Hemodynamic Assessment of underLying myocyTe Function in Right Heart Failure (HALT-RHF)

Right ventricular (RV) failure is recognized to worsen patient outcomes in the setting of heart failure with reduced ejection fraction (HFrEF)-related pulmonary hypertension (PH), yet the investigators fall short in trying to identify and treat it. The current proposal will (1) determine the best clinical indicators of intrinsic RV myocyte contractile failure in humans with HFrEF-PH, (2) clarify underlying mechanisms, and (3) test novel treatments on RV myocytes. The long-term goal of this proposal will be to better identify and treat RV failure in humans suffering from HFrEF-PH.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Hypertension; Heart Failure With Reduced Ejection Fraction; Right Heart Failure Due to Left Heart Failure

Detailed Description

This proposal aims to improve diagnosis and mechanistic understanding of right ventricular (RV) myocyte dysfunction in heart failure patients with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). RV dysfunction is common and hastens poor outcomes in HFrEF-PH. Despite its importance, clinical ability to characterize it remains imprecise. This frustrates prognostic and therapeutic efforts in many scenarios, such as the prediction of RV failure following left ventricular assist device. In 2023, the investigators reported that RV myocyte contractile reserve indices, such as calcium-activated isometric tension and length-dependent active tension, are reduced in RV tissue of explanted end-stage human HFrEF-PH hearts. Notably, clinical indices correlated modestly with calcium-activated tension but completely failed to capture depression of length-dependent tension, the latter a key contributor to RV Frank-Starling reserve. This deficiency highlights one possible reason why clinical indices fail to identify RV failure. A shortcoming of this work was its study of end-stage disease, and the investigators believe better clinical correlates of myocyte dysfunction from earlier-stage disease may provide more insight at a time point when interventions would still be helpful. The investigators central hypothesis is that clinical identification of RV myocyte disease in HFrEF-PH requires measuring RV contractile reserve, as is elicited during exercise. The investigators prior study of primary PH patients supports this, and new preliminary data in patients with PH secondary to heart failure does so as well. Delving deeper, the investigators recently reported a novel deficiency of the sarcomere thick filament in HFrEF-PH RV myocytes, driven by an excess of myosin in the inactive super-relaxed state that hinders its recruitment to form cross-bridges by either calcium- or stretch-activation. The latter is important as it is not seen in small rodents, and only recently reported in pigs, thus newly linking super-relaxed myosin to RV myocyte and chamber reserve in humans. The investigators new phospho-proteomic data shows less myosin binding protein-C phosphorylation yet more phosphorylation of several sarcomere Z-disc proteins, and supports the potential role based on kinase and phosphatase modifications.

This proposal was spawned by these recent findings. The investigators objectives are to: (1) identify clinical indices that capture RV myocyte reserve failure in earlier-to-mid stage HFrEF-PH; (2) uncover mechanisms of myocyte length-dependent contractile depression; and (3) test sarcomere-activating drugs that might prove useful for HFrEF-PH RV failure. The investigators combine state-of-the-art pressure-volume loop and clinical assessments of RV chamber function with phenotyping of the myocyte contractile apparatus. The investigators further explore a new role of super-relaxed myosin in depressed myocyte reserve. The proposal leverages my translational and basic muscle expertise developed over the past several years with K23 support, and a stellar collaborative team. Its objectives align with NHLBI strategic visions for the RV and advanced HF. There are three Specific Aims:

Aim 1. Test whether clinical measures of RV exercise reserve better reflect RV myocyte contractile dysfunction in earlier-stage HFrEF-PH. HFrEF patients referred for right heart cath undergo a well-established protocol at Johns Hopkins to assess clinical hemodynamic and echocardiographic RV indices alongside RV pressure-volume loop parameters at rest and with supine bicycle exercise. RV endomyocardial biopsies are obtained, and isolated myocytes permeabilized to assess contractile mechanics and calcium- and length-activated tension. The investigators then test whether clinical RV exercise reserve parameters will more sensitively reflect RV myocyte contractile reserve limitations than commonly used resting measures of RV function.

Aim 2. Determine roles and identities of phosphorylation mediators of reduced HFrEF-PH RV myocyte length-dependent reserve. New phospho-proteomic data finds protein kinase A (PKA)-hypophosphorylation of thick filament proteins and hyperphosphorylation of Z-disc scaffold proteins in HFrEF-PH RV myocardium. PKA incubation increases myocyte length-dependent tension, while protein phosphatase 2a (which does not reverse PKA changes) improves calcium-activated tension. The investigators test the relevance to myocyte contractile reserve failure in HFrEF-PH in permeabilized RV myocytes by selective kinase and phosphatase incubation, then selectively mutate high-value phospho-modified sites to test the role in length-dependent activation.

Aim 3: Determine whether newer sarcomere-activating drugs restore HFrEF RV myocyte length-dependent tension. Two sarcomere-activating drugs are tested in HFrEF-PH RV myocytes: danicamtiv and CK-136, which should augment length-dependent tension better than similar, previously tested drugs. The investigators determine impact on skinned myocyte contractile reserve, then test if the clinical RV reserve indices identified in Aim 1 can predict impact on individual HFrEF-PH RV myocytes from the same patient.

Expected outcomes: the investigators will identify optimal clinical indices of RV reserve failure in HFrEF-PH, clarify myocyte mechanisms of length-dependent reserve, and test novel RV drugs. Findings will impact RV failure due to HFrEF-PH and should apply to its other causes as well. The investigators research team has exceptional expertise in translational RV phenotyping and muscle biophysics and is uniquely poised to deliver on this proposal.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Steven Hsu, MD; Phone Number: 410-502-0955; Email: steven.hsu@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins Hospital
      • Contact: Wendy I Foy; Phone Number: 410-955-8491; Email: wfoy2@jh.edu
      • Contact: Email: steven.hsu@jhmi.edu
      • Principal Investigator: Steven Hsu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will include patients who have heart failure with reduced ejection fraction, defined by a left ventricular ejection fraction less than or equal to 40-50%.

Description

Inclusion Criteria:

• Adult patients aged between 18 and 90 years of age
• Diagnosed with heart failure with reduced ejection fraction (LV ejection fraction ≤ 40-50%)
• Can safely hold direct oral anticoagulant (DOAC) vitamin K antagonist (VKA) for 48 hours prior to the procedure

Exclusion Criteria:

• Unable to interrupt VKA anticoagulation
• Point of care International Normalized Ratio (INR) > 1.5
• Pregnant patients
• Acute hospitalization or decompensation within 2 weeks prior to study date
• Participation in a study involving an investigational drug within 4 weeks prior to study date
• Inability to lie flat in the supine position
• Symptomatic hemodynamic instability at rest or during the procedure

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy based on Area Under Curve (AUC)	Diagnostic accuracy (AUC), as determined by combination of sensitivity and specificity, of multiple clinical metrics will be compared to determine which best identifies underlying right ventricular myocyte contractile dysfunction.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage improvement in ex vivo right ventricular tissue sample	Percentage improvement is defined as the percent difference in ex vivo right ventricular tissue sample myocyte contractility before and after experimental exposure to sarcomere-activating agent. Note this testing occurs on tissue samples, not in human subjects.	5 years
Predictive capacity (based on likelihood ratio)	Combining primary and secondary outcomes, the predictive capacity of clinical metrics will be determined for anticipating a response to sarcomere-activating agent.	5 years

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Steven Hsu, MD, Johns Hopkins School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2024
• Primary Completion (Estimated): March 31, 2029
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 1, 2024
• First Posted (Actual): March 7, 2024

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: heart failure; pulmonary hypertension; cardiomyopathy; heart failure with reduced ejection fraction; right heart failure
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Heart Failure; Cardiomyopathies; Hypertension, Pulmonary
• Other Study ID Numbers: IRB00426760; R01HL172830 (U.S. NIH Grant/Contract: NHLBI/NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No