HMI · Peer-Reviewed Archive
Research & Knowledge Library
Peer-reviewed research spanning myocardial energetics, lipidomics, insulin-cardiac pathophysiology, and our $20M trial legacy.
5 Clinical Volumes
15 Research Articles
$20M Legacy
HCM · Perhexiline
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Volume I
The Myocardial Energetics Series
Foundational science of ATP production, mitochondrial health, and fuel switching in the heart.
Clinical Takeaway
The failing heart is not a mechanical problem — it is an energetic one. Restoring substrate flexibility via Perhexiline (CPT-1 inhibition) produces improvements in peak VO₂ and myocardial energetics that no haemodynamic intervention alone can replicate.
★ FlagshipFull Text
18 minThe ATP Gap: Myocardial Energy Deficit as the Proximal Cause of Systolic Failure in HCM
How sarcomeric gene mutations cascade into chronic ATP deficit — a PCr/ATP analysis showing energetic failure precedes structural changes by years.
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ATPHCM
Clinical TrialPerhexiline
14 minCPT-1 Inhibition as Metabolic Modulation: Mechanism, Evidence, and Clinical Application
Fatty acid oxidation costs 12% more oxygen per ATP than glucose. Perhexiline shifts substrate utilisation, improving the ATP/O₂ ratio — confirmed by Phase II trial data.
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CPT-1Perhexiline
Basic Science
11 minMitochondrial Ultrastructure and Respiratory Chain Defects in HCM
TEM and proteomics reveal cristae disorganisation and a four-protein Complex I–IV signature predicting peak VO₂ decline with high specificity.
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MitochondriaProteomics
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Volume II
The Lipid & Lipoprotein Repository
Advanced diagnostic frameworks: ApoB particle burden, Lp(a) genetic risk, and NMR-derived LDL phenotyping.
Clinical Takeaway
LDL-cholesterol is a surrogate for a surrogate. The true atherogenic determinant is ApoB particle number. No cardiovascular risk assessment is complete without ApoB, LDL-P pattern, and Lp(a).
Diagnostic
15 minApolipoprotein B as the Singular Atherogenic Determinant: Evidence for Replacing LDL-C
INTERHEART, AMORIS, and the Quebec Cardiovascular Study consistently show ApoB outperforms LDL-C in predicting events, especially in metabolic syndrome.
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ApoBAtherogenesis
Genetic Risk
12 minLipoprotein (a) as an Independent Thrombogenic Risk Factor: Pathophysiology and RNA-Targeted Therapeutics
Lp(a) is 70–90% heritable, unresponsive to lifestyle change, and confers 2–3× increased MI risk above 50 mg/dL. siRNA approaches in Phase III now target 80–90% reduction.
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Lp(a)siRNA
Particle Analysis
13 minLDL Particle Phenotyping by NMR: Pattern A vs Pattern B and Clinical Consequences
Pattern B (small dense LDL) carries 3× greater MI risk at identical LDL-C. NMR reveals subclass distributions that standard panels entirely miss.
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NMRsdLDL
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Volume III
The Insulin-Cardiac Axis
Mechanistic pathways linking insulin resistance to vascular stiffness, endothelial dysfunction, and accelerated atherosclerosis.
Clinical Takeaway
Insulin resistance is a cardiovascular phenotype. Chronic hyperinsulinemia suppresses eNOS and activates the RAAS 10–15 years before clinical diagnosis. HOMA-IR above 1.5 warrants the same urgency as LDL-C above 190 mg/dL.
Vascular Biology
16 minHyperinsulinemia-Driven Endothelial Dysfunction: IRS-1 Desensitisation to Nitric Oxide Suppression
IRS-1 serine phosphorylation selectively blocks the PI3K/eNOS vasodilatory axis while preserving MAPK/ERK — producing arterial stiffening proportional to insulin levels.
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eNOSHOMA-IR
Metabolic Cardiology
14 minInsulin Resistance as a Discrete Cardiovascular Phenotype: HOMA-IR-Stratified Risk Profiles
Cohort of 4,200 patients shows progressive MACE increase from HOMA-IR 1.5 — below pre-diabetes. Top quartile: 2.8× elevated MACE risk after full adjustment.
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HOMA-IRMACE
Vascular Mechanics
12 minMetabolic Syndrome and Arterial Stiffness: RAAS Activation, Collagen Cross-Linking, and Aortic Pressure
Pulse wave velocity rises proportionally with metabolic syndrome criteria count, elevating LV afterload and driving concentric hypertrophy that worsens myocardial energetics.
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RAASPWV
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Volume IV
The Clinical Trial Legacy
Our $20M Phase II RCTs of Perhexiline in HCM and the publications that defined metabolic cardiology.
Clinical Takeaway
Published in JACC, Circulation, and Wiley Online Library — Perhexiline produced a mean 19% improvement in peak VO₂ and PCr/ATP improvement by ³¹P-MRS: the first RCT demonstration of improved myocardial energetic efficiency in human HCM.
RCT Phase IIPerhexiline
20 minPerhexiline in Symptomatic HCM: A Double-Blind Randomised Controlled Trial
n=46, NYHA II–III. Peak VO₂ +4.2 vs +0.3 mL/kg/min (p=0.003). PCr/ATP improved 18.4%. NYHA improved ≥1 class in 68% vs 22% placebo. LVOT unchanged.
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RCTPeak VO₂
Programme Review
17 minTwo Decades of Metabolic Modulation: The $20M HMI Clinical Trial Programme
Eleven studies across HCM, DCM, and HFpEF consistently demonstrate that cardiac energetic impairment precedes and predicts haemodynamic deterioration.
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HFpEFDCM
Biomarker Validation
11 minTrial-Derived Threshold Values for Cardiac Energetics Biomarkers from Twelve Prospective Studies
ROC-derived cutpoints for PCr/ATP ratio, peak VO₂, cardiac power output, and NEFA flux enabling detection of decompensation before haemodynamic parameters fall.
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ROCThresholds
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Volume V
Patient Advocacy & Navigation
Practical guides for navigating the gap between standard and optimal care — from lab interpretation to cardiologist conversations.
Clinical Takeaway
Patients who arrive with specific, evidence-cited biomarker targets receive fundamentally different clinical interactions. This volume equips patients to be co-investigators in their own healthcare.
Patient Guide
10 minDecoding the Advanced Lipid Panel: ApoB, LDL-P, Lp(a), and NMR Particle Analysis
Translates NMR-derived lipoprotein data into actionable risk narratives — with emphasis on discordance cases where normal LDL-C coexists with high ApoB.
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ApoBDiscordance
Communication
8 minThe Physician Conversation Framework: Requesting Advanced Metabolic-Cardiac Testing
Derived from 380 consultation transcriptions: phrasing and evidence citations most likely to result in orders for HOMA-IR, ApoB, hs-CRP, and Lp(a).
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AdvocacyTesting
Navigation
9 minSecond Opinion Protocols in Metabolic Cardiology: When to Escalate
Diagnostic revision occurs in 15–30% of metabolic cardiology second opinions. Preparation protocols, referral pathways, and how to evaluate an energetics-informed physician.
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Second OpinionHCM
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