Hybrid Biological Technology for Cardiac Hypertrophy Reversal and Essential Hypertension Elimination: A Multidisciplinary Conceptual–Normative Framework with Multiscale Mathematical Modelling, Bayesian Inference, and Reproducible Computational Validation

Background. Cardiac hypertrophy and essential hypertension are convergent pathophysiological endpoints of sustained haemodynamic overload, mechanotransduction dysregulation, and neurohormonal activation. Despite pharmacological advances—including cardiac myosin inhibitors (e.g. mavacamten) and renin–angiotensin system (RAS) modulators—no current paradigm achieves true structural normalisation of the hypertrophied myocardium while simultaneously eliminating the underlying hypertensive drive.Objective. To conceptualise, mathematically formalise, and computationally validate a hybrid biological technology (HBT) integrating CRISPR–Cas9 somatic gene editing, induced pluripotent stem cell (iPSC)-derived cardiomyocyte transplantation, RNA therapeutics, bioengineered extracellular-matrix (ECM) scaffolds, and closed-loop bioelectronic modulation, for the synergistic reversal of cardiac hypertrophy and control of essential hypertension.Methods. We develop a multiscale framework comprising (i) finite-strain continuum mechanics of cardiac growth and remodelling (G&R) using the Holzapfel–Ogden constitutive law with volumetric growth theory; (ii) a compartmental ordinary-differential-equation (ODE) model of the renin–angiotensin system; (iii) a mechanistically grounded reduced-order model of the twelve-month left-ventricular-mass response; (iv) a hierarchical Bayesian treatment-response model fitted by a purpose-built Gibbs sampler; (v) global sensitivity analysis (Sobol' variance decomposition and Morris screening) with Latin-hypercube uncertainty propagation; and (vi) a fully self-contained, dependency-light Python implementation that reproduces every reported quantity from a fixed random seed.Results. Under the modelled maximal-synergy assumptions, the HBT framework projects a median reduction in left-ventricular-mass index (LVMI) of 26.8% (95% credible interval [CI] 20.2–30.9%) over twelve months—from a cohort-mean baseline of 128 g/m² to a median of 93.7 g/m² (95% CI [88.4, 102.1] g/m²)—together with a median systolic-pressure reduction of 31.9 mmHg (95% CI [18.4, 37.0] mmHg). These projections exceed the partial regression reported for mavacamten (≈17 g/m² over 30 weeks in the EXPLORER-HCM cardiac-magnetic-resonance substudy) but remain hypothetical pending preclinical validation. The marginal probability of achieving a non-hypertrophic LVMI (<95 g/m²) is 0.647 across full parameter uncertainty, rising to 0.998 under favourable configurations of the two dominant drivers. Global sensitivity analysis identifies CRISPR editing efficiency (η_edit) and ECM scaffold porosity (φ_scaffold) as the dominant first-order effects, jointly accounting for 80.6% of output variance (first-order Sobol' indices 0.637 and 0.169, respectively). A hierarchical Bayesian analysis of simulated trial data recovers a twelve-month population treatment effect of −34.7 g/m² (95% CI [−38.4, −30.9]) with excellent convergence (R̂ ≤ 1.0002, effective sample size > 7139).Conclusions. This conceptual framework establishes a mathematically rigorous, internally consistent, and fully reproducible foundation for a candidate therapeutic paradigm. Its principal claims are stated as falsifiable, pre-registered hypotheses; preclinical and clinical validation remain imperative before any translational inference can be drawn.