Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model.

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated ß-galactosidase (SA-ß gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC-CMs as a 'disease in a dish' model to provide insights into multiple aspects of this complex disease.

Optical mapping and optogenetics in cardiac electrophysiology research and therapy: a state-of-the-art review.

State-of-the-art innovations in optical cardiac electrophysiology are significantly enhancing cardiac research. A potential leap into patient care is now on the horizon. Optical mapping, using fluorescent probes and high-speed cameras, offers detailed insights into cardiac activity and arrhythmias by analysing electrical signals, calcium dynamics, and metabolism. Optogenetics utilizes light-sensitive ion channels and pumps to realize contactless, cell-selective cardiac actuation for modelling arrhythmia, restoring sinus rhythm, and probing complex cell-cell interactions. The merging of optogenetics and optical mapping techniques for 'all-optical' electrophysiology marks a significant step forward. This combination allows for the contactless actuation and sensing of cardiac electrophysiology, offering unprecedented spatial-temporal resolution and control. Recent studies have performed all-optical imaging ex vivo and achieved reliable optogenetic pacing in vivo, narrowing the gap for clinical use. Progress in optical electrophysiology continues at pace. Advances in motion tracking methods are removing the necessity of motion uncoupling, a key limitation of optical mapping. Innovations in optoelectronics, including miniaturized, biocompatible illumination and circuitry, are enabling the creation of implantable cardiac pacemakers and defibrillators with optoelectrical closed-loop systems. Computational modelling and machine learning are emerging as pivotal tools in enhancing optical techniques, offering new avenues for analysing complex data and optimizing therapeutic strategies. However, key challenges remain including opsin delivery, real-time data processing, longevity, and chronic effects of optoelectronic devices. This review provides a comprehensive overview of recent advances in optical mapping and optogenetics and outlines the promising future of optics in reshaping cardiac electrophysiology and therapeutic strategies.

Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels.

Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known. Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue. Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study.

BACKGROUND: Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. METHODS AND FINDINGS: For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. CONCLUSIONS: Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. TRIAL REGISTRATION: Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom.

Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems.

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the ß-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart.

RATIONALE: Cardiovascular disease represents a global pandemic. The advent of and recent advances in mouse genomics, epigenomics, and transgenics offer ever-greater potential for powerful avenues of research. However, progress is often constrained by unique complexities associated with the isolation of viable myocytes from the adult mouse heart. Current protocols rely on retrograde aortic perfusion using specialized Langendorff apparatus, which poses considerable logistical and technical barriers to researchers and demands extensive training investment. OBJECTIVE: To identify and optimize a convenient, alternative approach, allowing the robust isolation and culture of adult mouse cardiac myocytes using only common surgical and laboratory equipment. METHODS AND RESULTS: Cardiac myocytes were isolated with yields comparable to those in published Langendorff-based methods, using direct needle perfusion of the LV ex vivo and without requirement for heparin injection. Isolated myocytes can be cultured antibiotic free, with retained organized contractile and mitochondrial morphology, transcriptional signatures, calcium handling, responses to hypoxia, neurohormonal stimulation, and electric pacing, and are amenable to patch clamp and adenoviral gene transfer techniques. Furthermore, the methodology permits concurrent isolation, separation, and coculture of myocyte and nonmyocyte cardiac populations. CONCLUSIONS: We present a novel, simplified method, demonstrating concomitant isolation of viable cardiac myocytes and nonmyocytes from the same adult mouse heart. We anticipate that this new approach will expand and accelerate innovative research in the field of cardiac biology.

Intensive training and reduced volume increases muscle FXYD1 expression and phosphorylation at rest and during exercise in athletes.

The present study examined the effect of intensive training in combination with marked reduction in training volume on phospholemman (FXYD1) expression and phosphorylation at rest and during exercise. Eight well-trained cyclists replaced their regular training with speed-endurance training (10-12 × âˆ¼30-s sprints) two or three times per week and aerobic high-intensity training (4-5 × 3-4 min at 90-95% of peak aerobic power output) 1-2 times per week for 7 wk and reduced the training volume by 70%. Muscle biopsies were obtained before and during a repeated high-intensity exercise protocol, and protein expression and phosphorylation were determined by Western blot analysis. Expression of FXYD1 (30%), actin (40%), mammalian target of rapamycin (mTOR) (12%), phospholamban (PLN) (16%), and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) γ/δ (25%) was higher (P < 0.05) than before the training intervention. In addition, after the intervention, nonspecific FXYD1 phosphorylation was higher (P < 0.05) at rest and during exercise, mainly achieved by an increased FXYD1 Ser-68 phosphorylation, compared with before the intervention. CaMKII, Thr-287, and eukaryotic elongation factor 2 Thr-56 phosphorylation at rest and during exercise, overall PKCα/ß, Thr-638/641, and mTOR Ser-2448 phosphorylation during repeated intense exercise as well as resting PLN Thr-17 phosphorylation were also higher (P < 0.05) compared with before the intervention period. Thus, a period of high-intensity training with reduced training volume increases expression and phosphorylation levels of FXYD1, which may affect Na(+)/K(+) pump activity and muscle K(+) homeostasis during intense exercise. Furthermore, higher expression of CaMKII and PLN, as well as increased phosphorylation of CaMKII Thr-287 may have improved intracellular Ca(2+) handling.

Na+/Ca2+ exchange and Na+/K+-ATPase in the heart.

This paper is the third in a series of reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on cardiac Na(+)/Ca(2+) exchange (NCX) and Na(+)/K(+)-ATPase (NKA). While the relevance of Ca(2+) homeostasis in cardiac function has been extensively investigated, the role of Na(+) regulation in shaping heart function is often overlooked. Small changes in the cytoplasmic Na(+) content have multiple effects on the heart by influencing intracellular Ca(2+) and pH levels thereby modulating heart contractility. Therefore it is essential for heart cells to maintain Na(+) homeostasis. Among the proteins that accomplish this task are the Na(+)/Ca(2+) exchanger (NCX) and the Na(+)/K(+) pump (NKA). By transporting three Na(+) ions into the cytoplasm in exchange for one Ca(2+) moved out, NCX is one of the main Na(+) influx mechanisms in cardiomyocytes. Acting in the opposite direction, NKA moves Na(+) ions from the cytoplasm to the extracellular space against their gradient by utilizing the energy released from ATP hydrolysis. A fine balance between these two processes controls the net amount of intracellular Na(+) and aberrations in either of these two systems can have a large impact on cardiac contractility. Due to the relevant role of these two proteins in Na(+) homeostasis, the emphasis of this review is on recent developments regarding the cardiac Na(+)/Ca(2+) exchanger (NCX1) and Na(+)/K(+) pump and the controversies that still persist in the field.

The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic kidney disease.

Cardiotonic steroids (CTS) are a new class of hormones that circulate in the blood and are divided into two distinct groups, cardenolides, such as ouabain and digoxin, and bufadienolides, such as marinobufagenin, telocinobufagin and bufalin. They have the ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na(+) concentration in every living cell. Although digoxin has been prescribed to heart failure patients for at least 200 years, the realization that CTS are endogenously produced has intensified research into their physiological and pathophysiological roles. Over the last two decades, substantial evidence has accumulated demonstrating the effects of endogenously synthesised CTS on the kidneys, vasculature and the heart. In this review, the current state of art and the controversies surrounding the manner in which CTS mediate their pathophysiological effects are discussed. Several potential therapeutic strategies have emerged as a result of our increased understanding of the role CTS play in health and disease.

Male and female atria exhibit distinct acute electrophysiological responses to sex steroids.

The electrophysiological properties of the hearts of women and men are different. These differences are at least partly mediated by the actions of circulating estrogens and androgens on the cardiomyocytes. Experimentally, much of our understanding in this field is based on studies focusing on ventricular tissue, with considerably less known in the context of atrial electrophysiology. The aim of this investigation was to compare the electrophysiological properties of male and female atria and assess responses to acute sex steroid exposure. Age-matched adult male and female C57BL/6 mice were anesthetized (4 % isoflurane) and left atria isolated. Atria were loaded with Di-4-ANEPPS voltage sensitive dye and optical mapping performed to assess action potential duration (APD; at 10 %, 20 %, 30 %, 50 %, and 70 % repolarization) and conduction velocity in the presence of 1 nM and 100 nM 17ß-estradiol or testosterone. Male and female left atria demonstrated similar baseline action potential duration and conduction velocity, with significantly greater APD70 spatial heterogeneity evident in females. 17ß-estradiol prolonged action potential duration in both sexes - an effect that was augmented in females. Atrial conduction was slowed in the presence of 100 nM 17ß-estradiol in both males and females. Testosterone prolonged action potential duration in males only and did not modulate conduction velocity in either sex. This study provides novel insights into male and female atrial electrophysiology and its regulation by sex steroids. As systemic sex steroid levels change and intra-cardiac estrogen synthesis capacity increases with aging, these actions may have an increasingly important role in determining atrial arrhythmia vulnerability.

A novel mouse model recapitulates the effects of rs2254524 variant in the lanosterol synthase gene on salt sensitivity and organ damage.

OBJECTIVE: The blood pressure (BP) response to salt intake (salt sensitivity) shows great variability among individuals and is more frequent in hypertensive patients. Elevated levels of the steroid hormone Endogenous Ouabain (EO) are associated with hypertension (HT) and salt sensitivity. The lanosterol synthase gene ( LSS ) plays a key role in the biosynthesis of steroids and its rs2254524 variant (Val642Leu) is linked to salt sensitivity in humans. This study aims to investigate the pathophysiological significance of the Lss missense variation in a new knock-in mouse model of salt-sensitive HT onset. METHODS: We generated a mouse model carrying the murine homolog (Val643Leu) of the human LSS variant. C57BL/6N LssV643L/V643L mice were fed different NaCl diets (low-salt, LSD; normal-salt, NSD; high-salt, HSD) and were characterized at functional, histological, and molecular levels. RESULTS: At baseline, mutant mice showed an enlarged kidney compared to the wild-type (WT) counterpart, but the Lss V643L variant did not affect EO biosynthesis nor systolic BP at 3 and 12 months. In HSD, we observed an increased systolic BP only in 12-month-old LssV643L/V643L mice, compared to NSD. Moreover, only the HSD LssV643L/V643L mice showed cardiac hypertrophy and a higher incidence of cardiac fibrosis compared to WT at 12 months. Finally, the Lss mRNA level was differentially regulated by HSD in the adrenal gland, liver, and heart of LssV643L/V643L mice compared to WT. CONCLUSIONS: The novel Lss mouse model resembles the salt-sensitive HT phenotype observed in hypertensive patients and provides a good model of salt-sensitive HT and HT-mediated organ damage.

Impact of Obesity on Atrial Fibrillation Pathogenesis and Treatment Options.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF increases the risk of stroke, heart failure, dementia, and hospitalization. Obesity significantly increases AF risk, both directly and indirectly, through related conditions, like hypertension, diabetes, and heart failure. Obesity-driven structural and electrical remodeling contribute to AF via several reported mechanisms, including adiposity, inflammation, fibrosis, oxidative stress, ion channel alterations, and autonomic dysfunction. In particular, expanding epicardial adipose tissue during obesity has been suggested as a key driver of AF via paracrine signaling and direct infiltration. Weight loss has been shown to reverse these changes and reduce AF risk and recurrence after ablation. However, studies on how obesity affects pharmacologic or interventional AF treatments are limited. In this review, we discuss mechanisms by which obesity mediates AF and treatment outcomes, aiming to provide insight into obesity-drug interactions and guide personalized treatment for this patient subgroup.

Novel regulation of cardiac Na pump via phospholemman.

As the only quantitatively significant Na efflux pathway from cardiac cells, the Na/K ATPase (Na pump) is the primary regulator of intracellular Na. The transmembrane Na gradient it establishes is essential for normal electrical excitability, numerous coupled-transport processes and, as the driving force for Na/Ca exchange, thus setting cardiac Ca load and contractility. As Na influx varies with electrical excitation, heart rate and pathology, the dynamic regulation of Na efflux is essential. It is now widely recognized that phospholemman, a 72 amino acid accessory protein which forms part of the Na pump complex, is the key nexus linking cellular signaling to pump regulation. Phospholemman is the target of a variety of post-translational modifications (including phosphorylation, palmitoylation and glutathionation) and these can dynamically alter the activity of the Na pump. This review summarizes our current understanding of the multiple regulatory mechanisms that converge on phospholemman and govern NA pump activity in the heart. The corrected Fig. 4 is reproduced below. The publisher would like to apologize for any inconvenience caused. [corrected].

Nitric oxide regulates cardiac intracellular Na⁺ and Ca²âº by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism.

In the heart, Na/K-ATPase regulates intracellular Na(+) and Ca(2+) (via NCX), thereby preventing Na(+) and Ca(2+) overload and arrhythmias. Here, we test the hypothesis that nitric oxide (NO) regulates cardiac intracellular Na(+) and Ca(2+) and investigate mechanisms and physiological consequences involved. Effects of both exogenous NO (via NO-donors) and endogenously synthesized NO (via field-stimulation of ventricular myocytes) were assessed in this study. Field stimulation of rat ventricular myocytes significantly increased endogenous NO (18 ± 2 µM), PKCε activation (82 ± 12%), phospholemman phosphorylation (at Ser-63 and Ser-68) and Na/K-ATPase activity (measured by DAF-FM dye, western-blotting and biochemical assay, respectively; p<0.05, n=6) and all were abolished by Ca(2+)-chelation (EGTA 10mM) or NOS inhibition l-NAME (1mM). Exogenously added NO (spermine-NONO-ate) stimulated Na/K-ATPase (EC50=3.8 µM; n=6/grp), via decrease in Km, in PLM(WT) but not PLM(KO) or PLM(3SA) myocytes (where phospholemman cannot be phosphorylated) as measured by whole-cell perforated-patch clamp. Field-stimulation with l-NAME or PKC-inhibitor (2 µM Bis) resulted in elevated intracellular Na(+) (22 ± 1.5 and 24 ± 2 respectively, vs. 14 ± 0.6mM in controls) in SBFI-AM-loaded rat myocytes. Arrhythmia incidence was significantly increased in rat hearts paced in the presence of l-NAME (and this was reversed by l-arginine), as well as in PLM(3SA) mouse hearts but not PLM(WT) and PLM(KO). We provide physiological and biochemical evidence for a novel regulatory pathway whereby NO activates Na/K-ATPase via phospholemman phosphorylation and thereby limits Na(+) and Ca(2+) overload and arrhythmias. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

Hypertension and cardiomyopathy associated with chronic kidney disease: epidemiology, pathogenesis and treatment considerations.

Chronic kidney disease (CKD) is a complex condition with a prevalence of 10-15% worldwide. An inverse-graded relationship exists between cardiovascular events and mortality with kidney function which is independent of age, sex, and other risk factors. The proportion of deaths due to heart failure and sudden cardiac death increase with progression of chronic kidney disease with relatively fewer deaths from atheromatous, vasculo-occlusive processes. This phenomenon can largely be explained by the increased prevalence of CKD-associated cardiomyopathy with worsening kidney function. The key features of CKD-associated cardiomyopathy are increased left ventricular mass and left ventricular hypertrophy, diastolic and systolic left ventricular dysfunction, and profound cardiac fibrosis on histology. While these features have predominantly been described in patients with advanced kidney disease on dialysis treatment, patients with only mild to moderate renal impairment already exhibit structural and functional changes consistent with CKD-associated cardiomyopathy. In this review we discuss the key drivers of CKD-associated cardiomyopathy and the key role of hypertension in its pathogenesis. We also evaluate existing, as well as developing therapies in the treatment of CKD-associated cardiomyopathy.

Localized cardiomyocyte lipid accumulation is associated with slowed epicardial conduction in rats.

Transmural action potential duration differences and transmural conduction gradients aid the synchronization of left ventricular repolarization, reducing vulnerability to transmural reentry and arrhythmias. A high-fat diet and the associated accumulation of pericardial adipose tissue are linked with conduction slowing and greater arrhythmia vulnerability. It is predicted that cardiac adiposity may more readily influence epicardial conduction (versus endocardial) and disrupt normal transmural activation/repolarization gradients. The aim of this investigation was to determine whether transmural conduction gradients are modified in a rat model of pericardial adiposity. Adult Sprague-Dawley rats were fed control/high-fat diets for 15 wk. Left ventricular 300 µm tangential slices were generated from the endocardium to the epicardium, and conduction was mapped using microelectrode arrays. Slices were then histologically processed to assess fibrosis and cardiomyocyte lipid status. Conduction velocity was significantly greater in epicardial versus endocardial slices in control rats, supporting the concept of a transmural conduction gradient. High-fat diet feeding increased pericardial adiposity and abolished the transmural conduction gradient. Slowed epicardial conduction in epicardial slices strongly correlated with an increase in cardiomyocyte lipid content, but not fibrosis. The positive transmural conduction gradient reported here represents a physiological property of the ventricular activation sequence that likely protects against reentry. The absence of this gradient, secondary to conduction slowing and cardiomyocyte lipid accumulation, specifically in the epicardium, indicates a novel mechanism by which pericardial adiposity may exacerbate ventricular arrhythmias.