Heart failure does not begin when a cardiologist makes the diagnosis. By the time an ejection fraction falls below 40 percent, or an atrium lapses into persistent fibrillation, the underlying biology has usually been unfolding for years, sometimes decades. That is the provocative argument of a new opinion article published in Frontiers in Cardiovascular Medicine, in which two researchers from IHU Liryc and the University of Bordeaux contend that time itself must be treated as an indispensable causal dimension of cardiovascular disease. Their proposal amounts to a call for a four-dimensional cardiovascular biology, one in which disease is understood not as a static threshold crossed at a single moment, but as a longitudinal trajectory shaped by biological aging, adaptive reserves, and nonlinear dynamics across molecular, cellular, tissue, and inter-organ scales.
The authors, Guido Caluori and Sebastien Chaigne, ground their case in a striking pattern that recurs across the cardiovascular spectrum. Cellular and tissue remodeling, including cardiac hypertrophy, myocardial stiffening, and impaired diastolic filling, precedes clinical symptoms and diagnosis. Atrial fibrosis and mitochondrial remodeling may develop long before atrial fibrillation appears. Endothelial dysfunction precedes hypertension and atherosclerosis. Even rare conditions such as J-wave syndromes are now considered cardiomyopathies with subtle structural abnormalities that standard imaging cannot detect. Disturbances in protein homeostasis and metabolic adaptation also occur well before clinical manifestations. Sudden cardiac events, in other words, are often the visible end of biological processes that have been running silently for years.
These temporal trajectories differ markedly across pathologies, are not linear, and are modulated by age, sex, lifestyle, and inter-organ interactions. That interindividual variability, the authors argue, calls for a personalized temporal framework for diagnosis and therapy rather than a single, universally applied diagnostic threshold. Current clinical categories illustrate the problem. Heart failure is subdivided into phenotypes with reduced, mildly reduced, and preserved ejection fraction, which share common pathophysiological mechanisms, including neurohormonal modulation, myocardial fibrosis, and inflammation, but differ in their temporal trajectories and therapeutic responses. Similarly, the conventional classification of atrial fibrillation into paroxysmal and persistent forms, later expanded to include long-standing persistent and permanent categories, fails to capture individual risk profiles and the progressive nature of the underlying atrial myopathy. These labels likely represent overlapping but temporally and mechanistically divergent trajectories rather than strict separate entities.
Diagnostic thresholds, the authors contend, anchor disease to the moment of clinical recognition rather than to its biological origin. Hypertension is diagnosed when blood pressure exceeds a fixed numerical value; heart failure is defined once the ejection fraction falls below a critical value. Yet the cardiovascular system may be biologically much older or younger than its chronological age. The coronary endothelium of a 50-year-old patient may exhibit a molecular signature typically observed in older subjects, characterized by the accumulation of senescent cells and impaired nitric oxide signaling. Conversely, an octogenarian with a biologically younger myocardium, marked by preserved mitochondrial function, low systemic inflammation, and maintained protein homeostasis, may remain healthy beyond the expected clinical limits. An ejection fraction measured at a single moment reflects vulnerability and biological age only at the time it is measured, not the trajectory that produced it.
This mismatch between biological and chronological cardiovascular age leads directly to what the authors call the tipping point problem. Biological systems initially buffer stress through compensatory mechanisms, but once a critical threshold is crossed, they shift rapidly and irreversibly toward a pathological state. Disease does not emerge abruptly; it reflects a progressive erosion of adaptive reserve that proceeds toward a tipping point. This framework may explain why clinically stable periods can precede sudden and unexpected decompensation. Drawing on the mathematics of critical transitions in complex systems, the authors note that as a system approaches a critical threshold, critical slowing down and changes in its dynamics, including increased variance and instability, may provide early-warning signals of the transition. Applied to cardiovascular disease trajectories, this approach may help identify subclinical signs of maladaptive capacity before irreversible decompensation, yet these signals remain largely invisible to current diagnostic tools.
The dynamics differ across heart failure phenotypes and directly influence the optimal timing of intervention. Heart failure with reduced ejection fraction often reaches a tipping point marked by irreversible cardiomyocyte loss and fibrosis, whereas heart failure with preserved ejection fraction may progress more gradually through accumulating diastolic dysfunction and microvascular impairment. The mildly reduced phenotype may represent an intermediate and potentially more reversible stage. Determining where patients are positioned along this trajectory is crucial for identifying the window during which intervention can still prevent irreversible decompensation. The authors propose a staged temporal model, beginning with an adaptive, compensated phase characterized by very low fibrosis and preserved electrical and endothelial function, detectable only through subtle changes in BNP, slight elevations in hs-CRP, and minor diastolic dysfunction on echocardiography, and ending with advanced disease marked by refractory heart failure and severe structural damage.
The middle phases of this model are where the therapeutic opportunity lies. In the pre-pathology phase, fibrosis and inflammation initiate, endothelial dysfunction develops, and metabolic remodeling begins, with detectable signals including elevated galectin-3, subtle ECG changes, altered heart rate variability, and early diastolic filling abnormalities. This is the opportunity for targeted prevention and risk stratification using biomarkers and imaging. At the tipping point itself, compensatory mechanisms fail, and the balance between phenotypes shifts, often signaled by paroxysmal atrial fibrillation, acute decompensated heart failure, or a first myocardial infarction. Once decompensation occurs, reversibility is limited and the focus shifts to symptom control, risk reduction, and device or ablative strategies. The insidious phase, the authors emphasize, represents a key but systematically underexplored therapeutic window, when intervention may be most effective but where detection is limited.
To make this framework operational, the authors argue that current cardiovascular research remains largely reductionist and linear. Systems biology has transformed the field through multi-omics integration, spatial transcriptomics, single-cell sequencing, and computational physiology, but these advances remain incomplete without explicit integration of time. Most experimental models rely on young male animals and fail to recapitulate human biological aging and cumulative environmental exposures such as smoking, diet, inactivity, and obesity. The authors point to cumulative electrophysiological remodeling that develops over years, reflecting a gradual disruption of ion-channel homeostasis, mechano-electrical coupling, and repolarization reserve that grows with biological aging and environment. This progressive remodeling is associated with QT interval prolongation and increased repolarization heterogeneity on the ECG, reflecting a growing ionic imbalance and destabilization of spatial and regional electrophysiological control systems. Because most atrial fibrillation and heart failure models are induced in young animals, which lack the age-related calcium dysregulation, oxidative stress, fibrosis, and reduced repolarization reserve that underlie arrhythmogenesis in humans, such models poorly recapitulate transient arrhythmogenic events, including early and delayed afterdepolarizations at the cellular level.
The authors propose integrating biological age as a mechanistic dimension of disease rather than treating it as a simple time-based variable. Biological age should reflect molecular damage, immune remodeling, mitochondrial dysfunction, and ion-channel alterations. Epigenetic clocks such as GrimAge and PhenoAge enable estimation of biological age independently of chronological age. Integrating these measures into digital twin frameworks would allow reconstruction of disease trajectories and quantification of the velocity of aging over time, distinguishing adaptive, pre-pathological, unstable, and decompensated states and capturing transitions rather than static categories. Structural remodeling, electrophysiological instability, inflammatory signaling, and metabolic aging likely interact synergistically to reduce cardiovascular adaptive capacity over time. The authors also note that the term four-dimensional has previously been used in cardiovascular chronobiology to describe the circadian regulation of cardiac physiology across hourly-to-daily timescales; here, however, the fourth dimension captures the longitudinal trajectory of disease development and biological aging over years, a distinct temporal scale and conceptual framework.
The most speculative section of the article confronts the question of biological time inversion. Partial in vivo reprogramming through transient Yamanaka factor expression has been shown to reset epigenetic landscapes while preserving cellular identity, restoring chromatin accessibility and regenerative capacity in aged tissues. Naked mole rats may reach an age of 40 years with remarkably limited cardiovascular aging. Heterochronic parabiosis models indicate that exposure to a young systemic milieu can reverse cardiac hypertrophy and improve myocardial function in aged mice, although the identity and reproducibility of circulating rejuvenating factors remain controversial, particularly for candidates such as GDF11. Partial reprogramming has also restored vision in aged mice, supporting the concept of persistent epigenetic plasticity in adult mammalian tissues. These findings challenge the classical view of aging as a strictly linear and irreversible trajectory, suggesting instead a dynamic continuum of modifiable biological states. The authors caution, however, that the magnitude, durability, and safety of such effects remain highly context-dependent, with unresolved risks including tumorigenicity, loss of cellular identity, and long-term genomic instability. In the cardiovascular system, where remodeling emerges from tightly integrated mechanical, metabolic, and inflammatory signaling, such plasticity appears partial and temporally constrained. Biological time modulation, they conclude, should be viewed not as a true reversal of aging, but as a constrained reprogramming of cardiovascular trajectories within a broader four-dimensional disease continuum.
The implications for precision cardiology are considerable. Emerging approaches based on biomarkers and wearable or implantable devices will increasingly enable real-time monitoring of individual disease trajectories for earlier detection of warning signals before irreversible remodeling occurs. A central challenge is to identify the therapeutically actionable window during which pathological remodeling remains reversible in order to limit disease progression. The next paradigm shift in cardiovascular research, the authors argue, will be fundamentally conceptual, requiring integration of the principles of personalized medicine and a move from static, symptom-driven definitions of disease toward dynamic, trajectory-based frameworks grounded in systems biology. The focus will shift from detecting electromechanical and structural abnormalities to unveiling early signs of instability across different levels of biological organization. Without integrating biological time as a fourth dimension, cardiovascular biology remains fundamentally incomplete, and progress toward improved patient outcomes will continue to be constrained by the lack of more integrative and translational research frameworks.
Whether the four-dimensional framework will reshape clinical practice remains to be seen. But the core insight is difficult to dismiss: cardiovascular diseases rarely begin at symptom onset, and when heart failure, atrial fibrillation, or coronary disease becomes clinically apparent, the underlying biology has often been active for years. The observed pathology reflects the final stage of a prolonged silent process. Recognizing that the individual cardiovascular system may be biologically older or younger than its chronological age represents a mechanistic determinant with implications for prevention and clinical intervention. Redefining heart failure phenotypes and atrial fibrillation categories through a temporal and biological age framework transforms them from diagnostic labels into dynamic disease states. This shift allows interventions to be timed to an individual’s progression toward phenotype-specific tipping points, rather than to symptom onset. It also suggests that causality in cardiovascular disease should be understood in direct relation to biological trajectories and their evolution over time, rather than solely by the timing of events. For a field long organized around thresholds crossed at single moments, that reframing may prove the most consequential idea of all.
Subject of Research: Time as an indispensable causal dimension in cardiovascular diseases: toward a four-dimensional biology
Article Title: Time as an indispensable causal dimension in cardiovascular diseases: toward a four-dimensional biology
Article References: Caluori, G., & Chaigne, S. (2026). Time as an indispensable causal dimension in cardiovascular diseases: toward a four-dimensional biology. Frontiers in Cardiovascular Medicine, 13, Article 1952188. https://doi.org/10.3389/fcvm.2026.1952188
Image Credits: AI Generated
DOI: 10.3389/fcvm.2026.1952188
Keywords: Time, indispensable, causal, dimension, cardiovascular, diseases, toward, four-dimensional, biology, scientific research
News Source: Ophelia Keating. (October 17, 2026). Time as an indispensable causal dimension in cardiovascular diseases: toward a four-dimensional biology. Scienmag.
