Personalized evaluation of the passive myocardium in ischemic cardiomyopathy via computational modeling using Bayesian optimization.

Biomechanics-based patient-specific modeling is a promising approach that has proved invaluable for its clinical potential to assess the adversities caused by ischemic heart disease (IHD). In the present study, we propose a framework to find the passive material properties of the myocardium and the unloaded shape of cardiac ventricles simultaneously in patients diagnosed with ischemic cardiomyopathy (ICM). This was achieved by minimizing the difference between the simulated and the target end-diastolic pressure-volume relationships (EDPVRs) using black-box Bayesian optimization, based on the finite element analysis (FEA). End-diastolic (ED) biventricular geometry and the location of the ischemia were determined from cardiac magnetic resonance (CMR) imaging. We employed our pipeline to model the cardiac ventricles of three patients aged between 57 and 66 years, with and without the inclusion of valves. An excellent agreement between the simulated and the target EDPVRs has been reached. Our results revealed that the incorporation of valvular springs typically leads to lower hyperelastic parameters for both healthy and ischemic myocardium, as well as a higher fiber Green strain in the viable regions compared to models without valvular stiffness. Furthermore, the addition of valve-related effects did not result in significant changes in myofiber stress after optimization. We concluded that more accurate results could be obtained when cardiac valves were considered in modeling ventricles. The present novel and practical methodology paves the way for developing digital twins of ischemic cardiac ventricles, providing a non-invasive assessment for designing optimal personalized therapies in precision medicine.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Adaptive Reductions in Left Ventricular Diastolic Compliance Protect the Heart From Stretch-Induced Stunning.

Swine subjected to 2 weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but left ventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LV ejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiac adaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain how LV stiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF.

Seipin Knockout Mice Develop Heart Failure With Preserved Ejection Fraction.

The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients.

Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure.

The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time. BMS-986231 significantly decreased LV filling pressures, end-diastolic stiffness, the time-constant of relaxation, end-diastolic wall stress, systemic vascular resistance, and myocardial oxygen consumption. BMS-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects.

Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction.

Inotropic support is often required to stabilize the hemodynamics of patients with acute decompensated heart failure; while efficacious, it has a history of leading to lethal arrhythmias and/or exacerbating contractile and energetic insufficiencies. Novel therapeutics that can improve contractility independent of beta-adrenergic and protein kinase A-regulated signaling, should be therapeutically beneficial. This study demonstrates that acute protein kinase C-α/ß inhibition, with ruboxistaurin at 3 months' post-myocardial infarction, significantly increases contractility and reduces the end-diastolic/end-systolic volumes, documenting beneficial remodeling. These data suggest that ruboxistaurin represents a potential novel therapeutic for heart failure patients, as a moderate inotrope or therapeutic, which leads to beneficial ventricular remodeling.

Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction.

BACKGROUND: Functional iron deficiency (FID) is an independent risk factor for poor outcome in advanced heart failure with reduced EF, but its role in heart failure with preserved EF (HFPEF) remains unclear. We aimed to investigate the impact of FID on cardiac performance determined by pressure-volume loop analysis in HFPEF. METHODS: 26 HFPEF patients who showed an increase in LV stiffness by pressure-volume (PV) loop analysis obtained by conductance-catheterization, performed exercise testing, echocardiographic examination including tissue Doppler and determination of iron metabolism: serum iron, ferritin and transferrin saturation. HFPEF patients who provided ferritin <100 µg/l or ferritin of 100-299 µg/l in combination with transferrin saturation <20% were defined as having FID. In 14 patients the expression of transferrin receptor was determined from available endomyocardial biopsies. RESULTS: Fifteen out of 26 HFPEF patients showed FID without anemia. Compared to control subjects and HFPEF patients without FID, HFPEF patients with FID showed an up-regulation of the myocardial transferrin receptor expression (p<0.05). No differences between HFPEF patients with and without iron deficiency were found in heart dimensions, systolic and diastolic function obtained by PV-loop and echocardiography analysis. According to the linear regression analysis, LV stiffness was correlated with peak oxygen uptake (r=-0.636, p<0.001) but not with the ferritin level or transferrin saturation. No relation was found between FID and exercise capacity. The association of LV stiffness with exercise performance was independent from the level of iron deficiency. CONCLUSION: In non-anemic HFPEF patients, cardiac dysfunction and impaired exercise capacity occur independently of FID.

Hemodynamic Support: Science and Evaluation of the Assisted Circulation with Percutaneous Assist Devices.

Pathophysiologic mechanisms that lead to hemodynamic abnormalities in cardiogenic shock (including hypotension, hypoperfusion, and elevated venous pressures) are reviewed within the framework of pressure-volume analysis. This approach provides the foundation for understanding how different modes of circulatory support impact key these cardiovascular parameters in various clinical settings. Four fundamentally different modes of circulatory support are reviewed, including aortic counterpulsation, left atrial-to-arterial pumping, right atrial-to-arterial pumping, and left ventricular-to-aortic pumping. Each approach has a distinct hemodynamic fingerprint with regard to effects on the ventricular pressure-volume loop and key hemodynamic and metabolic parameters.