What this is
- Cardiometabolic diseases are increasingly recognized as interconnected disorders, traditionally managed in isolation.
- The American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, but it overlooks the liver's role.
- This perspective introduces an expanded framework, the Cardiovascular-Renal-Hepatic-Metabolic () syndrome, to include the liver.
- The framework aims to improve prevention, diagnosis, and management strategies for these overlapping conditions.
Essence
- The syndrome framework integrates the liver into the understanding of cardiometabolic diseases, recognizing its critical role in disease progression. This holistic approach aims to enhance clinical strategies for diagnosis and treatment.
Key takeaways
- The syndrome expands the CKM model by including the liver, which is essential for understanding cardiometabolic health. This inclusion acknowledges the liver's role in metabolic dysfunction and its bidirectional relationship with cardiovascular and renal diseases.
- Emerging therapies targeting shared pathophysiological mechanisms can benefit multiple organ systems. Recent clinical trials have shown that medications like SGLT2 inhibitors and GLP-1 receptor agonists provide advantages across conditions such as obesity, heart failure, and chronic kidney disease.
- Integrated care models are necessary to address the fragmented management of diseases. A multidisciplinary approach can improve patient outcomes by ensuring comprehensive evaluation and treatment across all affected systems.
Caveats
- The proposed framework is still conceptual and requires further validation through empirical research. Its effectiveness in clinical practice has yet to be established.
- Fragmented healthcare delivery remains a significant challenge, potentially hindering the implementation of integrated care models. Overcoming these barriers is essential for improving patient management.
Definitions
- Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome: A systemic disorder characterized by interconnected dysfunction among cardiovascular, renal, hepatic, and metabolic systems, driven by shared pathophysiological mechanisms.
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1. Introduction
We are witnessing a global pandemic of cardiometabolic disorders, which has slowed or even reversed earlier declines in cardiovascular disease (CVD) mortality, prompting stronger efforts to improve prevention and treatment strategies [1]. Over the past five years, our understanding of these conditions has evolved dramatically. Obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD (ASCVD), heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were once treated as separate conditions. Today, they are recognized as interconnected disorders sharing common pathophysiological pathways that drive parallel disease progression [2]. Simultaneously, new medications such as sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), combined gastric inhibitory polypeptide (GIP)/GLP-1 receptor agonists, and finerenone have demonstrated benefits across multiple conditions in this spectrum, improving both quality of life and hard clinical outcomes [3,4].
In 2023, the American Heart Association (AHA) introduced the Cardiovascular-Kidney-Metabolic (CKM) syndrome to emphasize the interconnected roles of the heart, blood vessels, kidneys, and metabolism. However, this model does not fully account for the liverâs role within this spectrum. MASLD, the hepatic manifestation of metabolic dysregulation, is both a driver and a consequence of metabolic dysfunction. Its progression to metabolic dysfunction-associated steatohepatitis (MASH) is closely intertwined with insulin resistance and obesity, creating a bidirectional relationship that exacerbates the development and progression of atherosclerosis, HF, and CKD [5,6].
According to the 2024 guidelines of the EASL-EASD-EASO, cardiometabolic criteria are now part of the definition and diagnosis of MASLD, which was previously termed non-alcoholic fatty liver disease (NAFLD) before 2023 [7]. Specifically, the most common cardiometabolic disorders associated with MASLD include overweight/obesity (âŒ90%), prediabetes/T2DM (âŒ60%), prehypertension/arterial hypertension (âŒ85%), hypertriglyceridemia (âŒ75%), low high-density lipoprotein cholesterol (HDL-C, âŒ60%), and HF with preserved ejection fraction (HFpEF, âŒ50%) [8,9]. Furthermore, individuals with MASLD are at an increased risk of cardiovascular mortality (hazard ratio [HR] 1.30), non-fatal CVD (HR 1.40), coronary artery disease (odds ratio [OR] 1.33), HF (OR 1.5), CKD (HR 1.43), T2DM, and diabetes-related peripheral polyneuropathy (HRs 2.19 and 2.48, respectively), and obstructive sleep apnea (OSA, HR 2.22) [7]. This group of associated conditions and additional disorders related to increased cardiometabolic risk create the spectrum of Cardiovascular-Renal-Hepatic-Metabolic diseases (Figure 1).
Current evidence highlights that MASLD is not only common among individuals with other cardiometabolic diseases, but also plays a key role in the progression of CKM syndrome. This underscores the need for a more comprehensive framework that includes MASLD and its intricate connections to cardiometabolic and renal health. In this context, we propose expanding the CKM syndrome to a Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome. This new framework recognizes the liverâs central role in inter-organ dynamics and aims to improve clinical strategies for prevention, diagnosis, and management. By defining this expanded syndrome, exploring its interconnected pathways, and outlining integrated diagnostic and treatment approaches, this manuscript hopes to provide a more holistic and effective way to address these overlapping diseases during the ongoing cardiometabolic health crisis.
2. Defining and Staging the CRHM Syndrome
The concept of metabolic syndrome (MetS) has long been recognized in medical practice, with insulin resistance identified as a key pathophysiological driver. MetS is clinically defined by the presence of three or more of the following five criteria [5,6]:âȘWaist circumference â„88 cm for women and â„102 cm for men (â„80 cm for women and â„90 cm for men in individuals of Asian descent).âȘHDL-C <40 mg/dL for men and <50 mg/dL for women.âȘTriglycerides (TG) â„150 mg/dL.âȘElevated blood pressure (systolic â„130 mm Hg or diastolic â„80 mm Hg, or use of antihypertensive medications).âȘFasting blood glucose â„100 mg/dL, or the use of antidiabetic medications.
Building on the foundation of MetS, in 2023, the AHA introduced the CKM syndrome, which has been defined as âA systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD, and the cardiovascular system leading to multiorgan dysfunction and a high rate of adverse cardiovascular outcomes. CKM syndrome includes both individuals at risk for CVD due to the presence of metabolic risk factors, CKD, or both and individuals with existing CVD that is potentially related to or complicates metabolic risk factors or CKD.â
Although this model addresses the interplay between the cardiovascular, renal, and metabolic systems, it does not fully capture the role of the liver. MASLD, and particularly its progression to MASH and cirrhosis, is bidirectionally associated with metabolic dysregulation, atherosclerosis, HF, and CKD. With this in mind, we propose expanding the CKM syndrome to a Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome, defined as: âA systemic disorder that leads to parallel multiorgan dysfunction driven by shared pathophysiological mechanisms, including metabolic inflammation (meta-inflammation) and dysregulation, especially insulin resistance. This syndrome includes early stages with risk factorsâwhere prevention can slow progressionâas well as established cardiovascular, renal, and hepatic manifestations and the interactions between them, including ASCVD, HF, CKD, and MASLD/MASH/cirrhosis.â Based on this definition, we propose a modified staging system that integrates the liver as a central player (Table 1). By integrating the liver into this framework, clinicians and researchers can adopt a more comprehensive view of how metabolic, cardiovascular, renal, and hepatic factors interact. This lays the groundwork for a more cohesive approach to diagnosis, risk stratification, and therapeutic interventions.
Our proposed framework aligns closely with the recent concept of classifying obesity into preclinical and clinical stages. On January 14, 2025, The Lancet Diabetes & Endocrinology published its commission on the definition and diagnostic criteria of clinical obesity [10]. The commission defines obesity as a condition characterized by excess adiposity, with or without abnormal adipose tissue distribution or function, and with multifactorial causes that remain incompletely understood. Preclinical obesity is described as a state of excess adiposity without current evidence of organ dysfunction or limitations in daily activities. However, it carries a variable, but generally heightened, risk of progressing to clinical obesity and developing related non-communicable diseases, such as type 2 diabetes, cardiovascular disease, certain cancers, and mental health disorders. In contrast, clinical obesity is defined as a chronic, systemic illness associated with evidence of impaired organ or tissue function and/or age-adjusted limitations in daily activities. These limitations may reflect the specific impact of excess adiposity on mobility and basic activities of daily living, such as bathing, dressing, toileting, continence, and eating. In our proposed framework, Stage 1 corresponds to preclinical obesity, representing early dysfunction due to adiposity but without significant clinical manifestations. Stages 2 through 4 correspond to clinical obesity, capturing the progressive systemic effects of excess adiposity on organ function.
3. Pathophysiology of the CRHM Syndrome
3.1. Excess Adiposity
The pathophysiology of the CRHM syndrome is grounded by how excess/dysfunctional adiposity and additional cardiometabolic risk factors are bidirectionally associated with the development of renal, hepatic, and cardiovascular dysfunction. The Central driver of this syndrome process is excess adiposity, which is characterized by chronic inflammation and drives the development of other CRHM risk factors, including arterial hypertension, T2DM, and dyslipidemia, while also promoting atherosclerosis, cardiac, renal and hepatic dysfunction. Understanding these pathways helps clinicians recognize that what begins with adipose dysfunction and mild metabolic disturbances can escalate into advanced HF, CKD, and liver cirrhosis.
3.1.1. Adiposity and Insulin Resistance
Excess and especially dysfunctional adipose tissue, especially visceral, is characterized by increased infiltration of immune cells, particularly M1 pro-inflammatory macrophages, and reduced angiogenesis. These changes create hypoxia within adipose depots, which further exacerbates local inflammation. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ÎČ are released by macrophages and dysfunctional adipocytes. The interleukin inflammation resulting from this metabolic dysregulation is referred to as âmeta-inflammation,â which disrupts normal insulin signaling in peripheral tissues, including muscle, liver, and adipose tissue. Specifically, pro-inflammatory cytokines activate intracellular kinases, such as JNK and IKK-ÎČ, which phosphorylate insulin receptor substrate (IRS) proteins on serine residues instead of tyrosine. This aberrant phosphorylation impairs downstream signaling, reducing glucose uptake in peripheral tissues like skeletal muscle and adipose tissue while increasing hepatic gluconeogenesis [11,12].
Moreover, enlarged and dysfunctional adipose tissue releases higher levels of free fatty acids (FFAs) into circulation. These FFAs accumulate in liver and muscle cells, causing lipotoxicity. This ectopic fat deposition directly impairs insulin signaling and mitochondrial function, further exacerbating metabolic dysfunction [11].
Another hallmark of obesity is the dysregulation of adipokines. In obesity, leptinâa hormone responsible for regulating satiety and energy balanceâis chronically overproduced, leading to leptin resistance. This state reduces the brainâs ability to regulate appetite and energy expenditure, further driving weight gain. Leptin resistance is also closely linked to the development of insulin resistance. In addition, resistin, an adipokine that is elevated in obesity, promotes meta-inflammation and exacerbates insulin resistance. Conversely, adiponectin, an insulin-sensitizing and anti-inflammatory adipokine, decreases as adiposity increases [13].
3.1.2. Adiposity and Dyslipidemia
Excess adipose tissue continuously releases FFAs into the portal and systemic circulation. The liver utilizes these FFAs to synthesize TGs, which are then packaged into very low-density lipoproteins (VLDLs). Overproduction of VLDLs elevates plasma TG levels, a hallmark of obesity-related dyslipidemia. High levels of triglyceride-rich VLDLs promote the activity of cholesteryl ester transfer protein (CETP), which facilitates the exchange of triglycerides from VLDLs with cholesteryl esters from HDL. This process depletes HDL particles, resulting in lower plasma HDL levels. Moreover, the increased presence of VLDLs contributes to the formation of small dense low-density lipoprotein (sdLDL) particles, which are more atherogenic. Meta-inflammation, dysregulated adipokine profiles, and insulin resistance further disrupt lipoprotein metabolism, compounding the dyslipidemic profile associated with obesity [14].
3.1.3. Adiposity and Arterial Hypertension
Meta-inflammation and dysregulated adipokine profiles in obesity can activate the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), contributing to endothelial dysfunction and reduced nitric oxide (NO) production. These changes result in an increased heart rate and peripheral vascular resistance, as well as elevated adrenal aldosterone secretion, ultimately leading to elevated blood pressure. Chronic activation of the RAAS and SNS also promotes smooth muscle hypertrophy in blood vessels, further increasing peripheral vascular resistance. Additionally, dysfunctional adipose tissue directly stimulates aldosterone secretion, which contributes to sodium retention and exacerbates hypertension [15].
3.1.4. Adiposity and Renal Dysfunction
In the early stages of obesity and insulin resistance, increased blood volume and cardiac output (CO) can elevate the glomerular filtration rate (GFR), a phenomenon known as âhyperfiltration.â This hyperfiltration leads to chronic glomerular hypertension and dysfunction. Additionally, neurohormonal activation increases efferent arteriolar tone, raising intraglomerular pressure. The elevated mechanical stress within the glomeruli can damage podocytes, which are key cells in the kidneyâs filtration barrier, resulting in proteinuria and progressive nephron loss. Furthermore, chronic inflammation can contribute to renal injury by directly damaging tubular cells and promoting fibrosis [16].
3.1.5. Adiposity, MASLD and HFpEF
Excess FFAs released from adipose tissue accumulate inside cardiomyocytes and hepatocytes, causing steatosis. Insulin resistance impairs the hepatic and myocardial ability to efficiently utilize TGs and oxidize FFAs, perpetuating the intracellular buildup of lipid droplets. Excess FFAs are prone to oxidation, generating reactive oxygen species (ROS) that lead to myocardial and hepatic damage and dysfunction. Furthermore, dysfunctional adiposity drives meta-inflammation and the release of pro-inflammatory cytokines, stimulating fibrotic remodeling and left ventricular hypertrophyâhallmarks of HFpEFâas well as liver fibrosis, which is a hallmark of MASLD. Dysregulated adipokine profiles, increased aldosterone production, and RAAS activation, resulting from dysfunctional adiposity, further perpetuate myocardial and hepatic damage and fibrosis. Over time, these processes may progress from asymptomatic myocardial dysfunction to HFpEF, as well as from MASLD to MASH and liver cirrhosis [17,18]. Reflecting their shared pathophysiology, HFpEF has been termed the âNASH of the heart,â underscoring the parallel roles of adiposity-driven toxicity and meta-inflammation in these two metabolically driven diseases [19].
3.2. Coexistence of Diabetes and Hypertension and Progression to CKD
When diabetes and hypertension coexist, their deleterious effects on the kidneys are significantly amplified:âȘGlomerular Hyperfiltration: Both conditions elevate glomerular pressure and exacerbate hyperfiltration, accelerating damage to podocytes and other glomerular cells. In diabetes, chronic hyperglycemia increases glucose filtration through the kidneys. To compensate, renal tubules reabsorb more glucose and sodium, raising intraglomerular pressure and promoting hyperfiltration. Similarly, systemic hypertension transmits high pressure to the glomeruli, leading to hyperfiltration in early stages and eventually progressing to glomerular sclerosis (hardening and scarring) [20,21].âȘRAAS: Insulin resistance and hyperglycemia can enhance RAAS activity, which is often elevated in idiopathic arterial hypertension. Elevated angiotensin II causes preferential constriction of the efferent arteriole, increasing intraglomerular pressure. Increased aldosterone secretion and sodium and fluid retention further compound this pressure, leading to chronic glomerular injury. Over time, RAAS-driven damage contributes to structural changes in renal vasculature, such as hyaline arteriosclerosis in afferent arterioles and hyperplastic arteriosclerosis in more severe cases [20,21].âȘVascular Remodeling: Persistent hypertension thickens the walls of small renal arteries and arterioles, narrowing the lumen and impairing blood flow. This ischemic injury to nephrons exacerbates kidney damage [20,21].âȘAdvanced Glycation End Products (AGEs): Prolonged hyperglycemia promotes the formation of AGEs in kidney tissues. These AGEs alter protein structures, such as collagen in the glomerular basement membrane, triggering inflammation, fibrosis, and oxidative stress [20,21].âȘEndothelial Dysfunction and Chronic Inflammation: Endothelial dysfunction, driven by pro-inflammatory cytokines and oxidative stress from both diabetes and hypertension, damages glomeruli and renal vessels. Chronic inflammation activates mesangial cells and fibroblasts, leading to extracellular matrix deposition, nephron loss, and a gradual decline in GFR [20,21].
3.3. Liver-Cardiovascular Interactions
3.3.1. How Cardiac Dysfunction Affects the Liver
3.3.2. How Hepatic Dysfunction Affects the Cardiovascular System
3.4. Cardiovascular-Kidney Interactions
3.4.1. How Cardiovascular Dysfunction Affects the Kidneys
3.4.2. How Renal Dysfunction Affects the Cardiovascular System
3.5. Liver-Kidney Interactions
3.5.1. How Hepatic Dysfunction Affects the Kidneys
3.5.2. How Renal Dysfunction Affects the Liver
3.6. Additional Modifying Factors in the Pathophysiology of CRHM Syndrome
In the sections above, we have emphasized how adiposity serves as the central driver and initial event in the development and progression of the CRHM syndrome. However, in addition to this, aging, sex hormone dynamics, environmental stressors, and genetic factors also play pivotal roles in the pathophysiology and progression of the syndrome. Aging is intrinsically linked to increased frailty, systemic low-grade inflammation (âinflammagingâ), and mitochondrial dysfunction, all of which exacerbate metabolic, cardiovascular, renal, and hepatic dysfunction [ml-omics]. Frailty contributes to sarcopenic obesity, impaired glucose metabolism, and reduced physiological reserves, further compounding organ dysfunction [46,47,48].
Sex dimorphism, driven by differences in sex hormones, adds another layer of complexity. Estrogen, for example, exerts protective effects on cardiovascular, hepatic, and metabolic health, while its decline in postmenopausal women is associated with increased risks of visceral adiposity, dyslipidemia, and systemic inflammation [49]. Similarly, testosterone deficiency in men is linked to insulin resistance, reduced lean mass, and heightened cardiovascular risk [50].
Environmental stressors, including air pollution, smoking, physical inactivity, and chronic psychosocial stress, can further amplify CRHM progression through shared pathways such as oxidative stress, endothelial dysfunction, and chronic inflammation. Exposure to fine particulate matter (PM2.5) and environmental toxins has been shown to exacerbate atherosclerosis, kidney damage, and hepatic steatosis [51].
Finally, genetic factors and epigenetics also play a crucial role. It is well-documented that some individuals without obesity develop T2DM, while others with mild abdominal obesity do so, and some with severe, long-standing obesity remain free of T2DM. This variability in susceptibility highlights how adiposityâs effects are influenced by genetic predispositions and epigenetic modifications. Recognizing these additional factors provides a more comprehensive understanding of the interconnected pathways driving the CRHM syndrome.
Figure 2 depicts the intricate pathophysiological interactions leading to the progression of the CRHM syndrome. In this framework, adiposity represents the first stage of the CRHM syndrome. Excess and/or dysfunctional adipose tissue, via a constellation of mechanisms (e.g., meta-inflammation, adipokine dysregulation), drives the development of additional CRHM risk factors (arterial hypertension, T2DM, and dyslipidemia) while also directly contributing to the pathogenesis and progression of MASLD, CKD, and CVD. These CRHM diseases are pathophysiologically interconnected through multiple mechanisms, including neurohormonal activation, chronic inflammation, oxidative stress, toxin accumulation, hypoperfusion, and congestion, perpetuating vicious cycles of progressive parallel organ dysfunction. The fourth and final stage of the CRHM syndrome is clinically established CVD, including HF and/or ASCVD. Demographic factors (e.g., age, sex, race), genetic predisposition, as well as environmental and lifestyle factors (e.g., smoking, alcohol, physical activity, nutrition, chronic stress, sleep, environmental pollution) are additional key mediators in the pathogenesis and progression of the CRHM syndrome.
4. Evaluation of the CRHM Syndrome
A comprehensive evaluation is crucial for identifying and characterizing the interplay of metabolic, cardiovascular, renal, and hepatic factors in individuals with the CRHM syndrome. One of the most important considerations in managing the CRHM syndrome is proper clinical staging, which allows for early interventions aimed at slowing or preventing progression to advanced stages. Below is a consolidated table (Table 2) that outlines primary assessments and possible follow-up investigations across multiple domains, along with the rationale for each. This structured approach aids clinicians in staging the disease, targeting early interventions, and preventing progression to advanced organ damage.
Key Takeaways
By systematically integrating these evaluations, clinicians can build a robust framework for diagnosing, staging, and ultimately managing patients within the CRHM spectrum. This multifaceted approach enables early intervention and can slow or even halt progression toward advanced HF, renal failure, and/or cirrhosis, thereby improving long-term health outcomes.
5. Novel Therapeutic Options for the CRHM Syndrome
Over the past five years, clinical trials have shown promising results for therapies such as GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, SGLT2 inhibitors, and finerenone across the CRHM spectrum [55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88]. These agents target shared mechanismsâinsulin resistance, inflammation, fluid retention, and neurohormonal imbalanceâproviding benefits that reach beyond single-organ conditions. As a result, traditional distinctions among cardiology, endocrinology, nephrology, and hepatology are giving way to a more integrated approach. By leveraging the pleiotropic effects of these medications, clinicians can streamline treatment and enhance outcomes for patients with overlapping cardiometabolic disorders. An overview of the novel and emerging therapeutic approaches for the CRHM syndrome along with the evidence from phase III clinical trials is presented in Table 3 and illustrated in Figure 3.
Many clinical trials are underway to further expand the indications of novel agents for the CRHM spectrum. Finerenone, already approved for diabetic CKD, is being investigated to determine its benefits in HF across the entire spectrumâincluding acute HFâas well as in non-diabetic CKD [71]. Meanwhile, the ESSENCE trial is evaluating novel therapies for MASH, with preliminary positive results reported but not yet published [86]. There is also a need for dedicated studies of GLP-1RAs in non-diabetic CKD. Moreover, promising data on GLP-1RAs and dual GIP/GLP-1RAs for HF and especially HFpEF from the SELECT, STEP-HFpEF, STEP-HFpEF DM, FLOW, and SUMMIT trials underscore the importance of additional research, particularly for HFrEF where evidence is scarce. Collectively, these efforts aim to expand treatment options and improve outcomes across the intertwined conditions that define the CRHM syndrome.
6. Implications for Clinical Practice and Patient Care
Despite advances in the understanding and management of CRHM diseases, traditional care models, which are often structured around individual organ systems or isolated specialties, fail to address the multifaceted and interconnected nature of the CRHM syndrome. This fragmented nature of current healthcare delivery results in siloed care, where patients are managed by multiple specialistsâcardiologists, endocrinologists, nephrologists, hepatologists, and othersâeach focusing on a narrow aspect of the disease process. Consequently, patients frequently undergo redundant diagnostic tests, receive conflicting treatment recommendations, and are exposed to polypharmacy, increasing the risk of medication errors and adverse effects. This fragmented system can overwhelm patients, leading to confusion and poor adherence to treatment plans, perpetuating disease progression and poor outcomes.
To address these challenges, healthcare systems and professional societies must prioritize the establishment of integrated care models that dismantle traditional silos. These models should center around comprehensive, patient-focused clinics, uniting a multidisciplinary team of specialists, including cardiologists, endocrinologists, nephrologists, hepatologists, sleep specialists, exercise physiologists, dietitians, psychologists, and other allied health professionals. Such a coordinated framework ensures that all aspects of the CRHM syndrome are evaluated and managed collectively, fostering continuity of care and improved outcomes. Furthermore, the formation of guidelines for an integrated approach in the investigation and management of the CRHM syndrome can potentially unify its management across different specialties.
Equally essential is the formation of structured fellowships and subspecialty training programs dedicated to the management of CRHM diseases. By equipping healthcare professionals with the knowledge and skills to address the full CRHM, such initiatives can drive a shift from fragmented to integrated and continuous care.
7. Conclusions
The evolving concept of cardiometabolic disease underscores the deep interconnections among the heart, kidneys, liver, and metabolic pathways. While the CKM syndrome laid crucial groundwork for unifying these systems, the inclusion of the liver in the CRHM framework acknowledges the vital influence of MASLD and its progression to MASH on disease outcomes. By integrating hepatic dysfunction into clinical staging, diagnostics, and therapy selection, clinicians gain a more comprehensive view of patient risk and opportunities for intervention.
Novel therapeutic agentsâsuch as SGLT2 inhibitors, GLP-1 receptor agonists, dual GIP/GLP-1 receptor agonists, and finerenoneâdemonstrate that targeting shared mechanisms can confer multi-organ protection. Recent trials indicate significant benefits in conditions spanning obesity, HF, CKD, and MASLD, blurring traditional boundaries among cardiology, nephrology, hepatology, and endocrinology. Ongoing research, including dedicated trials for non-diabetic CKD, HFrEF, and MASH, promises to refine the scope of these therapies, broaden their indications, and potentially transform management of patients with overlapping cardiometabolic disorders.
Despite these advances, care for patients with overlapping CRHM diseases remains highly fragmented, often siloed within individual specialties such as cardiology, nephrology, hepatology, and endocrinology. The proposed CRHM syndrome provides an opportunity to unify existing guidelines, develop new consensuses, and foster interdisciplinary collaboration among these fields. By emphasizing the interconnected nature of the heart, kidneys, liver, and metabolic pathways, CRHM syndrome could also pave the way for the establishment of novel fellowships or subspecialties dedicated to training clinicians along the entire CRHM spectrum, ensuring a new generation of specialists equipped to deliver holistic, patient-centered care.