The Missing Transition: Why the 2026 Universal Definition Stages Heart Failure but Does Not Explain How a Syndrome Becomes a Disease

 

Heart failure remains one of the central clinical realities of cardiovascular medicine. The recent 2026 AHA/ACC/ESC/WHF Expert Consensus Document, Second Universal Definition of Heart Failure, defines heart failure as a clinical syndrome with diverse causes, recognized through a combination of symptoms, signs, biomarkers, imaging, and structural or functional cardiac abnormalities. This is correct and clinically useful. Yet this definition does not fully exhaust the nature of heart failure across its entire course.

There is an important distinction between the origin of heart failure and its later clinical status. Heart failure may initially arise as a syndrome of ischemic heart disease, hypertension, valvular pathology, cardiomyopathy, arrhythmia, pulmonary disease, renal disease, or systemic disorders. In this sense, it is indeed secondary. However, at later stages heart failure often becomes the principal determinant of the patient's health, symptoms, functional capacity, repeated decompensations, hospitalization risk, response to treatment, and prognosis. At that point, it no longer behaves merely as a syndrome attached to another disease. It behaves as a disease in its own right.

This idea is not new. In our earlier work on chronic heart failure, we argued that medicine already recognizes analogous transitions in other fields. A primary disease may generate a syndrome, and that syndrome may then grow into a new disease entity when it acquires independent clinical dominance. The example of chronic kidney disease is especially instructive: diverse renal insults may initiate the process, but over time the shared functional disorder of the kidney becomes a disease category with its own stages, prognostic implications, and therapeutic strategy. The original cause remains important, but it is no longer the only organizing principle of care. The same reasoning can be applied to chronic heart failure.

Why the Transition Is Biologically Real, Not Only Clinical

The 2026 universal definition partly confirms this view, even if it does not state it explicitly. The document presents heart failure not only as a syndrome, but also as a staged and dynamic condition. It distinguishes individuals at risk for heart failure, those with pre-heart failure, those with symptomatic heart failure, and those with advanced disease. It emphasizes that once symptomatic heart failure is established, the diagnosis is generally considered permanent, even if the patient improves. It also recognizes trajectories such as worsening heart failure, decompensated heart failure, improvement, remission, and recovery — the language of a chronic disease state with its own natural history, not of a transient syndrome.

What the consensus document describes clinically, contemporary myocardial biology now explains mechanistically. Once an initiating insult — myocardial infarction, chronic pressure overload, inflammatory activation, metabolic stress, or aging — activates cardiac fibroblasts into myofibroblasts, a self-amplifying cycle is established: disorganized extracellular matrix (ECM) remodeling increases energy dissipation and lowers cardiac efficiency, which raises cardiomyocyte metabolic demand and oxidative stress, which in turn damages capillary networks and displaces the trophic signals cardiomyocytes need to survive, driving cardiomyocyte dedifferentiation and death, and death itself triggers further fibrotic replacement that deepens the cycle. Critically, this cycle, once established beyond a certain threshold, is "essentially irreversible with the therapeutic tools currently available," and it continues to advance whether or not the original causal disease is controlled. 

This distinction matters enormously for the syndrome-versus-disease question. It means that the etiologic disease (hypertension, ischemia, valvulopathy) functions only as a trigger for a process that, once initiated, runs on its own internal biological logic — fibroblast activation, matrix stiffening, capillary rarefaction, cardiomyocyte dystrophy — largely independent of whether the trigger itself is still active. A patient whose hypertension is now well controlled can still have progressive heart failure, because the fibrotic scaffold cycle, not the blood pressure, has become the operative disease process. This is the mechanistic counterpart to the CKD analogy: just as the kidney's shared functional disorder becomes a disease category independent of its diverse triggers, the heart's fibrotic remodeling cycle becomes a self-sustaining disease process independent of its inciting cardiovascular condition. 

Diagnostic Autonomy Reinforces Disease Status

The case for heart failure's autonomy is strengthened further by an emerging diagnostic argument, not just a therapeutic one. Current cardiac assessment is built almost entirely around chamber biomechanics — ejection fraction, strain, torsion, chamber geometry — which describe how the heart moves but not the condition of the connective tissue scaffold that generates, constrains, and progressively distorts that motion. This creates three recurrent clinical blind spots: patients with similar ejection fractions can follow markedly different trajectories because their underlying scaffold burden differs; conditions like HFpEF show severe disease despite preserved conventional mechanics because the myocardium is stiffened and capillary-impoverished even while it still moves adequately; and patients can experience declining exercise tolerance and metabolic reserve while ejection fraction remains normal, because deteriorating energetic efficiency — not motion — is the first thing to fail. 

The practical implication is that heart failure is beginning to require its own diagnostic architecture — layered biomechanics, tissue characterization (native T1 mapping, extracellular volume quantification), and biochemical markers of matrix turnover — organized around scaffold integrity rather than around the causal disease that originally produced it. A condition that requires a dedicated, disease-specific diagnostic framework, distinct from the framework used for its originating causes, has moved well beyond the status of a downstream syndrome. 

What International Classification Already Recognizes

International disease classification supports this broader interpretation. In ICD-10, heart failure is already classified among diseases of the heart, under the I50 category. In ICD-11, this position becomes even more explicit, with heart failure occupying its own block within diseases of the circulatory system and including distinct subcategories such as congestive heart failure, left ventricular failure, right ventricular failure, biventricular failure, and unspecified heart failure. International classification systems already recognize heart failure as a disease entity for purposes of nosology, statistics, coding, and health-system organization — a convergence that now has a plausible biological substrate behind it.

This convergence between classification, clinical trajectory, and underlying biology is important. It indicates that medicine, perhaps implicitly, already understands that heart failure is not only a syndrome of other diseases. Once symptomatic and especially once advanced, it becomes a disease state with genuine biological autonomy, driven by its own self-amplifying fibrotic cycle. The etiologic disease does not disappear, but it descends to the level of cause, while heart failure itself — as an ECM-driven disease process — rises to the forefront as the condition most immediately governing the patient's life.

Therapeutic Implications

The practical importance of this conceptual shift lies in treatment strategy.

• In early stages, the priority is treatment of causal and predisposing diseases — hypertension, coronary artery disease, diabetes, obesity, valvular abnormalities, toxic exposures, genetic conditions — to prevent or delay the emergence of heart failure. Therapeutic logic here is primarily etiologic.

• Once chronic symptomatic heart failure becomes established, and especially in advanced stages, the therapeutic center of gravity shifts to heart failure itself: decongestion, neurohormonal modulation, phenotype-directed therapy, rhythm and conduction management, device therapy, prevention of recurrent decompensation, and in some patients advanced therapies or palliative care.

• Current pharmacologic mainstays — ACE inhibitors/ARBs, mineralocorticoid antagonists, beta-blockers, SGLT2 inhibitors — each slow the fibrotic cycle at one biochemical point, but none were designed against the scaffold as an explicit target, none is applied according to scaffold condition, and none reverses established collagen cross-linking, capillary loss, or cardiomyocyte dystrophy. This is the pharmacologic signature of a disease being treated indirectly and partially, precisely because the field has not yet built the diagnostic infrastructure to target it directly. 

In such patients, heart failure is no longer simply one expression of another disease; it is the dominant, self-sustaining disease process that demands primary therapeutic attention — and, increasingly, its own dedicated diagnostic and therapeutic science.

A More Complete Formulation

This is where the current consensus may still underestimate heart failure conceptually. It organizes the syndrome very well, and it stages the clinical trajectory accurately, but it does not fully articulate the biological transition by which the syndrome becomes a disease. As a result, the reader may still think of heart failure mainly as derivative, even when the document itself describes a permanent, staged, progressive, and therapeutically autonomous condition — one now increasingly explicable through a self-amplifying extracellular matrix remodeling cycle. 

A more complete formulation would preserve both sides of the truth. Heart failure is a syndrome in origin and definition, because it emerges from multiple diseases and is recognized through a constellation of findings rather than a single lesion. Yet heart failure becomes a disease in its own right in the later course, when its fibrotic scaffold cycle acquires biological independence and, with it, dominance over symptoms, prognosis, hospitalizations, and treatment strategy. The categories are not mutually exclusive; they describe different moments — and different levels of biological organization — within the same clinical evolution.

Such a formulation would help clinicians think more clearly. It would clarify when management of the causal disease remains primary and when heart failure itself must take first place. It would align guideline language more closely with ICD-10 and ICD-11, and with the emerging mechanistic and diagnostic science of myocardial fibrosis. Most importantly, it would reflect real bedside medicine, where many patients are no longer governed principally by ischemia, hypertension, or valvular pathology as isolated entities, but by the chronic, self-sustaining disease state of heart failure that these pathologies have produced.

In this sense, recognizing the transition from syndrome to disease is not a semantic exercise. It has direct implications for diagnosis, staging, therapeutic prioritization, prognosis, and communication. The 2026 universal definition is a major step forward, but it can be read more deeply than it states itself — and the emerging biology of the cardiac extracellular matrix now supplies the missing mechanistic argument for why, in many patients, heart failure begins as a syndrome and ends as a disease in its own right. 

This book of ours might come in handy for you, too.

Mykola Iabluchanskyi together with Andriy Yabluchanskiy