Clinical Trials

Primary Inclusion Criteria:

• Subject has severe (Grade III or greater per the ASE criteria, which includes severitygrades of 3+ and 4+) primary MR (mixed etiology is acceptable provided theprincipal mechanism of action is a degenerative mitral valve) as assessed bythe ECL.

• Subject is at least 75 years of age

• Completion of a Cytokinetics study investigating CK-3773274. If unable to complete due to circumstances not related to compliance or safety, Medical Monitor may review and determine eligibility.
• LVEF ≥ 55%

• Ejection Fraction >=45%
• In the hospital setting >24 hours for the management of acute decompensated heart failure (ADHF), or diagnosed with ADHF after being hospitalized for another reason

• Failing aortic bioprosthetic valve demonstrating ≥ moderate stenosis and/or ≥ moderate insufficiency
• Bioprosthetic valve size suitable for SAPIEN X4 THV based on computed tomography angiography (CTA) analysis
• NYHA functional class ≥ II

• Chronic symptomatic heart failure (HF)
• Ongoing stable GDMT HF management and management of comorbidities according to the 2022 ACC/AHA Guidelines for the Management of Heart Failure.

• A LVEF ≤ 50% within 6 months prior to enrollment
• Resting QRS duration ≥ 130 ms as evidenced by a historical 12-lead ECG prior to enrollment OR
• Anticipated right ventricular pacing > 40% OR
• Device in place with right ventricular pacing > 40%; AND

• Documented history of symptomatic or asymptomatic paroxysmal or persistent AF
• CHA2DS2-VASC score of 1-4 without prior stroke or TIA
• Participant is on a DOAC at time of screening

• Presence of severe or greater tricuspid regurgitation as determined by the Echo Core Lab
• Patient is symptomatic despite medical therapy
• The local Site Heart Team determines the Patient is appropriate for transcatheter valve intervention

Patient will undergo treatment with a Thoraflex Hybrid device

• PE symptom(s) duration ≤ 14 days from index procedure
• PE diagnosis ≤ 48 hours prior to index procedure
• CTA evidence of proximal PE (filling defect in at least one main or lobar pulmonary artery based on Investigator determination)
• CTA evidence of dilated RV with an RV/LV ratio of ≥ 0.9 at baseline based on Investigator determination
• Systolic blood pressure ≥ 90 mmHg without need for vasopressors (initial SBP may be ≥ 80 mmHg if the pressure recovers to ≥ 90 mmHg with intravenous fluids prior to index procedure)
• Stable heart rate < 130 BPM prior to index procedure

• Ascending Aortic pathologies warranting surgical repair
• Anatomic compatibility with the ASG device based on Gore Imaging Sciences review
• Must be considered high-risk for open surgical repair

Atrial fibrillation or flutter, paroxysmal or sustained not due to a reversible cause, and eligible to receive anticoagulation therapy

Listed for heart transplantation

• Failing aortic bioprosthetic valve demonstrating ≥ moderate stenosis and/or ≥ moderate insufficiency
• Bioprosthetic valve size suitable for SAPIEN X4/X4S THV based on computed tomography angiography (CTA) analysis
• NYHA functional class ≥ II

Ambulatory with an age of 22-85 years at time of enrollment

Heart Failure with EF ≥ 40% (by TTE within last 3 months)

NYHA Class II or III

• NYHA Class II or III or ambulatory NYHA class IV symptoms
• A diagnosis of World Health Organization (WHO) Group 2 PH-HFpEF with qualifying hemodynamics verified by right heart catheterization
• A qualifying Baseline RHC performed within 120 days of Day 1

Diagnosis of ATTR-CM

Medical history of HF

Treatment for HF/ATTR-CM is optimized and symptoms are clinically stable

• Persistent or permanent AF - OR- Paroxysmal AF in participants with a history of ischemic stroke or systemic embolism
• Increased risk of stroke, defined as a CHA2DS2-VASc score of ≥ 4
• Treatment with OAC for at least 90 days prior to enrollment, AND no documented plan to permanently discontinue treatment with OAC for the expected duration of the trial

• Recent use of an FDA-approved immune checkpoint inhibitor
• A diagnosis of myocarditis
• Hospitalized at the time of randomization
• On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg of solumedrol per day for myocarditis within 24 hours of first administration of study drug

• Part 1: Cases will include subjects with severe AS according to ASE guidelines. Controls will include subjects with no significant AV disease, defined as a peak AV velocity <2 m/sec and no more than mild aortic regurgitation
• Part 2: Subjects with severe AS according to ASE guidelines who are scheduled for a transcatheter aortic valve replacement (TAVR) procedure
• Part 3: Subjects with mild, moderate, and severe AS according to ASE guidelines
• Part 4: Subjects with AS of any severity according to ASE guidelines, who are referred for exercise echocardiography

• NYHA functional class II or III
• A diagnosis of HCM
• For oHCM, LVOT peak gradient ≥ 30 mm Hg at rest OR during a Valsalva maneuver at Screening visit
• For nHCM, LVOT peak gradient < 30 mm Hg at rest AND during a Valsalva maneuver at Screening visit
• Screening LVEF ≥ 50%. For patients on a cardiac myosin inhibitor, the Screening LVEF must be ≥ 55%

• Stable New York Heart Association (NYHA) Class II or III HF diagnosis, evident at least 6 months prior to enrolment as confirmed by medical history
• Documented prior objective evidence of heart failure
• Meets 1 or more of the following criteria at the initial Screening measurement:
• A high sensitivity cardiac troponin I > 34 pg/mL
• For participants with body mass index (BMI) <30 kg/m2, a Screening NT-proBNP >300 pg/mL
• For participants with BMI≥30.0 kg/m2, a Screening NT-proBNP >240 pg/mL
• Body mass index (BMI) ≥18 kg/m2 and ≤45 kg/m2
• Screening ejection fraction ≥50%

• Multivessel or left main CAD is present for which revascularization is intended and for which there is equipoise between CABG and PCI according to local Heart Team assessment

• Symptomatic coronary artery disease (CAD)
• Must have attempted treatment with the maximally tolerated dose of at least three of the four (preferably all four) approved classes of anti-anginal agents: long-acting nitrates, calcium channel blockers (either a dihydropyridine or a non-dihydropyridine), beta blockers, and ranolazine
• Subject has either no treatment options for revascularization by coronary artery bypass grafting or by percutaneous coronary intervention, or is otherwise unsuitable or high risk for revascularization as determined by the local heart team, and confirmed by a Central Screening Eligibility Committee

• A history of recurrent pericarditis* with stable disease and currently being treated with an IL-1 blocker, scheduled to be discontinued
• Pericarditis pain ≤ 2 on the 11-point Numerical Rating Scale (NRS) for at least the prior 7 days
• C-Reactive Protein (CRP**) < 1.0 mg/dL within the 7 days of screening prior to Day 1 (Visit 1)

• Previously had an index (first) episode of pericarditis which, in the judgement of the Investigator based on the available data, met the criteria for an acute pericarditis event
• In the judgement of the Investigator, based upon the available diagnostic information, has an ongoing symptomatic episode of pericarditis, or may have an episode of recurrent pericarditis within the screening period
• CRP assessment by local laboratory assessment prior to first dose of study treatment on Day 1, either:
• a. CRP > 10 mg/L, or b. CRP ≤ 10 mg/L
• Pericarditis pain score ≥ 4 based on the 11-point NRS on Day 1

• Patient has a history of heart failure
• Patient has a left ventricular ejection fraction measured within 6 months of study enrollment recorded in the medical record
• Patient is scheduled to undergo a right heart catheterization (RHC) procedure per standard of care, which will include direct PCWP and PAP measurement
• Patient is willing to wear the CardioTag device during their RHC procedure

• Subject with symptomatic severe or greater tricuspid regurgitation
• Subject is evaluated by Institutional Heart Team9 as being at increased operative risk
  • TR severity of at least 3 (severe) on a scale of 0 (none) to 5 (torrential), assessed by independent core lab and
  • Symptoms requiring use of diuretics

• Femoral vein access and transseptal catheterization are feasible with the CardioMech MVRS guide catheter as determined by the investigator.
• Patient is symptomatic (NYHA class II, III or ambulatory IV).
• Patient is intermediate or high surgical risk for mitral valve repair
• Patient has moderate to severe (≥3+) or severe (≥4+) mitral valve regurgitation (per American Society of Echocardiography (ASE) guidelines) due to mitral valve prolapse or flail of the P2 segment and has mitral valve anatomy and physiology that is suitable for the proposed procedure as determined by the investigator, site’s multidisciplinary heart team, core laboratories and Screening Eligibility Committee.

• Symptomatic according to New York Heart Association (NYHA) functional class (FC) II or highera
• Severe AR, as assessed by Imaging Core Laboratory
• High risk for surgery as judged by a multi-disciplinary heart team

• Patient is clinically indicated for a saline contrast TTE study with a suspected right-to-left shunt

• Mitral valve disease resulting in mitral regurgitation (MR ≥ Grade III) and/or severe mitral valve stenosis (mitral valve area ≤ 1.5cm2 and/or mean transmitral gradient ≥10 mmHg at normal heart rate) per American Society of Echocardiography criteria
• New York Heart Association (NYHA) Functional Class II, III, or ambulatory IV
• LVEF ≥ 30%
• LVEDD ≤ 70 mm

• De novo Type A aortic dissection (≤30 days from symptom onset to index endovascular procedure) compatible with the treatment requirements of the ASG device
• Primarily intended to be treated by placement of the ASG device in the ascending aorta. Distal adjunctive procedures not in contact with the ASG device may be performed during the index endovascular procedure at the discretion of the Investigator
• Anatomic compatibility of the ascending aorta required for implanting the ASG device

Has a history, or current clinical diagnosis, of pericarditis that, in the opinion of the Investigator, is consistent with the 2015 ESC Guidelines for the Diagnosis and Management of Pericardial Diseases definition (Adler 2015), based on documented available data, fulfilling at least 2 of the following 4 criteria:

• Pericarditic chest pain
• Pericardial rub
• New widespread ST segment elevation or PR segment depression according to ECG findings
• Pericardial effusion (new or worsening)

Presents at Screening with signs and symptoms of acute pericarditis (Qualifying Pericarditis Episode) despite treatment with standard therapies that represents either:

• At least the second recurrence (i.e., at least the third pericarditis episode), with the initial acute pericarditis episode having been followed by a symptom-free interval;

OR

• Persistent pericarditis signs and symptoms despite initial improvement without a symptom-free interval.

• Has moderate CAVS (confirmed by the Imaging Core Laboratory)
• Has a left ventricular ejection fraction of 45% at the time of Screening as determined by the Imaging Core Laboratory
• Has an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 as measured by the Chronic Kidney Disease Epidemiology Collaboration 2021 formula at the time of Screening

• Has a body mass index (BMI) ≤35 kg/m2
• Has adequate acoustic windows for echocardiography
• Has a clinical diagnosis of HCM consistent with current American College of Cardiology/American Heart Association and European Society of Cardiology Guideline definition with unexplained LVH in the absence of other cardiac or systemic disease which can produce the magnitude of hypertrophy observed
• Has had confirmation of nHCM by central review process based on screening rest and
• exercise stress echocardiography that meets criteria

• Moderate-severe or severe MR (grade 3+ to 4+); either degenerative MR (DMR) or functional (FMR)
• Symptomatic MR (i.e., NYHA Class ≥ II) despite optimal or maximally tolerated guideline-directed medical therapy (GDMT)
• Deemed to be at elevated risk for conventional mitral valve surgery by the heart team

• Clinical diagnosis of chronic heart failure for at least 3 months prior to screening visit (V1), with each of the following criteria:
  • New York Heart Association (NYHA) Class II-IV at V1
  • Left ventricular ejection fraction (LVEF) > 40% based on most recent assessment available in medical records
• Evidence of the following on screening echocardiogram performed during V2, based on analysis by central reader:
  • LVEF >40%
  • If LVEF ≥50%, with one or more structural heart abnormalities
• Evidence for elevated cardiac filling pressures within 12 months of screening (V1)

• Planned and clinically indicated for cardiac surgical procedure requiring cardiac bypass and opening of the pericardium
• CHA2DS2-VASc ≥ 3

Inclusion:

• A diagnosis of recurrent symptomatic PAF, which is defined as continuous AF episode lasting longer than 30 seconds but terminates spontaneously or with intervention within 7 days of onset

Exclusion:

• Continuous AF lasting more than 7 days. This includes persistent atrial fibrillation (PsAF) (both early or long-standing) by diagnosis or continuous duration > 7 days
• AF that required three (3) or more distinct cardioversions in the preceding 12 months
• LA anteroposterior > 5.0 cm (by MRI, CT, or TTE)

• Type 2 diabetes mellitus requiring pharmacologic therapy or with their most recent A1c > 6.5%, prediabetes
• Have a device (e.g., smartphone, tablet, computer) for communication with the central cardiologist-led team managing drug treatment for the CAD stage-based care group

• Have an established diagnosis of ATTR-CM (ATTRwt or ATTRv), with cardiac amyloid infiltration, increased LV wall thickness, and HF
• Increased LV wall thickness, as assessed by centralised review of echocardiography, showing interventricular septal wall thickness ≥12 mm
• Chronic HF (NYHA I-IV)
• NT-proBNP concentration ≥1000 pg/mL at screening. Note: Participants with NT-proBNP levels between 1000 and 2000 pg/mL may be enrolled until a cap of 35% of the total study population is reached.
• Completed >50 meters on the 6MWT at screening

• Patient has one of the following indications for open surgery based on computed tomography angiography (CTA) completed within 90 days of informed consent
  • Acute, subacute, or chronic dissection that involves the aortic arch and the descending thoracic aorta, with or without involvement of the ascending aorta
  • Aneurysm that involves the aortic arch and the descending thoracic aorta, with or without involvement of the ascending aorta

• The subject is a candidate for TAVR using the DurAVR® THV System, and a SAPIEN series THV system or an Evolut series THV System.
• The local Heart Team* agrees that the subject has an appropriate indication for, and will benefit from, TAVR due to native calcific valve severe aortic stenosis

• Symptomatic mitral valve disease resulting in mitral regurgitation (MR ≥ Grade III) and/or severe mitral valve stenosis (mitral valve area ≤ 1.5cm2 or both moderate MR and moderate MS, per American Society of Echocardiography criteria
• New York Heart Association (NYHA) Functional Class II, III, or ambulatory IV
• LVEF ≥ 30%
• LVEDD ≤ 70 mm

• Has a body weight of at least 40 kg at Screening
• Has a history of pericarditis that in the opinion of the Investigator was consistent with the 2015 ESC Guidelines for the Diagnosis and Management of Pericardial Diseases
• Currently, has RP which is well controlled, i.e., including having CRP < 0.5 mg/dL within 14 days of Baseline and a pericarditis pain NRS score ≤ 3 at Baseline
• Has a documented history of CRP elevation (> 1 mg/dL) associated with at least one prior acute pericarditis episode, whether the incident event or any pericarditis recurrence

• Has a diagnosis of DCM due to probable disease-causing variants of MYH7, TTN, or other identified genetic DCM variants, or with familial DCM
• Has New York Heart Association (NYHA) Class II-IV at Screening with stable symptoms for ≥1 month
• Has chronic DCM, defined as not due to acute or possibly reversible conditions (e.g., hyper/hypothyroidism, infectious cause, tachyarrhythmia, iron overload), according to the Investigator

• Subject is eligible for percutaneous coronary intervention (PCI)
• Target lesion is a de novo lesion located in a native coronary artery and meets at least 1 of the 3 criteria

• Despite Optimal Medical Therapy (OMT) per the local Heart Team, patient has signs of TR, symptoms from TR, or prior HF hospitalization from TR. Patient must be on OMT per the local Heart Team at the time of TR assessment (TTE) for trial eligibility. OMT includes stable oral diuretic medications, unless patient has a documented history of intolerance
• Functional and/or degenerative TR graded as at least severe on a TTE (assessed by the Echo Core Lab (ECL) using a 5-grade classification proposed by Hahn et al. 2023
• The local Heart Team determines that the patient is appropriate for TTVR

• Subject has history of documented paroxysmal (AF that is intermittent and terminates within ≤ 7 days of onset) or persistent/long standing persistent atrial fibrillation (AF that is continuous and sustains for > 7 days and requires intervention) within one year prior to enrollment. Documentation may include ECG, transtelephonic monitor (TTM), Holter monitor or telemetry strip from the study hospital or an outside physician
• Subject is scheduled to undergo non-emergent cardiac surgical procedure(s) to be performed on cardiopulmonary bypass including open-heart surgery via sternotomy for one or more of the following: Mitral valve repair or replacement, Aortic valve repair or replacement, Ascending aortic aneurysms, Atrial Septal Defect (ASD)/Patent Foramen Ovalle (PFO) or Coronary artery bypass procedures
• Left ventricular ejection fraction ≥ 30% (determined by echocardiography or cardiac catheterization performed within 60 days of enrollment as documented in patient medical history)

The study population will include subjects who are appropriate candidates for HRPCI with planned percutaneous hemodynamic support during the procedure.

HRPCI is defined by the following clinical criteria:

Left ventricular ejection fraction (LVEF) <50% with:

1) ULMCA disease, OR

2) 3-vessel disease (≥50% diameter stenosis) with planned PCI in at least 1 vessel, OR

3) last patent vessel.

• NYHA Class II or III or ambulatory NYHA Class IV symptoms
• A diagnosis of World Health Organization (WHO) Group 2 PH-HFpEF with qualifying hemodynamics verified by right heart catheterization
• A qualifying Baseline RHC performed within 120 days of Day 1