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HFpEFDev

Device-Based Solutions to Improve Cardiac Physiology and Hemodynamics in Heart Failure With Preserved Ejection Fraction

8 June 2024

Heart Failure with Preserved Ejection Fraction (HFpEF)

HFpEF is a type of heart failure where the pumping action (measured by ejection fraction) is normal or near-normal, but the heart muscle is stiff, impairing its ability to relax and fill with blood properly. It is a multifactorial disease with various etiologies and phenotypes. Due to the complexity of the condition and limited data, guidelines and treatments are lacking.

Characteristics

  • Diminished ventricular compliance: The heart's ventricles become stiffer, making it harder to fill with blood during diastole.
  • Diastolic dysfunction: The heart's ability to relax and fill with blood during the diastolic phase is impaired, leading to inadequate blood flow.
  • Symptoms of heart failure despite normal ejection performance, including:
    • Pulmonary hypertension: Increased blood pressure in the pulmonary arteries, causing strain on the right side of the heart.
    • Limited cardiac reserve: The heart's reduced ability to increase its output during stress or exercise.
    • Autonomic imbalance: A disruption in the autonomic nervous system, affecting heart rate and blood pressure regulation, which can contribute to cardiovascular issues.
    • Exercise intolerance: Difficulty or inability to perform physical activities at the expected level.

Causation

HFpEF is often caused by thickening and stiffening of the left ventricular (LV) wall due to:

  • Isoform shifts
  • Alterations in its phosphorylation state
  • Oxidative stress–induced disulfide bridge formation
  • LV pressure overload

Assessment

Echocardiography

Echocardiography is commonly used to assess HFpEF, particularly focusing on:

  • Ejection Fraction: The percentage of blood pumped out of the ventricles with each heartbeat.
  • Parameters to assess diastolic function:
    • E/A Ratio: The ratio of early (E) to late (A) ventricular filling velocities.
    • E/e’ Ratio: The ratio of mitral inflow velocity (E) to mitral annular early diastolic velocity (e’), indicating left ventricular filling pressures.
    • Left Atrial Volume Index (LAVI): Increased left atrial size suggests chronic elevated filling pressures.
    • Left Ventricular Mass Index (LVMI): Increased LV mass can indicate hypertrophy, common in HFpEF.

Hemodynamic Measurements

  • Right heart catheterization:
    • Pulmonary capillary wedge pressure (PCWP): Measurement reflecting the pressure in the left atrium, used to estimate left ventricular filling pressures.
    • Left ventricular end-diastolic pressure (LVEDP): Pressure in the left ventricle at the end of filling (diastole), indicating ventricular compliance and preload.
  • Pressure-Volume characteristics: End-diastolic pressure-volume relationship (EDPVR).

Treatment

Therapeutic Options

Tested

  • Neurohormonal Blockers: Efforts to use these agents for HFpEF treatment have not shown conclusive benefits.
  • cGMP-Protein Kinase G Signaling: Trials with agents like inorganic nitrates and soluble guanylate cyclase stimulators have not demonstrated clinical benefit.
  • Inotropic Modulators: Agents like milrinone have failed to meet primary endpoints in trials.

Emerging Therapies

  • Interleukin-1 receptor antagonist
  • Sodium-glucose co-transporter 2 inhibitor
  • Beta-adrenergic agonist
  • Cardiosphere-derived cell-based therapy

Device-based Solutions

Devices show promise in improving the hemodynamics and symptomatology of patients with HFpEF. However, none have yet received U.S. FDA approval, and further clinical evidence is required to establish their long-term safety and efficacy.

Atrial Shunts

Devices designed to lower elevated left atrial pressure by creating a conduit between the left atrium and other chambers or structures.

  • IASD: A bare-metal nitinol frame device creating an 8-mm opening between the atria, allowing blood to flow down the pressure gradient. It is deployed percutaneously and is under clinical investigation.
  • V-Wave Shunt: An hourglass-shaped self-expanding nitinol frame covered with porcine pericardial tissue. It is implanted percutaneously and has shown promise in preclinical and clinical studies.
  • AFR: A self-expandable double-disk nitinol mesh braided into two flat discs. It is designed for interatrial shunting and is currently being evaluated in various trials.
  • Transcatheter Atrial Shunt System: A bare-nitinol implant with a 7-mm internal diameter for shunting from the left atrium to the coronary sinus. It aims to reduce pulmonary capillary wedge pressure and is being assessed in clinical trials.

Left Ventricular Expanders

Technologies aimed at improving diastolic recoil and ventricular filling by augmenting the elastic recoil of the left ventricle.

  • ImCardia: A self-expanding device exerting outward and circumferential forces to enhance ventricular filling by augmenting the elastic recoil of the LV from the endocardium or epicardium.
  • CoPulse: A device with a flexible membrane that assists early diastolic recoil of the LV chamber by storing elastic energy during cardiac contraction and transferring it to the LV wall in the diastolic phase.
  • LAAD: The Left Atrial Assist Device, which requires mitral valve removal for implantation, aims to improve diastolic recoil and enhance cardiac relaxation.

Electrical Stimulators and Neuromodulators

Therapies that target autonomic imbalance and mechanical desynchrony to improve cardiac function:

  • BAROSTIM NEO (CVRx, Inc): Device that improves autonomic balance by stimulating carotid baroreceptors to increase parasympathetic tone and reduce sympathetic drive, aimed at enhancing heart rate recovery and chronotropic reserve in HFpEF patients.
  • Optimizer Smart System (Impulse Dynamics): System that boosts heart muscle contractility without increasing oxygen consumption by applying high-voltage, long-duration biphasic stimulation to the right ventricular septum during the refractory period, targeting improved exercise tolerance and quality of life in HFpEF patients.
  • Cardiac Resynchronization Therapy (CRT) Devices: CRT devices synchronize cardiac contractions to enhance heart function using a pulse-generating device with three leads, and are being investigated for use in HFpEF patients with conduction delays and mechanical dyssynchrony.