# Heart Failure: Epidemiology, Pathophysiology, and Management

## TL;DR

This review explores heart failure's epidemiology, calcium-related mechanisms, and management strategies to improve diagnosis and treatment.

## Contribution

The paper introduces a mechanistic network linking calcium dynamics with inflammation and mitochondrial dysfunction in heart failure.

## Key findings

- Calcium-handling differences vary across heart failure subtypes under physiological and pathological conditions.
- Alterations in calcium-regulating proteins and pathways are integrated into a network model for mechanistic understanding.
- Emerging therapies target specific mechanisms in heart failure through calcium homeostasis-related points and lines.

## Abstract

Heart failure (HF) is one of the leading causes of hospitalization and mortality worldwide. Despite continuous updates to modern clinical guidelines regarding HF classification and management, mortality and rehospitalization rates remain persistently high. Enhancing the prevention and treatment of HF therefore represents a major challenge both now and in the future. In this review, we synthesize HF epidemiology and systematically mapped the calcium‑handling differences under physiological and pathological conditions, as well as the patterns of calcium‑homeostasis dysregulation across the major HF subtypes (heart failure with reduced ejection fraction; heart failure with preserved ejection fraction). Moreover, we summarize alterations in key calcium‐regulating proteins (points) and calcium homeostasis‐related pathways (lines), and further integrate these nodes into a network model that links Ca2
+ dynamics remodeling with inflammation, oxidative stress, and mitochondrial dysfunction. Building on this mechanistic network, we discuss both conventional HF management strategies and emerging therapeutic developments that target distinct mechanisms through points and lines. Finally, we outline the unmet needs and future directions across the current “diagnosis–treatment–monitoring” continuum, with the overarching goal of advancing precision diagnosis, individualized therapy, and the establishment of a comprehensive HF management framework.

This article takes calcium homeostasis as the point of departure to provide an overview of heart failure from three perspectives—epidemiology, pathophysiological mechanisms, and management strategies—and summarizes the current unmet needs and future directions in the field.