Khan, Saifullah

Pediatric heart failure is a heterogeneous, high-risk clinical syndrome that differs fundamentally from adult heart failure in its etiologies, pathophysiology, and therapeutic responses. Although its absolute prevalence is lower, children experience disproportionate morbidity and mortality, with up to 40% of patients with symptomatic cardiomyopathy progressing to death or transplantation within 2 years of diagnosis. Congenital heart disease, cardiomyopathies, and genetic or metabolic disorders dominate the etiologic spectrum, while developmental differences in myocardial signaling, neurohormonal activation, and ventricular remodeling limit direct extrapolation of adult guideline-directed medical therapy. Evidence supporting pharmacologic treatment remains limited, and most therapies are symptom-modifying rather than outcome-modifying, particularly in single-ventricle physiology. Advances in mechanical circulatory support and heart transplantation have substantially improved survival, yet pose unique anatomic, physiological, and ethical challenges in children. This review synthesizes contemporary evidence across medical, device-based, and transplant therapies, highlights lesion- and age-specific considerations, and identifies critical research gaps needed to advance outcomes in pediatric heart failure.

Cancer-associated venous thromboembolism (CA-VTE) is a leading, severe, and potentially life-threatening complication in patients with malignancy. Low–molecular-weight heparin has historically been the standard of care; however, direct oral anticoagulants, particularly direct factor Xa inhibitors, have emerged as effective alternatives. These agents offer the convenience of oral administration, predictable pharmacokinetics, elimination of routine laboratory monitoring, and improved adherence. Despite the expanding role of direct oral anticoagulants in CA-VTE management, concerns regarding bleeding risk—particularly in patients with gastrointestinal and genitourinary malignancies—remain central to clinical decision-making. In this narrative review, we evaluate the efficacy, safety, and clinical applicability of apixaban for the treatment and prophylaxis of CA-VTE. Current evidence from randomized controlled trials, including CARAVAGGIO and AMPLIFY, demonstrates that apixaban has noninferior efficacy compared with low–molecular-weight heparin and conventional anticoagulation strategies, with comparable or lower rates of recurrent venous thromboembolism. In addition, apixaban appears to have a favorable safety profile, with no statistically significant increase in major bleeding in selected cancer populations, including those without active gastrointestinal lesions. Apixaban’s pharmacokinetic properties, including limited renal clearance and stable drug exposure, further enhance its clinical utility in oncologic populations. However, evidence supporting apixaban use across all cancer subtypes remains limited and heterogeneous, highlighting the need for additional comparative and real-world studies.

Hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet blood pressure control rates remain suboptimal despite the availability of effective therapies. Contemporary guidelines increasingly recommend early use of combination therapy, recognizing that most patients require multiple agents to achieve target blood pressure. Widaplik, a recently Food and Drug Administration-approved fixed-dose, single-pill triple combination of telmisartan, amlodipine, and indapamide, represents the first triple therapy approved for initial treatment of hypertension in adults likely to need multidrug therapy. This review summarizes the pharmacologic rationale for low-dose triple therapy, highlighting complementary mechanisms targeting the renin-angiotensin-aldosterone system, vascular resistance, and sodium retention. We examine evidence from pivotal phase 3 trials demonstrating rapid, sustained blood pressure reductions, higher control rates compared with dual therapy, and favorable tolerability. We also discuss safety considerations, practical limitations, and gaps in evidence, including long-term cardiovascular outcomes. Widaplik represents a paradigm shift toward simplified, early combination therapy aimed at improving hypertension control and reducing cardiovascular risk.

Coronary microvascular dysfunction (CMD) is increasingly recognized as a central mechanism underlying myocardial ischemia, heart failure with preserved ejection fraction, and adverse cardiovascular outcomes in patients with and without obstructive coronary artery disease. The coronary microcirculation plays a critical role in regulating myocardial perfusion through tightly coordinated myogenic, metabolic, and endothelial pathways. Disruption of these mechanisms results in impaired vasodilatory capacity, abnormal coronary flow reserve, and microvascular ischemia. This review summarizes the anatomy and physiology of coronary microcirculation and examines the pathophysiologic mechanisms driving CMD, including endothelial dysfunction, structural remodeling, inflammation, and neurohormonal dysregulation. Contemporary diagnostic strategies are reviewed, with emphasis on invasive coronary function testing and advanced noninvasive imaging modalities such as positron emission tomography and cardiac magnetic resonance imaging. The clinical implications of CMD across diverse disease states, including ischemia with nonobstructive coronary arteries, heart failure, and cardiomyopathies, are discussed. Finally, current therapeutic approaches, prognostic considerations, and emerging research directions aimed at improving diagnosis and targeted treatment of CMD are highlighted.

Coronary artery spasm (CAS) is a dynamic vasomotor disorder characterized by transient, intense constriction of epicardial coronary arteries, leading to myocardial ischemia in patients with and without obstructive coronary artery disease. CAS plays a central role in vasospastic angina, ischemia with nonobstructive coronary arteries and myocardial infarction with nonobstructive coronary arteries, malignant arrhythmias, and sudden cardiac death. Its pathophysiology is multifactorial, involving endothelial dysfunction, vascular smooth muscle hyperreactivity, inflammation, oxidative stress, autonomic imbalance, and genetic susceptibility, with notable ethnic and sex-related differences. Diagnosis relies on integration of clinical features, electrocardiographic changes, and invasive coronary provocation testing using acetylcholine or ergonovine, supported by advanced imaging and functional assessment when microvascular involvement is suspected. Management is centered on calcium channel blockers and nitrates, aggressive risk factor modification, particularly smoking cessation, and individualized strategies for refractory or high-risk patients. Improved recognition and standardized diagnostic pathways are essential to optimize outcomes and reduce life-threatening complications associated with CAS.

Shock is a life-threatening state of circulatory failure characterized by inadequate tissue oxygen delivery and cellular hypoxia. Lactate has emerged as a central biomarker in the diagnosis, risk stratification, and management of shock, yet its interpretation is complex and context dependent. Although traditionally viewed as a marker of anaerobic metabolism and tissue hypoperfusion, hyperlactatemia in distributive shock, particularly sepsis, frequently reflects multifactorial mechanisms, including increased aerobic glycolysis, adrenergic stimulation, mitochondrial dysfunction, and impaired hepatic clearance. This review examines the pathophysiology and classification of shock, the biochemical basis of lactate production and clearance, and the prognostic significance of both static lactate levels and lactate kinetics. We synthesize evidence supporting lactate as a robust prognostic marker while highlighting limitations of lactate-targeted resuscitation strategies. Emerging data favor multimodal approaches integrating lactate trends with complementary perfusion markers such as capillary refill time and central venous oxygen saturation. Lactate should be interpreted as one component of a comprehensive physiological assessment rather than an isolated therapeutic target.