Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs. RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively. CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

Inhaled treprostinil in pulmonary hypertension associated with COPD: PERFECT study results.

BACKGROUND: Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. METHODS: Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. RESULTS: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. CONCLUSIONS: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

The Use of Risk Assessment Tools and Prognostic Scores in Managing Patients with Pulmonary Arterial Hypertension.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a chronic, progressive, and incurable disease with significant morbidity and mortality. Despite increasingly available treatment options, PAH patients continue to experience disease progression and increased rates of hospitalizations due to right heart failure. Physician's ability to comprehensively assess PAH patients, determine prognosis, and monitor disease progression and response to treatment remains critical in optimizing outcomes. RECENT FINDINGS: Risk assessment in PAH should include a range of clinical, hemodynamic, and exercise parameters, performed in a serial fashion over the course of treatment. Approaches to risk assessment in PAH patients include the use of risk variables, scores, and equations that stratify the impact of both modifiable (e.g., 6-min walk distance, functional class, brain natriuretic peptide), and non-modifiable (e.g., age, gender, PAH etiology) risk factors. Such tools allow physicians to better determine prognosis, allocate treatment resources, and enhance the consistency of treatment approaches across providers. Comprehensive and accurate risk prediction is essential to make individualized treatment decisions and optimizing outcomes in PAH.

Right Ventricular Dysfunction and Its Contribution to Morbidity and Mortality in Left Ventricular Heart Failure.

PURPOSE: In patients with left-sided HF, there has been less emphasis on the pathophysiology of the RV in terms of diagnostic evaluation and treatment, versus focus on structural abnormalities of the LV. This review seeks to delineate the importance of RV dysfunction in terms of its contribution to symptomatic limitations and cardiovascular outcomes in patients with left-sided HF. RECENT FINDINGS: Recent studies have demonstrated that RV dysfunction is common in both HFpEF and HFrEF, but more pronounced in HFrEF. LV dysfunction and atrial fibrillation are most commonly associated with RV dysfunction in left-sided HF. RV dysfunction may develop due to afterload-dependent and afterload-independent pathways. Regardless, RV dysfunction is strongly associated with functional limitations and worsened survival in patients with left-sided HF. In patients with HFpEF, a recent study showed that RV failure was the most common cause of overall mortality. Among LVAD patients and patients post-cardiac transplantation, RV dysfunction is also strongly associated with survival. Despite a number of previous and ongoing clinical trials that target the RV directly or decrease RV afterload in left-sided HF, there are no definitive therapies specifically targeting RV dysfunction in left-sided HF patients CONCLUSIONS: RV dysfunction is an important determinant of symptomatic limitations and cardiovascular outcomes in patients with left-sided HF. Further research is needed to developed pharmacotherapy that may target the RV specifically in left-sided HF patients.

Catch 22: a case of incessant ventricular tachycardia post-left ventricular assist device resulting in right ventricular failure, left ventricular cavity obliteration and failure of endocardial ventricular tachycardia ablation.

Ventricular tachycardia (VT) in the setting of left ventricular assist device (LVAD) therapy has been well described. We present a case of incessant ventricular tachycardia resulting in severe right ventricular (RV) failure and subsequent left ventricular (LV) cavity obliteration, which in turn diminished the feasibility of initial attempt at VT ablation.

Pulmonary hypertension in potential heart transplant recipients: current treatment strategies.

PURPOSE OF REVIEW: Pulmonary hypertension associated with left heart disease is the most commonly encountered form of pulmonary hypertension and is associated with a poor prognosis. As the global burden of heart failure grows, this associated disease can be a major impediment to those patients undergoing cardiac transplantation, given its association with post-transplant right ventricular failure. Unfortunately, the pathophysiology of pulmonary hypertension secondary to left heart failure remains poorly understood, thereby rendering targeted treatment strategies largely undefined. In this review, we provide a review of the currently available literature in this unique patient population. RECENT FINDINGS: The current focus on better defining the underlying pathophysiology and standardizing diagnostic and therapeutic approaches to pulmonary hypertension associated with left heart disease need to be interpreted and made applicable in the context of clinical practice. Given the relative paucity of successful, targeted pharmacological options, there is an increasing evidence that device-based therapies, used in conjuncture with medical therapy, may help in lowering the pulmonary pressures by causing sustained left ventricular unloading. SUMMARY: Pulmonary hypertension in the context of left heart disease is the most common form of pulmonary hypertension encountered in clinical practice and is associated with worse prognosis in patients being considered for cardiac transplantation. Therapies targeting left ventricular unloading, as well as pulmonary vascular remodeling, are being increasingly studied and used in daily practice.

Estimation of oxygen consumption in elderly patients with aortic stenosis.

BACKGROUND: Invasive evaluation of aortic stenosis requires measuring cardiac output. With the Fick equation, a measure of oxygen consumption (VO2) is required. Standard equations for estimating VO2 were derived in younger and healthier populations than the ones referred for possible transcatheter aortic valve replacement. The goal of this study was to determine the best method of estimating VO2 in elderly patients with aortic stenosis. METHODS: We directly measured VO2 in elderly patients undergoing invasive assessment of aortic stenosis. We compared standard equations estimating VO2 and two prespecified hypothesized equations for VO2 to determine which was most accurate. We also examined the subgroup of patients with low flow. RESULTS: Among 51 patients, aged 80-97 years, the mean VO2 was 198 mL/min. Using 125*body surface area (BSA) to estimate VO2 the average error was 35 mL/min, and 67% of values were within 25% of the true value. Using 3*Weight to estimate VO2, those numbers were 29 mL/min and 65%. The hypothesized equations did better: 100*BSA had error of -12 mL/min and 90% within 25% of measured VO2; for 2.5*Weight it was -9 mL/min and 84%. Among the 20 patients with low flow, hypothesized equations performed best. Using 2.5*Weight and 100*BSA there were 90% and 85% within 25% of measured VO2, respectively, compared to 55% and 75% when 3*Weight and 125*BSA were used. Weight and BSA were the only independent predictors of VO2. CONCLUSIONS: When estimating VO2 in an elderly population with aortic stenosis, the best equations are 2.5*Weight and 100*BSA.

New drugs and devices in the pipeline for heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction.

Heart failure (HF) is a growing problem in the USA and other industrialized nations. HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) each make up approximately half of the overall HF burden. Although a variety of medical and surgical therapies exist for the treatment of patients with HFrEF, morbidity and mortality remain high, and cardiac transplantation, considered the current gold standard for patients with HFrEF and severe symptoms, is reserved for relatively few eligible patients. Patients with HFpEF have more limited therapeutic options, because no medical therapy to date has been shown to improve survival in these patients. With the rising prevalence of HF and its increasing role in health care expenditure, there is a substantial need for new drug and device therapies for HFrEF and, in particular, HFpEF. This forms the topic of the current review.

Impact of Interventricular Interaction on Ventricular Function: Insights From Right Ventricular Pressure-Volume Analysis.

BACKGROUND: Interventricular interactions may be responsible for the decline in ventricular performance observed in various disease states that primarily affect the contralateral ventricle. OBJECTIVES: This study sought to quantify the impact of such interactions on right ventricular (RV) size and function using clinically stable individuals with left ventricular assist devices (LVADs) as a model for assessing RV hemodynamics while LV loading conditions were acutely manipulated by changing device speed during hemodynamic optimization studies (ie, ramp tests). METHODS: The investigators recorded RV pressure-volume loops with a conductance catheter at various speeds during ramp tests in 20 clinically stable HeartMate3 recipients. RESULTS: With faster LVAD speeds and greater LV unloading, indexed RV end-diastolic volume increased (72.28 ± 15.07 mL at low speed vs 75.95 ± 16.90 at high speed; P = 0.04) whereas indexed end-systolic volumes remained neutral. This resulted in larger RV stroke volumes and shallower end-diastolic pressure-volume relationships. Concurrently, RV end-systolic pressure decreased (31.58 ± 9.75 mL at low speed vs 29.58 ± 9.41 mL at high speed; P = 0.02), but contractility, as measured by end-systolic elastance, did not change significantly. The reduction in RV end-systolic pressure was associated with a reduction in effective arterial elastance from 0.65 ± 0.43 mm Hg/mL at low speed to 0.54 ± 0.33 mm Hg/mL at high speed (P = 0.02). CONCLUSIONS: Interventricular interactions resulted in improved RV compliance, diminished afterload, and did not reduce RV contractility. These data challenge the prevailing view that interventricular interactions compromise RV function, which has important implications for the understanding of RV-LV interactions in various disease states, including post-LVAD RV dysfunction.

Postoperative right ventricular failure after left ventricular assist device placement is predicted by preoperative echocardiographic structural, hemodynamic, and functional parameters.

BACKGROUND: Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation results in significant morbidity and mortality. Preoperative parameters from transthoracic echocardiography (TTE) that predict RVF after LVAD implantation might identify patients in need of temporary or permanent right ventricular (RV) mechanical or inotropic support. METHODS AND RESULTS: Records of all patients who had preoperative TTE before implantation of a permanent LVAD at our institution from 2008 to 2011 were screened, and 55 patients (age 54 ± 16 years, 71% male) were included: 26 had LVAD implantation alone with no postoperative RVF, 16 had LVAD implantation alone but experienced postoperative RVF, and 13 had initial biventricular assist devices (BIVADs). The LVAD with RVF and BIVAD groups (RVF group) were pooled for comparison with the LVAD patients without RVF (No RVF group). RV fractional area change (RV FAC) was significantly lower in the RVF group versus the No RVF group (24% vs 30%; P = .04). Tricuspid annular plane systolic excursion was not different among the groups (1.6 cm vs 1.5 cm; P = .53). Estimated right atrial pressure (RAP) was significantly higher in the RVF group versus the No RVF group (11 mm Hg vs 8 mm Hg; P = .04). Left atrial volume (LAV) index was lower in patients with RVF versus No RVF (27 mL/m(2) vs 40 mL/m(2); P = .008). Combining RV FAC, estimated RAP, and LAV index into an echocardiographic scoring system revealed that the TTE score was highly predictive of RVF (5.0 vs 2.8; P = .0001). In multivariate models combining the TTE score with clinical variables, the score was the most predictive of RVF (odds ratio 1.66, 95% confidence interval 1.06-2.62). CONCLUSIONS: Preoperative RV FAC, estimated RAP, and LAV index predict postoperative RVF in patients undergoing LVAD implantation. These parameters may be combined into a simple echocardiographic scoring system to provide an additional tool to risk-stratify patients being evaluated for LVAD implantation.

Role of phosphodiesterase-5 inhibitors in heart failure: emerging data and concepts.

Novel treatment of congestive heart failure (HF) involves utilizing unique pathways to improve upon contemporary therapies. Increasing the availability of cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase-5 (PDE5) is a relatively new, but promising therapeutic strategy. Preclinical studies suggest a favorable myocardial effect of PDE5 inhibitors by blocking adrenergic, hypertrophic and pro-apoptotic signaling, thereby supporting their use in HF. The clinical benefits of acute and chronic PDE5 inhibition on lung diffusion capacity, exercise performance and ejection fraction in humans are emerging and appear promising. Larger, controlled trials are now on-going to assess the safety, efficacy and tolerability of PDE5 inhibitors on morbidity and mortality in patients with both systolic and diastolic heart failure. If the results of these trials are positive, a new avenue for the treatment of HF will open, which will help curtail the societal effects of this costly and morbid disease.

Prognostic role of pulmonary hemodynamics before transcatheter aortic valve replacement among patients with severe aortic stenosis.

BACKGROUND: Pulmonary hypertension (PH) frequently co-exists in patients with severe aortic stenosis (AS). In this study, we sought to identify the implications of invasive pulmonary hemodynamics on major adverse cardiac events (MACE), biventricular function and NYHA functional class after transcatheter aortic valve replacement (TAVR). METHODS: Invasive hemodynamics via right heart catheterization (RHC) were performed pre-TAVR. Patients were stratified per mean PA pressure (mPAP), diastolic pulmonary gradient (DPG) and pulmonary vascular resistance (PVR), and followed at 1-month and 1-year intervals up to 6 years. MACE outcomes included cardiovascular death and heart failure hospitalizations post-TAVR. RESULTS: Among 215 patients, Kaplan-Meir estimates demonstrated an increased 1-year risk of MACE from 8% among those without pre-TAVR PH to 27% among patients with pre-existing PH. Specifically, the MACE risk was 32% among PH patients with PVR ≥ 3WU (p = .04) and 53% among PH patients with DPG ≥ 7 mm Hg (p < .01). On univariate Cox regression, RV stroke work index (RVSWI) (HR,1.02; p = .02), and pulmonary hemodynamic index (PHI) (HR,1.27; p = .047) were identified as additional predictors of MACE post-TAVR. On multivariable Cox regression analysis, SvO2 (HR, 0.95; p = .01) and PVR (HR, 1.2; p = .04) were demonstrated as predictive of MACE post-TAVR. A significant improvement in LVEF (2-Factor ANOVA, p < .01) and RV fractional area change (RVFAC%) (p < .01) was noted as assessed at baseline, 1-month and 1-year follow up post-TAVR. There was a significant interaction between pre-TAVR PH status and time post procedure with respect to NYHA functional class (p = .03), that is, the manner and degree of change in NYHA class over time depended on pre-TAVR PH status. CONCLUSIONS: Defining invasive pulmonary hemodynamics, such as mPAP, PVR, and DPG among patients with severe AS undergoing TAVR has significant prognostic implications. Routine risk stratification by utilizing invasive hemodynamics can better identify patients who will have functional improvement and improved outcomes post-TAVR.

Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation.

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. FINDINGS: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. INTERPRETATION: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains. FUNDING: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases.

Rapidly progressive pulmonary hypertension and right ventricular failure in a heart and kidney transplant recipient.

A 54-year-old man status post heart and kidney transplant presented with dyspnea. Imaging was consistent with lymphangitic carcinomatosis (LC), in the setting of biopsy proven adenocarcinoma. He developed pulmonary hypertension (PH) and died of right ventricular failure (RVF) 3 weeks later. Acute PH with radiographic features of LC in a high-risk patient warrants expedited malignancy investigation.

The impact of mitral regurgitation on patients undergoing catheter ablation of atrial fibrillation.

AIMS: Mitral regurgitation (MR) causes left atrium (LA) enlargement and subsequent atrial fibrillation (AF). The presence of MR may increase recurrence rates after AF ablation. The purpose of this study was to determine the impact of MR on recurrence rates after catheter ablation of AF. METHODS AND RESULTS: We compared 95 patients with moderate or greater baseline MR (defined by MR jet area to LA area ratio ≥ 0.2) and AF undergoing ablation to 95 randomly selected patients without significant MR undergoing AF ablation. Electrocardiographic recurrence at 1-year follow-up was the primary outcome. Patients in the MR cohort had mean MR/LA ratio 0.37 vs. 0.09 in controls (P< 0.0001). Mitral regurgitation patients had larger LA dimension (4.5 vs. 4.1 cm, P< 0.0001) and more persistent AF (71 vs. 28%, P< 0.0001). Mitral regurgitation patients had higher recurrence rates than controls (61 vs. 46%, P= 0.04). The degree of MR was higher in patients with recurrence (MR/LA ratio 0.25 vs. 0.20, P= 0.03), as was LA dimension (4.5 vs. 4.1 cm, P< 0.0001). In multivariate analyses, only LA size was an independent predictor of recurrence (odds ratio 2.9 per centimetre increase in LA dimension, P= 0.005). Fifty-five percent of MR patients had normal leaflet motion, with MR likely due to atrial remodelling secondary to AF. CONCLUSION: Mitral regurgitation was associated with increased AF recurrence after AF ablation, but its impact was mediated by LA size. Left atrium size was the only independent predictor of AF recurrence. The high percentage of MR that was likely secondary to AF may have impacted our findings and deserves further study.

Transition from parenteral prostacyclins to selexipag: safety and feasibility in selected patients.

There are limited data regarding the feasibility of transitioning from intravenous prostacyclins to selexipag in pulmonary arterial hypertension patients. We present a case series of successful transitions from intravenous prostacyclins to selexipag in the majority of carefully selected five stable pulmonary arterial hypertension patients using a standardized protocol in the outpatient setting.

A Case Report of a Patient With Pulmonary Arterial Hypertension Transitioned From Inhaled Iloprost to Selexipag.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance that can lead to right ventricular failure and death. The use of medications that affect the prostacyclin pathway is an important treatment strategy in PAH. Inhaled iloprost is a prostacyclin analogue, and selexipag is an oral, non-prostanoid, prostacyclin IP receptor agonist. Data are limited on transitioning patients from inhaled iloprost to selexipag. In this case report, we describe the successful transition of a 57-year-old female with heritable PAH from inhaled iloprost to selexipag over 8 weeks in an out-patient setting. After initiation of selexipag, the patient's inhaled iloprost dose was gradually reduced and eventually discontinued. The patient tolerated the transition well with stable symptoms, 6-minute walk distance, and pulmonary hemodynamics. Additional studies are needed to better define the comparative efficacy and safety of inhaled iloprost and selexipag.

Reasons for refusing parenteral therapy: a qualitative study of patients with pulmonary arterial hypertension.

While parenteral prostacyclin (pPCY) therapy, delivered either subcutaneously or intravenously, is recommended for pulmonary arterial hypertension patients with severe or rapidly developing disease, some patients refuse this treatment. This study aimed to understand, directly from patients with pulmonary arterial hypertension, why pPCY was refused and, in some cases, later accepted. Interviews were conducted with 25 pulmonary arterial hypertension patients who previously refused pPCY therapy (Group A: Refused/Never initiated (n = 9) and Group B: Refused/Initiated (n = 16)). Patients in both groups believed that pPCY could improve their symptoms, slow disease progression, and provide them a greater ability to perform activities. Reasons for refusal included concern over side effects and the perceived limitations of pPCY on daily activities. Group A perceived their decision as a balance between quality of life and prolonging life and most acknowledged they would reconsider pPCY if other treatment options were exhausted. Group B cited they initiated therapy due to a worsening of symptoms, disease progression, to improve quality of life, to be there for their family, or a desire to live. Following initiation, Group B indicated their experience met expectations with reduced symptoms, slowed disease progression, and perception of improved survival; concerns related to pPCY were described as manageable. Given the efficacy of pPCY therapy, clinicians should apply knowledge of these findings in clinical practice. Patients noted improvements to parenteral pump technologies to include smaller size, water resistance, and implantability may increase their acceptance of this modality. Development efforts should focus on technologies that increase the acceptance of pPCY when indicated.