Today, coronary failure with preserved ejection fraction (HFpEF) remains one among the toughest Gordian knots in cardiovascular medicine with no visible effective and acceptable therapies. due to the complexity, urgency, and gravity of the matter of HFpEF, this article has been divided into two parts – Part I deals with the outline of the matter , and partially II, the authors suggest innovative methodologies to affect the matter globally. Although we tested a size that integrates HFpEF, a less known complex syndrome due to maladaptive changes in the myocyte’s structural , functional, and biochemical aspects. Inflammation appears to be the underlying string which weaves together nitrosative/ oxidative stress, endothelial dysfunction, downregulation of gas (NO) bioavailability/ NO‑mediated signaling, impaired myocardial bioenergetics, disturbed calcium handling, and concentric hypertrophy. Most of the HF with reduced EF (HFrEF) randomized controlled trials (RCTs) are positive, while the bulk of HFpEF RCTs are either neutral, borderline, or negative resulting in an enormous vacuum within the therapeutic space of HFpEF. While few understand the statistical complexity of RCTs, many pretend to try to to so. Endeavor has been made within the present article to form the underlying concepts loud and lucid without going into statistical complexities. Attempts are being made to tackle this issue by adopting / experimenting with novel prototypes, enrichment tests, adaptive tests, paragliding studies, basket studies and machine-learning studies culminating in what could happen also be termed as “precision medicine, precision diagnosis, and precision therapy.” we’ve compared two recent negative HFpEF RCT’s (TOPCAT trial - Treatment of Preserved Cardiac Function coronary failure with an Aldosterone antagonist, INDIE trial — Inorganic nitrite delivery to improve HFpEF exercise potential with one successful HFrEF RCT (CASTLE AF trial — Catheter ablation vs traditional standard treatment) in Patients with Left Ventricular Dysfunction and Atrial Fibrillation), one negative HFrEF RCT (IRONOUT HF trial - Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), one positive HFmEF / HFpEF randomized, parallel-group, blinded, multicenter trial (REDUCE LAP-HF TRIAL Phase 2: A Study to guage the DC Devices, Inc. IASD™ System II to scale back Elevated Left Atrial Pressure in Patients with Heart Failure), one positive HFmEF / HFpEF non-randomized, multicenter, open label, single arm study (REDUCE LAPHF TRIAL Phase 1: A Study to guage the DC Devices, Inc. IASD™ System II to scale back Elevated Left Atrial Pressure in Patients with Heart Failure) so as to know why majority of HFpEF Clinical Trials fail.
