Pharmacological Update and Emerging Treatments of Pulmonary Hypertension.

Pulmonary hypertension (PH) is defined as elevated pressures in the pulmonary artery and is associated with significant morbidity and mortality. The World Health Organization classifies PH into 5 distinct groups based on underlying etiology, pathology, and modality of treatment. Therapeutic approach may be challenging due to the extensive spectrum of causes and underlying mechanisms mediating PH. The 5 groups include pulmonary arterial hypertension (group 1), PH secondary to left heart disease (group 2), PH secondary to chronic lung disease (group 3), chronic thromboembolic pulmonary hypertension (group 4), and PH due to miscellaneous causes (group 5). Although significant progress has been made in the treatment of group 1 PH, there is a continued need to develop new therapies for all types of PH. Additionally, most treatments currently available improve functional capacity and symptoms but without a significant benefit in mortality. In this review, we aim to describe the various etiologies of PH and their established pharmacotherapies, as well as expand on emerging therapeutic options for each group.

Utilization of hepatitis C virus infected donors in heart transplant recipients with elevated MELD-XI score.

BACKGROUND: The advent of direct-acting antivirals has helped to increase the safe utilization of organs from hepatitis C virus positive (HCV+) donors. However, the outcomes of heart transplantation (HT) using an HCV+ donor are unclear in recipients with underlying liver disease represented by an elevated model for end-stage liver disease excluding international normalized ratio (MELD-XI). METHODS: The United Network of Organ Sharing database was queried from Jan 2016 to Dec 2021. Post-transplant outcomes stratified by recipient MELD-XI score (low <10.37, medium, 10.38-13.39, and high >13.4) was compared between patients with HT from HCV+ (N = 792) and patients with HT from HCV-negative donors (N = 15,266). RESULTS: The median MELD-XI score was comparable (HCV+, 12.1, vs. HCV-negative, 11.8, p = .37). In the HCV+ group, donors were older (33 vs. 31 years, p < .001). Ischemic time of donor hearts (3.48 vs. 3.28 h, p < .001) and travel distance (250 vs. 157 miles, p < .001) were longer in HCV+ group. In the Kaplan Meier analysis with a median follow-up of 750 days, survival was comparable between the two groups (2-year survival, MELD-XI Low: HCV+, 92.4 ± 3.6% vs. HCV-negative, 91.1 ±.8%, p = .83, Medium: HCV+ 89.2 ± 4.3% vs. HCV-negative, 88.2 ± 1.0%, p = .68, and High: HCV+, 84.9 ± 4.5% vs. HCV-negative, 84.6 ± 1.1%, p = .75) In multivariate Cox hazard models, HCV donors were not associated with mortality in each MELD-XI subgroup (Low: adjusted hazard ratio (aHR), 1.02, p = .94; Medium: aHR, .95, p = .81; and High: aHR, .93, p = .68). CONCLUSION: Utilization of HCV+ hearts was not associated with an increased risk of adverse outcomes in recipients with an elevated MELD- XI score.

Cardiac Allograft Rejection: Strategies for Success in the Face of Immune Challenges.

Heart transplantation for patients with end-stage heart failure refractory to medical therapy has remained definitive treatment with significant advances in posttransplant care. Despite improvement in postoperative morbidity and mortality, acute cellular rejection (ACR) and antibody-mediated rejection (AMR) remain substantial challenges that can lead to allograft failure and patient mortality. Immunosuppressive agents have been the mainstay of both prevention and treatment for ACR and AMR; however, many challenges exist with traditional therapies. There are a multitude of molecular pathways involved in mediating the humoral and cellular response to rejection, offering various targets for treatment. This review summarizes therapies used in the management of ACR and AMR as extrapolated from use in induction therapy and treatment of other solid-organ transplant rejection. Future studies focused on cardiac transplant recipients are needed to expand therapeutic options.

Outcomes of Blacks Versus Whites with Cardiomyopathy.

Racial disparities in health outcomes have been widely documented in medicine, including in cardiovascular care. While some progress has been made, these disparities have continued to plague our healthcare system. Patients with cardiomyopathy are at an increased risk of death and cardiovascular hospitalizations. In the present analysis, we examined the baseline characteristics and outcomes of black and white men and women with cardiomyopathy. All patients with cardiomyopathy (left ventricular ejection fraction (LVEF) < 50%) cared for at University of Pittsburgh Medical Center (UPMC) between 2011 and 2017 were included in this analysis. Patients were stratified by race, and outcomes were compared between Black and White patients using Cox proportional hazard models. Of a total of 18,003 cardiomyopathy patients, 15,804 were white (88%), 1,824 were black (10%) and 375 identified as other (2%). Over a median follow-up time of 3.4 years, 7,899 patients died. Black patients were on average a decade younger (p <0.001) and demonstrated lower unadjusted all-cause mortality (hazard ratio [HR]: 0.83%; 95% CI 0.77 to 0.90; p < 0.001). However, after adjusting for age and other comorbidities, black patients had higher all-cause mortality compared to white patients (HR: 1.15, 95% CI 1.07 to 1.25; p < 0.001). These differences were seen in both men (HR:1.19, 95% CI 1.08 to 1.33; p < 0.001) and women (HR:1.12, 95% CI 0.99 to 1.25; p = 0.065). In conclusion, our data demonstrate higher all-cause mortality in black compared to white men and women with cardiomyopathy. These findings are likely explained, at least in part, by significantly higher rates of comorbidities in black patients. Earlier interventions targeting these comorbidities may mitigate the risk of progression to heart failure and improve outcomes.

Inflammatory and Antioxidant Gene Transcripts: A Novel Profile in Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery; however, antiarrhythmic strategies have not lowered the rate of POAF. This study aimed to identify specific gene transcripts of atrial inflammation, inflammatory handling, and oxidative stress associated with POAF. Left atrial tissue was obtained from 50 patients undergoing intended degenerative mitral repair who did not have any of the following risk factors for POAF: history of atrial fibrillation or other arrhythmia, left atrial diameter greater than 6.0 cm, or left ventricular ejection fraction less than 40%. Postoperative outcomes and left atrial tissue messenger ribonucleuc acid (mRNA) levels were recorded. Parametric 2-sample t-tests and chi-square tests were used to evaluate for statistical significance in comparing POAF and non-POAF groups. Within 30 days of surgery, 19 of 50 of patients (38%) developed POAF. There were no significant preoperative, intraoperative, or postoperative differences between POAF and non-POAF patients. In the tissue transcriptome analysis, POAF patients were found to have a worse preoperative inflammatory state with higher levels of tumor necrosis factor alpha, Interleukin-6, and nuclear factor of kappa light polypeptide gene enhancer in B-cells mRNA, worse inflammatory handling capacity with lower levels of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor mRNA, and reduced antioxidant defenses with lower levels of glutathione synthetase, glutathione reductase, and mitochondrial superoxide dismutase 2 mRNA. This study found POAF patients to have preoperative left atrial tissue profiles suggestive of more inflammation, worse inflammatory handling, and reduced antioxidant defenses against oxidative stress. Investigation of therapies targeted to the tissue-specific inflammatory transcriptome of POAF patients is warranted.

Anticoagulation following mitral valve repair.

BACKGROUND AND AIM: Anticoagulation after mitral valve repair is controversial and guidelines are not well-established. This study evaluated the association between postoperative warfarin use and complications after mitral valve repair, including bleeding and thromboembolic incidents, readmission, and mortality. METHODS: This retrospective study investigated 1097 patients who underwent elective mitral valve repair between April 2003 and March 2017, and was naïve to atrial fibrillation or prior cardiac surgery. This cohort had no other indication for or against anticoagulation. About 775 patients were placed on warfarin with international normalized ratio goal 2.5 and 322 patients were not anticoagulated. The association between anticoagulation and complications was assessed with univariate comparisons between groups and multiple logistic regression. RESULTS: Postoperative warfarin use was associated with a reduced composite of bleeding and thromboembolic complications (pulmonary embolism, TIA, stroke, pericardial effusion or cardiac tamponade, gastrointestinal bleeding, and reoperation for bleeding) with an odds ratio of 0.29 (95% confidence interval, 0.13-0.64, P = .003). There was no difference in 30-day or 6-month mortality or readmission rate between groups. Long-term survival estimates were superior in the warfarin group (10-year: 92% vs 85%; log-rank P < .001). CONCLUSIONS: Our analysis showed that postoperative warfarin use was associated with an overall reduced composite of bleeding and thromboembolic incidents and superior long-term survival. These findings suggest that anticoagulation with warfarin following mitral valve repair may be a safe and effective means for avoiding postoperative complications and that a large prospective randomized clinical trial is warranted.

Outcomes of Guideline-Directed Concomitant Annuloplasty for Functional Tricuspid Regurgitation.

BACKGROUND: Despite guideline recommendations, rates of concomitant tricuspid valve repair are suboptimal, possibly due to fear of complications. We reviewed morbidity, mortality, recurrent tricuspid regurgitation, and right ventricular remodeling after guideline-directed concomitant tricuspid valve repair. METHODS: We performed guideline-directed concomitant tricuspid valve repair on 171 consecutive patients who underwent left-sided valve surgery (degenerative mitral surgery or aortic valve replacement) between May 2012 and March 2016. Exclusion criteria included functional mitral regurgitation, rheumatic disease, active endocarditis, and concomitant coronary artery bypass grafting or complex aortic surgery. RESULTS: Mean age was 68 ± 12 years, and 47% (81 of 171) were women. Preoperative atrial fibrillation was present in 57% (98 of 171), and preoperative tricuspid regurgitation was moderate or higher in 64% (108 of 171). The rate of de novo pacemaker placement was 4.1% (7 of 171), and the 30-day mortality rate was 0.6% (1 of 171). Estimated survival was 95% ± 4% at 1 year and 92% ± 5% at 5 years. Freedom from moderate or worse residual/recurrent tricuspid regurgitation was 93% ± 6% at 6 months and 89% ± 8% at 3 years. Quantitative echocardiography found no significant increase in right ventricular dimensions or area at 1 year in subgroup analysis. Mean echocardiographic follow-up was 14.1 months, and mean clinical follow-up was 33.9 months. CONCLUSIONS: Guideline-directed concomitant tricuspid valve repair resulted in excellent safety end points and survival. At 14 months, freedom from moderate or worse tricuspid regurgitation was high, right ventricular performance did not worsen, and the pacemaker rate was comparable to rates after isolated mitral repair. Given these findings, adherence to current guidelines regarding functional tricuspid regurgitation should be encouraged.

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy.

MDI 301 is a novel 9-cis retinoic acid derivative in which the terminal carboxylic acid group has been replaced by a picolinate ester. MDI 301, a retinoic acid receptor-α - agonist, suppressed the growth of several human myeloid leukemia cell lines (HL60, NB4, OCI-M2, and K562) in vitro and induced cell-substrate adhesion in conjunction with upregulation of CD11b. Tumor growth in HL60-injected athymic nude mice was reduced. In vitro, MDI 301 was comparable to all-trans retinoic acid (ATRA) whereas in vivo, MDI 301 was slightly more efficacious than ATRA. Most importantly, unlike what was found with ATRA treatment, MDI 301 did not induce a cytokine response in the treated animals and the severe inflammatory changes and systemic toxicity seen with ATRA did not occur. A retinoid with these characteristics might be valuable in the treatment of promyelocytic leukemia, or, perhaps, other forms of myeloid leukemia.