R01HL173930

Mechanism of myocardial fibrosis induced by mitral valve prolapse - Mitral valve prolapse (MVP) affects 1 in 40 individuals and is complicated in 30-35% by ventricular arrhythmias that increase risk for sudden cardiac death (SCD).

Such arrhythmias are strongly associated with left ventricular (LV) myocardial fibrosis, primarily localized to regions physically connected with the prolapsing valve.

The mechanism of such fibrosis is currently unknown and studies are limited by lack of an available model.

Most (80%) of patients with malignant ventricular arrhythmias and SCD have only mild to moderate MR lacking surgical indications, a major gap in treatment and clinical guidelines.

Recent publications from our group and others link abnormal mechanics of the papillary muscle (PM) and inferobasal LV with co-localized fibrosis and risk of arrhythmias.

These data support the central hypothesis that MVP causes tension-induced LV fibrosis leading to arrhythmic events.

To test this, we have developed a surgical MVP model in sheep that uniquely isolates the mechanical stimulus and consistently produced regional fibrosis in six previously normal hearts over six months.

We will probe mechanistic links between altered biomechanics, fibrosis, and arrhythmia in MVP.

Aim 1 hypothesis: MVP-induced forces on the subvalvular apparatus cause regionalized LV fibrosis.

Ex vivo, we confirmed increased systolic forces on the PMs in MVP that will be quantified with MVP in vivo.

Progression of fibrosis will be quantified in this model over 3, 6, and 9 months along with serial longitudinal advanced parametric CMR imaging as used in patients.

Controls will include comparable primary MR without MVP (no fibrosis in 2 6-month pilots), sham surgery, and normal hearts.

This aim will link MVP-altered mechanical forces to LV structural changes as a function of time.

Aim 2 hypothesis: Increased stress activates a pro-fibrogenic molecular switch through mechano-responsive signaling pathways.

Our preliminary in vitro data show that stretch alters purinergic-ATP signaling and increases collagen deposition.

In MVP sheep tissues and stretched cardiac fibroblasts, changes in stressed LV regions and cells will be identified at the single-cell level that will test this and alternative mechanisms to reveal mechanically-induced cellular and molecular changes.

In sheep, we will compare valve-stressed and remote regions over time with those from normal and MR-only LVs; and cross-reference changes in existing surgical biopsies from 40 patients with fibrotic and nonfibrotic zones.

This aim will link MVP-increased tension to regional fibrogenesis.

Aim 3 will explore the hypothesis that MVP-induced fibrosis predisposes to ventricular arrhythmias.

In the MVP model and controls, rhythm will be monitored and PM endocardial electrograms recorded invasively at baseline and with isoproterenol, measuring repolarization markers of electrical instability and arrhythmic predisposition.

This aim will link pathologic and molecular findings from MVP-induced fibrosis to arrhythmic potential.

Impact: These interdisciplinary studies will identify intersections between mechanical stress and molecular pathways to reveal novel therapeutic targets to reduce fibrosis and arrhythmias and prevent SCD in young and otherwise healthy patients.

The General Hospital Corporation

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 96% from $1,862,169 to $3,657,264.