Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown.

Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by 2 intriguing features: ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia inducible factors (HIFs; especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeogenesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. HIFs act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. The activation of SIRT1, AMPK, and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. It is interesting that type 2 diabetes mellitus, obesity, chronic heart failure, and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by downregulating SIRT1, AMPK, and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK, and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.

Inflammation and microcalcification are interrelated processes contributing to atherosclerotic plaque vulnerability. Positron-emission tomography can quantify these processes in vivo. This study investigates (1) 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) uptake in culprit versus nonculprit carotid atheroma, (2) spatial distributions of uptake, and (3) how macrocalcification affects this relationship.

The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer (64Cu-DOTA-ECL1i).

The paucity of available hearts for transplantation means that more patients remain on durable left ventricular support for longer periods of time. The Registry to Evaluate the HeartWare Left Ventricular Assist System was an investigator-initiated multicenter, prospective, single-arm database established to collect post-Conformité Européene mark clinical information on patients receiving the HeartWare ventricular assist device system as a bridge to transplantation. This registry represents the longest multicenter follow-up of primary left ventricular assist device outcomes.

Limited data are available regarding the outcomes of patients supported by extracorporeal membrane oxygenation (ECMO) who undergo durable mechanical circulatory support implantation (dMCS). We analyzed the clinical characteristics, outcomes, and risk factors for mortality in patients who were bridged with ECMO to dMCS.

Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is associated with impaired aerobic capacity. We investigated the integrity of cardiac β-receptor responsiveness, an important mechanism involved in exertional increases in HR, in HFpEF and control subjects.

Limited progress has been made in the management of cardiogenic shock (CS). Morbidity and mortality of refractory CS remain high. The effects of mechanical circulatory support (MCS) are promising, although many aspects are elusive. We evaluated efficacy and safety of early combined MCS (Impella microaxial pump + venoarterial extracorporeal membrane oxygenation [VA-ECMO]) in refractory CS and aimed to determine factors for decision-making in combined MCS.

The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort.

Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of nonvitamin K antagonist oral anticoagulants in this population.

Background Since the direct oral anticoagulants (DOAC) were introduced, oral anticoagulant (OAC) prescription patterns have rapidly changed in patients with atrial fibrillation (AF). We aimed to evaluate the evolving trends of OAC use in a large nationwide cohort and specifically examine the changes in patient profiles treated with warfarin or DOAC and whether the time trends in OAC use affected clinical outcomes. Methods and Results Using the Korean Health Insurance Review and Assessment database, we divided OAC naive patients with AF into 3 groups according to the enrollment period between January 2015 and December 2017 (n=35 353 in cohort 1, n=36 631 in cohort 2, and n=44 819 in cohort 3). DOAC use increased from 59% to 89%, whereas warfarin use has decreased from 41% to 11% during the study period. Patients treated with warfarin were increasingly younger from cohort 1 to cohort 3 (mean age 68-65 years, P<0.001) with lower mean CHA2DS2-VASc scores (3.3-2.9, P<0.001), whereas those with DOAC did not show a significant difference in clinical characteristics over the study period. Warfarin group had improved clinical outcomes over time, reflecting dynamic changes in patient characteristics. Compared with warfarin group, unadjusted hazard ratios of composite outcome for DOAC group have changed over time (hazard ratio 0.77 [95% CI, 0.69-0.85] in cohort 1, hazard ratio 0.84 [95% CI, 0.73-0.97] in cohort 2, and hazard ratio 1.00 [95% CI, 0.78-1.25] in cohort 3). After propensity score weighting between warfarin and DOAC groups in each cohort, DOAC showed consistently lower risks of the composite outcome by approximately 23% to 25% compared with warfarin across 3 different periods. Conclusions In contemporary clinical practice, OAC prescription patterns and characteristics of patients treated warfarin or DOAC have dynamically changed. Despite these changes, DOAC showed a consistent better net clinical benefit compared with warfarin across different periods.