was associated with a fivefold increased risk of mortality (hazard ratio (HR) 5.071, 95% confidence interval 1.935-13.29, p = 0.001) and a value of P3NP above the cut-off point was associated with a twofold increased risk of mortality (HR 2.089, 95% CI 1.044-4.178, p = 0.002). In a multivariable Cox proportional hazards model, PICP values remained independent predictors of mortality (HR 1.22, 95% CI 1.1-1.31, p < 0.0001). Our data suggest that the collagen biomarker PICP is an independent predictor of mortality in ESRD patients who are not yet on dialysis.

Kidney transplantation: is it a solution to endothelial dysfunction?

BACKGROUND: Endothelial dysfunction is associated with elevated cardiovascular risk in patients with end-stage renal disease (ESRD). Kidney transplantation has demonstrated significant ability in reducing mortality and improving quality of life in recipients. Recent studies have also reported improvements in endothelial function following kidney transplantation; however, current literature is limited. METHODS: We performed a systematic review of PubMed/Medline, Web of Science, Scopus, Cochrane Library, and CINAHL databases for prospective cohort studies that assessed endothelial function prior to and following kidney transplantation via various clinical markers. Follow-up duration ranged from 1 month to 1 year. A meta-analysis of pooled data was conducted using random-effect models for four key markers: brachial artery flow-mediated dilatation (FMD), high-sensitivity C-reactive protein (hsCRP), nitroglycerin-mediated dilation (NMD), and adiponectin. RESULTS: We included nine studies in our final analysis with a total of 524 patients. Significant improvement of all four biomarkers was observed after transplantation. The mean difference was 2.81% (95% CI 1.92-3.71, p < 0.00001) for FMD, 17.27 mg/L (95% CI 5.82-28.72, p = 0.003) for hsCRP, 1.05%, (95% CI 0.56-1.54, p < 0.0001) for NMD, and 9.27 µg/mL (95% CI 5.96-12.57, p < 0.00001) for adiponectin. CONCLUSION: There is an immediate reversal of endothelial dysfunction in ESRD patients who undergo kidney transplantation, which may explain observed improvements in cardiovascular morbidity in transplant recipients. Future longitudinal studies are needed to understand possible re-emergence of endothelial dysfunction in the long-term postoperative period.

Effect of sodium-glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes of patients with type 2 diabetes at high cardiovascular risk and chronic kidney disease. Recent studies showed an increase in hemoglobin and hematocrit after SGLT2i treatment. MATERIALS AND METHODS: We did a systematic review and meta-analysis of randomized, double-blind, placebo-controlled studies of SGLT2i in patients with type 2 diabetes. We searched through PubMed/Medline, Web of Science, Embase (Elsevier), and the Cochrane Central Register of Controlled Trials (Wiley) from January 2010 to January 2021. RESULTS: We included seventeen randomized, double-blind, placebo-controlled studies. The total number of evaluated patients was 14,748. The treatment arm consisted of canagliflozin, dapagliflozin, empagliflozin and ipragliflozin. SGLT2i therapy significantly increased hemoglobin levels when compared to placebo (MD 5.60 g/L, 95% CI 3.73-7.47 g/L, P < 0.00001, considerable heterogeneity-I2 = 94%). Each SGLT2i also led to a significant increase in the hematocrit level when compared to placebo (MD 1.32%, 95% CI 1.21-1.44, P < 0.00001, considerable heterogeneity-I2 = 99%). CONCLUSIONS: SGLT2i led to significant increases in hemoglobin and hematocrit levels when compared to placebo. In addition to their cardiovascular effect, SGLT2i also increases hemoglobin and hematocrit levels.

Left atrial strain: A novel "biomarker" for chronic kidney disease patients?

Cardiovascular disease and chronic kidney disease are frequently inter-connected and this association leads to an exponential growth of cardiovascular risk. This risk is currently underestimated by the existing algorithms and there is a constant need for new markers to predict adverse outcomes in this special population. In general population left atrial strain has emerged as an important tool for both the diagnosis and prognostic stratification, but data regarding its role in chronic kidney disease patients is scarce. The purpose of this review is to summarize the current evidence regarding this matter. Left atrial size and function mirror the duration and severity of increased left ventricular filling pressures. Increased left atrial volume index and impaired left atrial strain parameters are independent predictors for adverse cardiovascular events. Left atrial strain is impaired before changes in volume appear, thus being able to predict both diastolic and systolic function in chronic kidney disease patients. Finally, left atrial strain can identify renal patients with impaired exercise capacity and this could have clinical applications in the rehabilitation of this patients.

Pushing the Limits of Medical Management in HCM: A Review of Current Pharmacological Therapy Options.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal reduction therapy (SRT) remains an invasive procedure with associated surgical risks and it requires the expertise of the operating centre, thus limiting its accessibility. It is therefore with high interest that researchers look for pharmacological alternatives that could provide higher rates of success. With new data gathering these past years as well as the development of a new drug class showing promising results, this review provides an up-to-date focused synthesis of existing medical treatment options and future directions for HCM pharmacological treatment.

Coronary artery bypass grafting versus percutaneous coronary intervention in end-stage kidney disease: A systematic review and meta-analysis of clinical studies.

The most significant complication of end-stage kidney disease (ESKD) is cardiovascular disease, mainly coronary artery disease (CAD). Although the effective treatment of CAD is an important prognostic factor, whether percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is better for treating CAD in this group of patients is still controversial. We searched Pubmed/Medline, Web of Science, Embase, the Cochrane Central Register of Controlled Trials articles that compared the outcomes of CABG versus PCI in patients with ESKD requiring dialysis. A total of 10 observational studies with 39,666 patients were included. Our analysis showed that when compared to PCI, CABG had lower risk of need for repeat revascularization (relative risk [RR] = 2.25, 95% confidence interval [CI] 2.1-2.42, p < 0.00001) and cardiovascular death (RR = 1.19, 95% CI 1.14-1.23, p < 0.00001) and higher risk for short-term mortality (RR = 0.43, 95% CI 0.38-0.48, p < 0.00001). There was no statistically significant difference between the PCI and CABG groups in the risk for late mortality (RR = 1.05, 95% CI 0.97-1.14, p = 0.25), myocardial infarction (RR = 1.05, 95% CI 0.46-2.36, p = 0.91) or stroke (RR = 1.02, 95% CI 0.64-1.61, p = 0.95). This meta-analysis showed that in ESKD patients requiring dialysis, CABG was superior to PCI in regard to cardiovascular death and need for repeat revascularization and inferior to PCI in regard to short term mortality. However, this meta-analysis has limitations and needs confirmation with large randomized controlled trials.

Cardiac Resynchronization Therapy in Non-Ischemic Cardiomyopathy: Role of Multimodality Imaging.

Non-ischemic cardiomyopathy encompasses a heterogeneous group of diseases, with a generally unfavorable long-term prognosis. Cardiac resynchronization therapy (CRT) is a useful therapeutic option for patients with symptomatic heart failure, currently recommended by all available guidelines, with outstanding benefits, especially in non-ischemic dilated cardiomyopathy. Still, in spite of clear indications based on identifying a dyssynchronous pattern on the electrocardiogram (ECG,) a great proportion of patients are non-responders. The idea that multimodality cardiac imaging can play a role in refining the selection criteria and the implant technique and help with subsequent system optimization is promising. In this regard, predictors of CRT response, such as apical rocking and septal flash have been identified. Promising new data come from studies using cardiac magnetic resonance and nuclear imaging for showcasing myocardial dyssynchrony. Still, to date, no single imaging predictor has been included in the guidelines, probably due to lack of validation in large, multicenter cohorts. This review provides an up-to-date synthesis of the latest evidence of CRT use in non-ischemic cardiomyopathy and highlights the potential additional value of multimodality imaging for improving CRT response in this population. By incorporating all these findings into our clinical practice, we can aim toward obtaining a higher proportion of responders and improve the success rate of CRT.

Role of Klotho in the Development of Essential Hypertension.

Klotho has antiaging properties, and serum levels decrease with physiological aging and aging-related diseases, such as hypertension, cardiovascular, and chronic kidney disease. Klotho deficiency in mice results in accelerated aging and cardiovascular injury, whereas Klotho supplementation slows down the progression of aging-related diseases. The pleiotropic functions of Klotho include, but are not limited to, inhibition of insulin/IGF-1 (insulin-like growth factor 1) and WNT (wingless-related integration site) signaling pathways, suppression of oxidative stress and aldosterone secretion, regulation of calcium-phosphate homeostasis, and modulation of autophagy with inhibition of apoptosis, fibrosis, and cell senescence. Accumulating evidence shows an interconnection between Klotho deficiency and hypertension, and Klotho gene polymorphisms are associated with hypertension in humans. In this review, we critically review the current understanding of the role of Klotho in the development of essential hypertension and the most important underlying pathways involved, such as the FGF23 (fibroblast growth factor 23)/Klotho axis, aldosterone, Wnt5a/RhoA, and SIRT1 (Sirtuin1). Based on this critical review, we suggest avenues for further research.

Efficiency of Hypertonic Saline in the Management of Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies.

INTRODUCTION: Acute decompensated heart failure (ADHF), with an incidence of 1-2%, is a clinical syndrome with significant morbidity and mortality despite therapeutic advancements and ongoing clinical trials. A recent therapeutic approach to patients with ADHF includes combination therapy with hypertonic saline solution (HSS) and furosemide, based on the hypothesis that resistance to loop diuretics occurs because of achievement of plateau in water and sodium excretion in patients receiving long-term loop diuretic therapy. OBJECTIVE: Our aim was to conduct a meta-analysis to evaluate the efficiency of combination HSS plus furosemide therapy in patients with ADHF in terms of mortality, readmissions, length of hospital stay, kidney function, urine output, body weight, and B-type natriuretic peptide (BNP). METHODS: A total of 14 studies-four observational and ten randomized studies (total 3398 patients)-were included in the meta-analysis. RESULTS: Our results demonstrate the superiority of combination HSS plus furosemide therapy over furosemide alone in terms of kidney function preservation (mean creatinine difference - 0.33 mg/dL; P < 0.00001), improved diuresis (mean difference [MD] 581.94 mL/24 h; P < 0.00001) and natriuresis (MD 57.19; P < 0.00001), weight loss (MD 0.99 kg; P < 0.00001), duration of hospital stay (MD - 2.72 days; P < 0.00001), readmissions (relative risk 0.63; P = 0.01), and mortality (relative risk 0.55; P < 0.00001). However, no difference in BNP levels was detected (MD 19.88 pg/mL; P = 0.50). CONCLUSION: Despite the heterogeneity and possible risk of bias among the studies, results appear promising on multiple aspects. A clear need exists for future randomized controlled trials investigating the role of combination HSS plus furosemide therapy to clarify these effects and their possible mechanisms.

Role of collagen turnover biomarkers in the noninvasive assessment of myocardial fibrosis: an update.

The pro-fibrotic milieu, as the result of the extracellular matrix remodeling, is a central feature in the pathophysiology of heart disease and contributes to its high morbidity and mortality. Fibrosis is a recognized risk factor for development of heart failure and arrythmias and is usually detected by cardiac magnetic resonance or endomyocardial biopsy. Collagen type I and type III are major components of the collagen network, and the assessment of their derived biomarkers could serve as estimate of the myocardial fibrotic content. This review summarizes data from numerous studies in which these biomarkers have proven their diagnostic and prognostic utility, setting the stage for further randomized clinical trials that might translate into early implementation of antifibrotic therapies.

What can hide behind an "idiopathic" dilated cardiomyopathy?

Myocarditis is an infectious-inflammatory disease with viral infections being one of the most common infectious cause. When it is superimposed to an individual genetic background, myocarditis may progress into a chronic heart muscle disorder, most often dilated cardiomyopathy (DCM), with a natural history similar to classic forms of genetic or idiopathic dilated cardiomyopathies. We present the case of a 30-year-old patient, with a persistent infectious episode in the last 8 weeks, pain and swelling in the large joints. At admission the patient had fever, tachycardia and a grade 2/6 systolic mitral murmur. Laboratory findings revealed inflammatory syndrome, hepatocytolysis syndrome and microalbuminuria. The electrocardiogram (ECG) showed possible right atrial tachycardia. The echocardiography revealed a globally enlarged heart with reduced ejection fraction and diffuse hypokinesia. When discussing the etiology of the DCM, the following were taken into consideration: a tachycardiomyopathy, ischemic etiology, genetic component, autoimmune etiology (elevated anti-Ro titer), and myocarditis. The diagnosis of myocarditis was confirmed by the cardiac magnetic resonance imaging which showed diffuse fibrosis of the interstitial space and an important increase of the extracellular volume. This case is distinguished by a particular immunological panel requiring dynamic monitoring in order to diagnose a possible associated autoimmune pathology.

Atrial fibrillation and chronic kidney disease conundrum: an update.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is frequently encountered in chronic kidney disease (CKD) subjects. CKD patients are already at high risk for cardiovascular (CV) complications and the addition of AF further aggravates the prognosis. Data is missing regarding on how to best approach CKD patients with AF, due to lack of randomized controlled trials (RCTs). AF and CKD have a double edged-sword relationship. On one hand, there are kidney-specific mechanisms which can alter cardiac structure and predispose to AF, and on the other hand the development of AF itself can accelerate the progression of CKD. Furthermore, the synergistic effect of these two entities raises serious issues concerning the balance between bleeding and thrombotic risk. Anticoagulant treatment can be challenging, especially in end stage renal disease (ESRD), where the net clinical benefit is still unclear. The decision of rate vs. rhythm control lies mostly on general consensus, rather than on RCTs. The purpose of this review is to reinforce the symbiotic relationship between AF and CKD, to briefly summarize the current state of the therapeutic approach in this particular population and to highlight novel potential therapeutic strategies.

Multi-modality cardiac imaging in advanced chronic kidney disease.

Cardiovascular disease (CVD) is the leading cause of death worldwide and is particularly frequent among those with severe renal impairment. Early diagnosis and therapeutic intervention may help alleviate the burden of cardiovascular complication within this population. In the last years, advances have been made toward developing noninvasive imaging techniques that could offer better insight into the cardiac involvement in end-stage renal disease (ESRD). Conventional transthoracic echocardiography remains the first-line investigation used to assess cardiac function, but encompassing in our daily practice, the newer approaches such as speckle-tracking imaging, cardiac computed tomography, or cardiac magnetic resonance can guide us to a more comprehensive understanding of CVD in ESRD. Given that patients with chronic kidney disease may not present with typical CVD symptoms, the amount of information brought by newer imaging techniques is crucial for an accurate diagnosis, risk stratification, and further management. The purpose of this review is to briefly summarize the specific applications of standard cardiac imaging techniques in patients with ESRD and to offer insight into the novel imaging modalities, highlighting the newest research in this field. By doing so, we aim to identify the most important imaging predictors of clinical outcomes in this population.

A comprehensive review on apolipoproteins as nontraditional cardiovascular risk factors in end-stage renal disease: current evidence and perspectives.

PURPOSE: Nontraditional cardiovascular risk factors such as lipoprotein(a) (Lp(a)), the genetic polymorphisms of apolipoprotein(a), apolipoprotein E (ApoE), and apolipoprotein B (ApoB) increase the prevalence of atherosclerosis in end-stage renal disease (ESRD) through quantitative and qualitative alterations. Given the high burden of cardiovascular fatal events in ESRD, this review aims to gather studies depicting apolipoproteins' changes in ESRD, to describe current evidence and to explore potential lipid-lowering therapies. METHODS: We searched the electronic database of PubMed, SCOPUS, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins in ESRD. Randomized controlled trials, observational studies (including case-control, prospective, or retrospective cohort), and reviews/meta-analysis were included if reference was made to apolipoproteins and cardiovascular consequences in ESRD. RESULTS: 21 studies met the inclusion criteria. We found a significant correlation between Lp(a) plasma concentrations and atherosclerosis. Lp(a) levels were independent risk factors for atherothrombosis and cardiovascular mortality. LMW apo(a) phenotype proved to be the best predictor for coronary events in ESRD. Single nucleotide polymorphisms in ApoE gene affected the expression and function of the protein, increasing the risk of cardiovascular events. ApoB had a significant correlation with the value of carotid intima-media thickness and vascular stiffness. CONCLUSIONS: The picture of "lipid milieu" in ESRD has not been clearly described. Novel studies show that specific apolipoproteins suffer modifications in uremic patients, being correlated with cardiovascular events. Probably in the next years, the treatment of dyslipidemia in ESRD will not merely target LDL or total cholesterol, but specific isoforms of apolipoproteins which seem to become the central part of the problem.

Cardioprotective apelin effects and the cardiac-renal axis: review of existing science and potential therapeutic applications of synthetic and native regulated apelin.

First described in 1998, apelin is one of the endogenous ligands of the apelinergic receptor. Since its discovery, its possible role in human physiology and disease has been intensively studied. Apelin is a native cardioprotective agent that the body synthesizes to create atheroprotective, antihypertensive, and regenerative effects in the body. By antagonizing the RAA system, apelin could play an important role in heart failure and hypertension. It is also involved in myocardial protection against ischemia/reperfusion injury, post-ischemic remodeling, and myocardial fibrosis. A small number of studies even suggest that serum apelin levels may be involved the development of life-threatening arrhythmias. All this information generated excitement about potential therapeutic effects in patients with heart failure and myocardial infarction. The therapeutic index of apelin is unknown but is anticipated to be favorable based on the small number of studies. In this review, we summarize the mechanisms by which apelin exerts its cardioprotective effects and its connection with the cardiorenal axis. Also, we report the potential therapeutic applications of synthetic and native regulated apelin. If larger studies can be performed, it is possible that apelin-mediated drug treatment may play a major role for a large number of patients worldwide in the future.

In search of lost time - a case of myocardial perforation in a patient with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is particularly hard to diagnose and manage. We present the case of a 49-year-old, a former professional football player, with a history of cardiac arrest in 2011 by ventricular tachycardia (VT) (normal coronary arteries). Between 2011 and 2019 the patient didn't present for reevaluation and resumed endurance sports activity. In 2019 he was directed to our clinic for a syncope followed by constrictive anterior chest pain and palpitations, the clinical expression of a VT for which cardioversion was required. Upon admission, the patient was at sinus rhythm with negative T waves in V1-V2. Echocardiography showed significant dilatation and dysfunction of the RV (TAPSE 16 mm, FAC 20%, S' 8.6 cm/s). To confirm the diagnosis of ARVC, cardiac MRI was performed, confirming fat infiltration in the RV free wall with biventricular involvement. Given the high arrhythmic risk, a two-chamber ICD was implanted. In the second postprocedural day, the patient presented important epigastric pain, with ECG signs of sensing and pacing malfunction and ventricular probe displacement on the radioscopy. Emergency surgery was performed, with successful extraction of the electrode. Postoperative progression was favorable under treatment with beta-blocker and amiodarone. In conclusion, this case is a particular one since we've documented two distinct phases in the evolution of the ARVC (electrical phase - 2011 and structural phase - 2019). Moreover, by resuming endurance sports activity and in concordance with the literature data, we can only assume that the progression of the disease was accelerated, with a greater arrhythmic risk.