Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.

Pulmonary Rehabilitation for Adults with Chronic Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.

Background: Despite the known benefits of pulmonary rehabilitation (PR) for patients with chronic respiratory disease, this treatment is underused. Evidence-based guidelines should lead to greater knowledge of the proven benefits of PR, highlight the role of PR in evidence-based health care, and in turn foster referrals to and more effective delivery of PR for people with chronic respiratory disease. Methods: The multidisciplinary panel formulated six research questions addressing PR for specific patient groups (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) and models for PR delivery (telerehabilitation, maintenance PR). Treatment effects were quantified using systematic reviews. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to formulate clinical recommendations. Recommendations: The panel made the following judgments: strong recommendations for PR for adults with stable COPD (moderate-quality evidence) and after hospitalization for COPD exacerbation (moderate-quality evidence), strong recommendation for PR for adults with interstitial lung disease (moderate-quality evidence), conditional recommendation for PR for adults with pulmonary hypertension (low-quality evidence), strong recommendation for offering the choice of center-based PR or telerehabilitation for patients with chronic respiratory disease (moderate-quality evidence), and conditional recommendation for offering either supervised maintenance PR or usual care after initial PR for adults with COPD (low-quality evidence). Conclusions: These guidelines provide the basis for evidence-based delivery of PR for people with chronic respiratory disease.

Readability and Non-English Language Resources of Heart Transplant Center Websites in the United States.

OBJECTIVE: Health literacy is associated with heart failure (HF) care and outcomes. Online resources offer important educational materials for patients seeking access to heart transplantation but tend to be complex and potentially ineffective for non-English speakers and those with low reading levels. The purpose of this study was to evaluate both the readability of patient-level information posted on United States heart transplant center websites and the availability of non-English resources. METHODS AND RESULTS: We performed a review of patient-facing information on websites of U.S. heart transplant centers identified through the United Network for Organ Sharing in August 2022. Written English text was extracted and assessed for readability by using the Fry Graph Readability score. Websites were additionally evaluated for non-English language text and translator tools. Standard ANOVA analysis was used to compare readability levels across transplant regions. The median Fry readability level to understand a piece of text for all regions was 15, which is equivalent to a college-junior reading level (range: 7-17, 7th grade to postgraduate level). There was no statistical difference in median Fry readability levels among regions (P = 0.16). Of the 139 eligible heart transplant center websites, only 56.1% (78/139) had non-English resources available for patients. Regions 5 (75% [15/20]) and 6 (75% [3/4]) had the highest percentage of non-English resources, and region 2 had the lowest (38% [6/16]). CONCLUSIONS: Heart transplant center online resources are inadequate, and many do not provide translations of the English language. Additional work is needed to standardize heart-transplant patient information for a diverse U.S.

Association between biventricular pacing and incidence of ventricular arrhythmias in the early post-operative period after left ventricular assist device implantation.

INTRODUCTION: Cardiac resynchronization therapy (CRT) and left ventricular assist devices (LVAD) improve outcomes in heart failure patients. Early ventricular arrhythmias (VA) are common after LVAD and are associated with increased mortality. The association between left ventricular pacing (LVP) with CRT and VAs in the early post-LVAD period remains unclear. METHODS: This was a retrospective study of all patients undergoing LVAD implantation from 1/2016 to 12/2019. Patients were divided into those with CRT and active LVP (CRT-LVP) immediately post-LVAD implant versus those without CRT-LVP. Implantable cardiac defibrillator electrograms were reviewed and early VAs were defined as sustained ventricular tachycardia (VT)/ventricular fibrillation occurring within 30 days of LVAD implantation. RESULTS: Of 186 included patients (mean age 53 years, 75% male, mean body mass index 28), 72 had CRT devices, 63 of whom had LV pacing enabled after LVAD implant (CRT-LVP group). Patients with CRT-LVP were more likely to have VA in the early postoperative period (21% vs. 4%; p = .0001). All 9 patients with CRT in whom LVP was disabled had no early VA. Among those with early VA, patients with CRT-LVP were more likely to have monomorphic VT (77% vs. 40%; p = .07). In multiple logistic regression, CRT-LVP pacing remained an independent predictor of early VA after adjustment for history of VA and AF. CONCLUSIONS: Patients with CRT-LVP after LVAD implant had a higher incidence of early VA (specifically monomorphic VT). Epicardial LV pacing may be proarrhythmic in the early postoperative period after LVAD.

The prognostic value of positron emission tomography in the evaluation of suspected cardiac sarcoidosis.

OBJECTIVES: To assess the prognostic value of positron emission tomography (PET) imaging in patients undergoing evaluation for known or suspected cardiac sarcoidosis (CS) while not on active immunotherapy. BACKGROUND: Previous studies have attempted to identify the value of PET imaging to aid in risk stratification of patients with CS, however, most cohorts have included patients currently on immunosuppression, which may confound scan results by suppressing positive findings. METHODS: We retrospectively analyzed 197 patients not on immunosuppression who underwent 18F-fluorodeoxyglucose (FDG) PET scans for evaluation of known or suspected CS. The primary endpoint of the study was time to ventricular arrhythmia (VT/VF), or death. Candidate predictors were identified by univariable Cox proportional hazards regression. Independent predictors were identified by performing multivariable Cox regression with stepwise forward selection. RESULTS: Median follow-up time was 531 [IQR 309, 748] days. 41 patients met the primary endpoint. After stepwise forward selection, left ventricular ejection fraction (LVEF) (HR 0.98, 95% CI 0.96-0.99, P = 0.02), history of VT/VF (HR 4.19, 95% CI 2.15-8.17, P < 0.001), and summed rest score (SRS) (HR 1.06, 95% CI 1.02-1.12, P = 0.01) were predictive of the primary endpoint. Quantitative and qualitative measures of FDG uptake on PET were not predictive of clinical events. CONCLUSIONS: Among untreated patients who underwent PET scans to evaluate known or suspected CS, LVEF, history of VT/VF, and SRS were associated with adverse clinical outcomes.

At a crossroads: coronavirus disease 2019 recovery and the risk of pulmonary vascular disease.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has led to almost 3,000,000 deaths across 139 million people infected worldwide. Involvement of the pulmonary vasculature is considered a major driving force for morbidity and mortality. We set out to summarize current knowledge on the acute manifestations of pulmonary vascular disease (PVD) resulting from COVID-19 and prioritize long-term complications that may result in pulmonary hypertension (PH). RECENT FINDINGS: Acute COVID-19 infection can result in widespread involvement of the pulmonary vasculature, myocardial injury, evidence of persistent lung disease, and venous thromboembolism. Post COVID-19 survivors frequently report ongoing symptoms and may be at risk for the spectrum of PH, including group 1 pulmonary arterial hypertension, group 2 PH due to left heart disease, group 3 PH due to lung disease and/or hypoxia, and group 4 chronic thromboembolic PH. SUMMARY: The impact of COVID-19 on the pulmonary vasculature is central to determining disease severity. Although the long-term PVD manifestations of COVID-19 are currently uncertain, optimizing the care of risk factors for PH and monitoring for the development of PVD will be critical to reducing long-term morbidity and improving the health of survivors.

Resting Oxygen Consumption and Heart Failure: Importance of Measurement for Determination of Cardiac Output With the Use of the Fick Principle.

BACKGROUND: Resting oxygen consumption (VO2) is often estimated and frequently used to guide therapeutic decisions in symptomatic heart failure (HF) patients. The relationship between resting VO2 and symptomatic HF and the accuracy of estimations of VO2 in this population are unknown. METHODS AND RESULTS: We performed a cross-sectional study of HF patients (n = 691) and healthy control subjects (n = 77). VO2 was measured with the use of a metabolic cart, and estimated VO2 was calculated with the use of the Dehmer, LaFarge, and Bergstra formulas and the thermodilution method. The measured and estimated VO2 were compared and the potential impact of estimations determined. In the multivariable model, resting VO2 decreased with increasing New York Heart Association (NYHA) functional class in a stepwise fashion (ß NYHA functional class IV vs control = -36 mL O2/min; P < .001). Estimations of VO2 with the use of derived equations diverged from measured values, particularly for patients with NYHA functional class IV limitations. The percentage difference of measured VO2 versus estimated VO2 was >25% in 39% (n = 271), 25% (n = 170), 82% (n = 566), and 39% (n = 271) of HF patients when using the Dehmer, LaFarge, Bergstra, and thermodilution-derived estimations of VO2 respectively. CONCLUSIONS: Resting VO2 decreases with increasing NYHA functional class and is lower than in control subjects. Using estimations of VO2 to calculate CO may introduce clinically important error.

Impact of Socioeconomic Factors on Patient Desire for Early LVAD Therapy Prior to Inotrope Dependence.

BACKGROUND: Worsening heart failure (HF) and health-related quality of life (HRQOL) have been shown to impact the decision to proceed with left ventricular assist device (LVAD) implantation, but little is known about how socioeconomic factors influence expressed patient preference for LVAD. METHODS AND RESULTS: Ambulatory patients with advanced systolic HF (n=353) reviewed written information about LVAD therapy and completed a brief survey to indicate whether they would want an LVAD to treat their current level of HF. Ordinal logistic regression analyses identified clinical and demographic predictors of LVAD preference. Higher New York Heart Association (NYHA) class, worse HRQOL measured by Kansas City Cardiomyopathy Questionnaire, lower education level, and lower income were significant univariable predictors of patients wanting an LVAD. In the multivariable model, higher NYHA class (OR [odds ratio]: 1.43, CI [confidence interval]: 1.08-1.90, P = .013) and lower income level (OR: 2.10, CI: 1.18 - 3.76, P = .012 for <$40,000 vs >$80,000) remained significantly associated with wanting an LVAD. CONCLUSION: Among ambulatory patients with advanced systolic HF, treatment preference for LVAD was influenced by level of income independent of HF severity. Understanding the impact of socioeconomic factors on willingness to consider LVAD therapy may help tailor counseling towards individual needs.

Associations Between Marijuana Use and Cardiovascular Risk Factors and Outcomes: A Systematic Review.

Background: Marijuana use is increasing in the United States, and its effect on cardiovascular health is unknown. Purpose: To review harms and benefits of marijuana use in relation to cardiovascular risk factors and clinical outcomes. Data Sources: PubMed, MEDLINE, EMBASE, PsycINFO, and the Cochrane Library between 1 January 1975 and 30 September 2017. Study Selection: Observational studies that were published in English, enrolled adults using any form of marijuana, and reported on vascular risk factors (hyperglycemia, diabetes, dyslipidemia, and obesity) or on outcomes (stroke, myocardial infarction, cardiovascular mortality, and all-cause mortality in cardiovascular cohorts). Data Extraction: Study characteristics and quality were assessed by 4 reviewers independently; strength of evidence for each outcome was graded by consensus. Data Synthesis: 13 and 11 studies examined associations between marijuana use and cardiovascular risk factors and clinical outcomes, respectively. Although 6 studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and were not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, dyslipidemia, acute myocardial infarction, stroke, or cardiovascular and all-cause mortality was insufficient. Although the current literature includes several long-term prospective studies, they are limited by recall bias, inadequate exposure assessment, minimal marijuana exposure, and a predominance of low-risk cohorts. Limitation: Poor- or moderate-quality data, inadequate assessment of marijuana exposure and minimal exposure in the populations studied, and variation in study design. Conclusion: Evidence examining the effect of marijuana on cardiovascular risk factors and outcomes, including stroke and myocardial infarction, is insufficient. Primary Funding Source: National Heart, Lung, and Blood Institute. (PROSPERO: CRD42016051297).

Identifying Stage D Heart Failure: Data From the Most Recent Registries.

PURPOSE OF REVIEW: Improving outcomes with durable mechanical circulatory support have led to expanding interest in the earlier recognition of patients destined to develop refractory heart failure (HF). The recognition of advanced HF has received increasing attention. RECENT FINDINGS: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry developed patient profiles of advanced HF to describe the spectrum of patients with refractory HF undergoing mechanical circulatory support. These patient profiles have been extended to advanced HF patients on medical therapy and used to align outcomes with medical and device therapy in the Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) registries and the ROADMAP study. Shared decision-making about treatment options for advanced HF requires individualized consideration of risks and benefits beyond survival. Future studies, including the ongoing Registry for Vital Information for VADs in Ambulatory Life (REVIVAL) study, will provide prognostic information for patients transitioning from stage C to stage D HF to help patients, caregivers, and physicians navigate the increasingly complex terrain of HF care.

Safety of regadenoson stress testing in patients with pulmonary hypertension.

OBJECTIVES: We sought to determine the safety of regadenoson stress testing in patients with PH. BACKGROUND: PH is increasingly recognized at more advanced ages. As many as one-third of patients with PH have coronary artery disease. Because of their physical limitations, patients with PH are unable to adequately exercise. Regadenoson can potentially have an adverse impact due to their tenuous hemodynamics. Current guidelines suggest performing a coronary angiography in patients with PH who have angina or multiple coronary risk factors. METHODS: We identified 67 consecutive patients with confirmed PH by catheterization (mean PA > 25 mmHg not due to left heart disease) who underwent MPI with regadenoson stress. Medical records were reviewed to determine hemodynamic and ECG response to regadenoson. RESULTS: No serious events occurred. Common side effects related to regadenoson were observed, dyspnea being the most common (70.6%). No syncope occurred. Heart rate increased from 74.6 ± 14 to 96.3 ± 18.3 bpm, systolic blood pressure increased from 129.8 ± 20.9 to 131.8 ± 31 mmHg, and diastolic blood pressure decreased from 77.1 ± 11.4 to 72.9 ± 15.3 mmHg. There was no ventricular tachycardia, ventricular fibrillation, or second- or third-degree atrioventricular block. CONCLUSION: Regadenoson stress MPI appears to be well tolerated and safe in patients with PH.

Current Perspectives on Systemic Hypertension in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent but incompletely understood syndrome. Traditional models of HFpEF pathophysiology revolve around systemic HTN and other causes of increased left ventricular afterload leading to left ventricular hypertrophy (LVH) and diastolic dysfunction. However, emerging models attribute the development of HFpEF to systemic proinflammatory changes secondary to common comorbidities which include HTN. Alterations in passive ventricular stiffness, ventricular-arterial coupling, peripheral microvascular function, systolic reserve, and chronotropic response occur. As a result, HFpEF is heterogeneous in nature, making it difficult to prescribe uniform therapies to all patients. Nonetheless, treating systemic HTN remains a cornerstone of HFpEF management. Antihypertensive therapies have been linked to LVH regression and improvement in diastolic dysfunction. However, to date, no therapies have definitive mortality benefit in HFpEF. Non-pharmacologic management for HTN, including dietary modification, exercise, and treating sleep disordered breathing, may provide some morbidity benefit in the HFpEF population. Future research is need to identify effective treatments, perhaps in more specific subgroups, and focus may need to shift from reducing mortality to improving exercise capacity and symptoms. Tailoring antihypertensive therapies to specific phenotypes of HFpEF may be an important component of this strategy.

A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension.

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Gastrointestinal bleeding following Heartmate 3 left ventricular assist device implantation: The Michigan Bleeding Risk Model.

BACKGROUND: Gastrointestinal bleeding (GIB) results in frequent hospitalizations and impairs quality of life in durable left ventricular assist device (LVAD) recipients. Anticipation of these events before implantation could have important implications for patient selection and management. METHODS: The study population included all adult HeartMate 3 (HM3) primary LVAD recipients enrolled in the STS Intermacs registry from January 2017 to December 2020. Using multivariable modeling methodologies, we investigated the relationships between preimplantation characteristics and postimplant bleeding, bleeding and death, and additional bleeding episodes on subsequent bleeding episodes and created a risk score to predict the likelihood of post-LVAD GIB based solely on preimplantation factors. RESULTS: Of 6,425 patients who received an HM3 LVAD, 1,010 (15.7%) patients experienced GIB. Thirteen preimplantation factors were independent predictors of post-LVAD GIB. A risk score was created from these factors and calculated for each patient. By 3 years postimplant, GIB occurred in 11%, 26%, and 43% of low-, medium- and high-risk patients, respectively. Experiencing 1 post-LVAD GIB event was associated with an increased risk for further GIB events, with 33.9% of patients experiencing at least 1 recurrence. While post-LVAD GIB was associated with mortality, there was no relationship between number of GIB events and death. CONCLUSIONS: The Michigan Bleeding Risk Model is a simple tool, which facilitates the prediction of post-LVAD GIB in HM3 recipients using 13 preimplant variables. The implementation of this tool may help in the risk stratification process and may have therapeutic and clinical implications in HM3 LVAD recipients.