Cardiac diagnostic testing continues to evolve, and controversies remain regarding the optimal utilization of different procedures. We sought to evaluate changes in long-term utilization trends for a wide range of cardiac diagnostic tests in the context of advancing technologies and updated guidelines.

Despite insufficient evidence to support direct-to-consumer genetic testing in routine clinical care, cardiovascular clinicians increasingly face questions about its utility and interpretation because individuals can purchase these tests directly from laboratories. A burgeoning marketplace offers an expanding array of testing options. In many cases, direct-to-consumer genetic testing advertises information that could inform one's risk of heritable disease, including insight into having a genetic predisposition to cardiovascular disease or data about gene-drug interactions that could affect response to cardiovascular medications. Navigating clinical questions about direct-to-consumer genetic testing involves understanding the evolution and oversight of the marketplace; the scope of direct-to-consumer genetic testing offerings; and the risks, benefits, and limitations of said testing. In this American Heart Association scientific statement, we summarize the state of the direct-to-consumer genetic testing industry, review types of cardiovascular genetic information that may be included in direct-to-consumer genetic testing, describe approaches to evaluate test quality, and provide resources for clinicians navigating questions about direct-to-consumer genetic testing. If direct-to-consumer genetic test information is used in clinical care, care should be taken to assess the limitations of the test, to contextualize the information specifically to the patient, and to corroborate potentially actionable monogenic findings.

Low-density lipoprotein (LDL) is internalized into cells mainly through LDLR (LDL receptor)-mediated endocytosis. In an acidic endosome, LDLR is released from LDL and recycles back to the cell surface, whereas LDL is left in the endosome and degraded in the lysosome. Circulating PCSK9 (proprotein convertase subtilisin/kexin 9) binds with LDLR and is internalized into the endosome, similar to LDL. In an acidic endosome, LDLR fails to disassociate from PCSK9, and both proteins are degraded in the lysosome. PCSK9 inhibitors are widely used for treating hypercholesterolemia. However, how PCSK9 diverts LDLR to the lysosome for degradation remains elusive. Some patients are resistant to PCSK9 inhibitors, for unknown reasons.

Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear.

Cardiac β3-adrenergic receptors (ARs) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect against myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. However, the underlying mechanisms remain elusive.

Sex differences in the risk factors, diagnosis, treatment, and outcomes of patients with cardiovascular disease have been well described; however, the bulk of the literature has focused on heart disease in women. Data on sex differences in peripheral vascular disease are ill defined, and there is a need to report and understand those sex-related differences to mitigate adverse outcomes related to those disparities. Although peripheral vascular disease is a highly diverse group of disorders affecting the arteries, veins, and lymphatics, this scientific statement focuses on disorders affecting the peripheral arteries to include the aorta and its branch vessels. The purpose of this scientific statement is to report the current status of sex-based differences and disparities in peripheral vascular disease and to provide research priorities to achieve health equity for women with peripheral vascular disease.

Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention.

Muscle proteins of the obscurin protein family play important roles in sarcomere organization and sarcoplasmic reticulum and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood.

Albuminuria-increased urine albumin excretion-is associated with cardiovascular mortality among patients with diabetes, hypertension, chronic kidney disease, or heart failure, as well as among adults with few cardiovascular risk factors. Many authors have hypothesized that albuminuria reflects widespread endothelial dysfunction, but additional work is needed to uncover whether albuminuria is directly pathologic or causative of cardiovascular disease. Urinary albumin-to-creatinine ratio is an attractive, unifying biomarker of cardiovascular, kidney, and metabolic conditions that may be useful for identifying and monitoring disease trajectory. However, albuminuria may develop through unique mechanisms across these distinct clinical phenotypes. This state-of-the-art review discusses the role of albuminuria in cardiovascular, kidney, and metabolic conditions; identifies potential pathways linking albuminuria to adverse outcomes; and provides practical approaches to screening and managing albuminuria for clinical cardiologists. Future research is needed to determine how broadly and how frequently to screen patients for albuminuria, whether it is cost-effective to treat low-grade albuminuria (10-30 mg/g), and how to equitably offer newer antiproteinuric therapies across the spectrum of cardiovascular-kidney-metabolic diseases.

Nickel-containing devices, such as the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder, are used for transcatheter patent foramen ovale closure. However, the impact of nickel hypersensitivity on postprocedural outcomes remains poorly understood. This study aimed to evaluate the risk of adverse events in patients with nickel hypersensitivity undergoing patent foramen ovale closure.

A preservation system, the Organ Care System (OCS; TransMedics) uses normothermic pulsatile perfusion during organ transport for heart transplantation. This system has demonstrated favorable outcomes in hearts recovered from extended-criteria donors after brain death (DBD) and donors after circulatory death (DCD).

Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.

We derived and validated proteomic risk scores (PRSs) for heart failure (HF) prognosis that provide absolute risk estimates for all-cause mortality within 1 year.