From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework

Abstract

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver-a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework-the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome-to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic.

Keywords: arterial hypertension; cardiometabolic medicine; cardiovascular-kidney-metabolic syndrome; cardiovascular-renal-hepatic-metabolic syndrome; chronic kidney disease; diabetes mellitus; dyslipidemia; heart failure; metabolic dysfunction-associated steatotic liver disease; obesity.

Figure 1

The spectrum of Cardiovascular-Renal-Hepatic-Metabolic diseases. Abbreviations. ASCVD (atherosclerotic cardiovascular disease); CKD (chronic kidney disease); CVD (cardiovascular disease); HF (heart failure); MASLD (metabolic dysfunction-associated steatotic liver disease); OSA (obstructive sleep apnea); PCOS (polycystic ovarian syndrome); POI (primary ovarian insufficiency).

Figure 2

Schematic illustration of the pathophysiological interplay and progression of the CRHM syndrome. Adiposity marks the first stage of the CRHM syndrome, where excess or dysfunctional fat tissue triggers mechanisms like meta-inflammation and adipokine imbalance, driving CRHM risk factors such as hypertension, T2DM, and dyslipidemia. It also directly contributes to MASLD, CKD, and CVD. These conditions are interconnected through shared mechanisms, including neurohormonal activation, inflammation, oxidative stress, and congestion, leading to progressive multi-organ dysfunction. The final stage is established CVD, such as HF or ASCVD. Factors like age, sex, genetics, lifestyle, and environmental exposures further influence the development and progression of CRHM. Abbreviations. ASCVD (atherosclerotic cardiovascular disease); CKD (chronic kidney disease); CVD (cardiovascular disease); CRHM (cardiovascular-renal-hepatic-metabolic); FFA (free fatty acids); FHH (functional hypogonadotrophic hypogonadism); HF (heart failure); MASLD (metabolic dysfunction-associated steatotic liver disease); OSA (obstructive sleep apnea); PCOS (polycystic ovarian syndrome); T2DM (type 2 diabetes mellitus).

Figure 3

Novel and emerging therapeutic approaches for CRHM syndrome. We should note that the use of finerenone in HFpEF, as well as the use of GLP-1RAs and GIP/GLP-1RAs in HF; diabetic CKD and MASLD have not yet been recommended by guidelines because the evidence from trials is very recent. Abbreviations ACEi (angiotensin-converting enzyme inhibitors); ARNi (angiotensin receptor-neprilysin inhibitors); ASCVD (atherosclerotic cardiovascular disease); BMI (body mass index); CKD (chronic kidney disease); DM (diabetes mellitus); eGFR (estimated glomerular filtration rate); GIP (glucose-dependent insulinotropic polypeptide); GLP-1RA (glucagon-like peptide-1 receptor agonist); HF (heart failure); HFmrEF (heart failure with mildly reduced ejection fraction); HFpEF (heart failure with preserved ejection fraction); HFrEF (heart failure with reduced ejection fraction); MASLD (metabolic dysfunction-associated steatotic Liver Disease); MRAs (mineralocorticoid receptor antagonists); SCORE2 (systematic coronary risk evaluation 2); SGLT2is (sodium–glucose cotransporter-2 inhibitors); TOD (target organ damage); T2DM (type 2 diabetes mellitus); UACR (urinary albumin-to-creatinine ratio).