Successful treatment of pulmonary hypertension following hematopoietic stem cell transplant with a single oral tadalafil: a case report.

A 46-year-old man who had undergone hematopoietic stem cell transplant twice because of acute lymphoblastic leukemia with recurrence presented with dyspnea, leading to a diagnosis of pulmonary arterial hypertension which was quickly and effectively treated with the phosphodiesterase type 5 inhibitor tadalafil. To our knowledge, pulmonary arterial hypertension related to hematologic malignancies requiring hematopoietic stem cell transplant is rarely reported. Importantly, the present case suggests that early diagnosis and treatment with a pulmonary vasodilator, such as tadalafil, can greatly decrease pulmonary vascular resistance in patients with severe pulmonary arterial hypertension after hematopoietic stem cell transplant and can then improve other symptoms. Accordingly, pulmonary vascular disease should be considered if respiratory symptoms develop following hematopoietic stem cell transplant, because treatment with pulmonary vasodilator may lead to significant improvement in pulmonary arterial hypertension.

Bariatric surgery in patients with advanced heart failure: A proposed multi-disciplinary pathway for surgical care in medically complex patients.

BACKGROUND: The objective of this study was to develop a multi-disciplinary care pathway to minimize perioperative complications in patients with advanced heart failure undergoing bariatric surgery. Patients with severe obesity and heart failure carry increased perioperative surgical risk compared to patients with no heart failure due to the severity of their cardiac disease state and associated comorbidities. Our bariatric program routinely excluded patients with advanced heart failure from undergoing bariatric surgery due to the high reported perioperative risk. However, knowing the potential beneficial impact of bariatric surgery for advanced heart failure, our program hoped that the thoughtful development of a perioperative pathway before inclusion of patients with advanced heart failure in the bariatric surgery program could minimize the morbidity of these high-risk patients in comparison to prior publications in the literature. METHODS: Two multi-disciplinary care pathways were developed, including advanced heart failure, anticoagulation specialists, and transplant cardiologists, to optimize bariatric care for severely obese patients with advanced heart failure with or without mechanical circulatory support and implementation was evaluated for short-term 30-day complications and 6 month cardiac and weight-loss outcomes. RESULTS: Two multi-disciplinary care pathways were developed and implemented on 5 patients with heart failure with reduced ejection fraction (pathway 1) and 3 patients requiring mechanical circulatory support (pathway 2). There were no in-hospital complications or mortality following either pathway, and there was only 1 emergency room visit and 1 re-admission. The average length of stay for patients with heart failure with reduced ejection fraction without mechanical circulatory support was 2.4 days and for heart failure with reduced ejection fraction with mechanical circulatory support was 4.3 days. Three patients met body mass index criteria for transplant listing at 6 months. Ejection fraction increased an average of 9% at 6 months postoperatively for patients with heart failure with reduced ejection fraction not requiring mechanical circulatory support. CONCLUSION: With multi-disciplinary care pathway development designed to maximize safety by intensely supporting preoperative cardiac optimization and medication titration postoperatively, bariatric surgery can be performed in patients with advanced heart failure with or without mechanical circulatory support, allowing patients the opportunity for weight loss as a bridge to transplant or potentially meaningful cardiac recovery.

Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology.

Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing.

A Dual-Lumen Percutaneous Cannula for Managing Refractory Right Ventricular Failure.

A right ventricular assist device (RVAD) using a dual-lumen percutaneous cannula inserted through the right internal jugular vein (IJV) might improve weaning in patients with refractory right ventricular (RV) failure. However, the reported experience with this cannula is limited. We reviewed the records of all patients receiving RVAD support with this new dual-lumen cannula at our institution between April 2017 and February 2019. We recorded data on weaning, mortality, and device-specific complications. We compared outcomes among three subgroups based on the indications for RVAD support (postcardiotomy, cardiogenic shock, and primary respiratory failure) and against similar results in the literature. Mean (standard deviation [SD]) age of the 40 patients (29 men) was 53 (15.5) years. Indications for implantation were postcardiotomy support in 18 patients, cardiogenic shock in 12, and respiratory failure in 10. In all, 17 (94%) patients in the postcardiotomy group were weaned from RVAD support, five (42%) in the cardiogenic shock group, and seven (70%) in the respiratory failure group, overall higher than those reported in the literature (49% to 59%) for surgically placed RVADs. Whereas published in-hospital mortality rates range from 42% to 50% for surgically placed RVADs and from 41% to 50% for RVADs with percutaneous cannulas implanted through the right IJV, mortality was 11%, 58%, and 40% in our subgroups, respectively. There were no major device-related complications. This percutaneous dual-lumen cannula appears to be safe and effective for managing refractory RV failure, with improved weaning and mortality profile, and with limited device-specific adverse events.

Association of preoperative duration of inotropy on prevalence of right ventricular failure following LVAD implantation.

AIMS: 20% to 40% of left ventricular assist device (LVAD) device implantations are complicated by right ventricular (RV) failure that results in significant morbidity and mortality. We hypothesized that the duration on milrinone infusion is an independent risk factor for RV failure following LVAD implantation. METHODS AND RESULTS: Retrospective demographic, clinical and hemodynamic data were collected on all adults with ACC/AHA stage D heart failure on intravenous milrinone who underwent LVAD implantation between 2012 and 2019. Patients (n = 104) were divided into two groups, those on milrinone <30 days (STM, n = 55) vs. ≥30 (LTM, n = 49). The primary endpoint was the prevalence of RV failure (need for inotropic support for more than 14 days or RV assist device) within 30 days post-LVAD implantation. There were no significant differences between STM and LTM patients with respect to demographic, echocardiographic, right heart catheterization data, or baseline medications. The mean age of patients was 55.6 ± 12 years (70% male patients). Mean duration on milrinone was 13.7 vs. 81.0 days in STM and LTM, respectively. Forty-five (43.3%) patients developed RV failure. LTM had higher prevalence of RV failure with odds ratio (OR) = 5.04 (95% CI 2.18-11.68, P = 0.0002). After adjusting for age, gender, and co-morbidity count, the OR was 6.33 (95% CI 2.51-15.93), P < 0.0001. CONCLUSIONS: In this retrospective study of ACC/AHA stage D HF patients, longer duration of milrinone infusion was associated with higher prevalence of RV failure after LVAD implantation.

Minimally Invasive Mechanical Circulatory Support Through the Perioperative Pulmonary Thromboendarterectomy Period: A Case Report.

A 64-year-old man being evaluated for pulmonary thromboendarterectomy (PTE) preoperatively experienced pulseless electrical activity secondary to right ventricular failure while undergoing bronchoscopy. After return of spontaneous circulation, a percutaneous right ventricular assist device (RVAD) was placed through the right internal jugular vein. He continued on right ventricular support with demonstration of right ventricular recovery over the following 8 days, and subsequently underwent PTE for treatment of his primary condition. He recovered and was weaned from his RVAD support uneventfully. The need for RVAD support has traditionally been a contraindication for PTE; however, circulatory assist devices have been used as a salvage procedure for right-heart failure after PTE. This case highlights the potential for percutaneous mechanical circulatory support in treating severe perioperative right ventricular dysfunction, and to facilitate successful recovery in patients undergoing PTE.

Impact of four times daily dosing of oral treprostinil on tolerability and daily dose achieved in pulmonary hypertension.

Oral treprostinil (TRE) is a prostacylin that is approved for the treatment of patients with pulmonary arterial hypertension (PAH). Dosing is approved for two or three times daily (t.i.d.); however, adverse effects, including gastrointestinal-related symptoms, may limit the ability to reach optimal doses. We report our experience with a four times daily (q.i.d.) regimen of oral TRE for goal-directed therapy of PAH. We describe three patients that were transitioned from infusion or inhaled TRE to oral TRE with initial t.i.d. dosing over a four-day hospital stay. All patients were subsequently further dose-adjusted in the outpatient setting; however, adverse effects limited additional up-titration despite persistent dyspnea. In a carefully monitored outpatient setting, patients were switched from t.i.d. to q.i.d. dosing of oral TRE. All three patients were successfully dosed q.i.d., having achieved a higher total daily dose compared with a t.i.d. dose regimen. Furthermore, patients were able to maintain functional class II symptoms with mitigation of adverse effects using the q.i.d. dose regimen.

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or inhaled prostacyclins: case series and treatment protocol.

Oral treprostinil (TRE) is a prostacylin approved for the management of pulmonary arterial hypertension (PAH). Few data exist to guide the use of oral TRE as a replacement for parenteral or inhaled prostacyclins. Therefore, the purpose of this report was to describe our experience with oral TRE to transition patients from parenteral or inhaled TRE. We describe a case series of patients admitted for a 4-day hospital stay to transition from parenteral or inhaled TRE. Appropriate criteria for transition included stable patients with improved symptoms/functional capacity, patients who could not tolerate intravenous prostacyclin due to infection or subcutaneous prostacyclin due to pain, and patient preference for transition. The dosing protocol for transition is described. A total of 9 patients generally representative of a typical PAH demographic and background medical therapy were included. Patients were initiated at either 0.5 or 1 mg 3 times daily and discharged on a median dose of 8 mg 3 times daily. Our protocol resulted in 6 of 9 patients who successfully transitioned at a median follow-up of 47 weeks. Two patients had to return to their previous prostacyclin therapy based on the presence of clinical worsening and adverse events (n = 1) and adverse events alone (n = 1). Another patient discontinued therapy due to plans for hospice care. Oral TRE may serve an important role in prostacyclin transitions in carefully selected, stable patients who receive background oral therapy for PAH.

Safety and efficacy of transition from inhaled treprostinil to parenteral treprostinil in selected patients with pulmonary arterial hypertension.

Guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend sequential add-on therapy for patients who deteriorate or fail to improve clinically. However, it is not known whether these patients also benefit from transitioning from inhaled prostacyclins to parenteral prostacyclins. We sought to characterize PAH patients receiving inhaled treprostinil who were transitioned to parenteral treprostinil. We conducted a multicenter retrospective study at 7 PAH centers and collected reasons, methods, safety, and outcome of patients transitioned from inhaled treprostinil to parenteral treprostinil. Twenty-six patients with pulmonary hypertension in group 1, 4, or 5 transitioned from inhaled treprostinil to parenteral treprostinil (10 intravenous, 16 subcutaneous). Twenty-four patients were also on one or two oral therapies. Reasons for transition were clinical deterioration, lack of clinical improvement, and pregnancy (19, 6, and 1 patients, respectively). Transitions occurred in hospital, clinic, or home (17, 7, and 2 patients, respectively). Parenteral infusion was started after the last inhaled treatment at maintenance dose (13 patients), after the inhaled therapy was downtitrated to 18 [Formula: see text]g (6 patients), or with an overlap of inhaled downtitration with parenteral uptitration (7 patients). The transition was safe; side effects included symptoms of prostacyclin overdose. Patients were followed for 3-18 months. At 3 months, 8 patients improved, 17 maintained their functional class, and 1 continued to deteriorate. In conclusion, selected PAH patients can be safely transitioned from inhaled treprostinil to parenteral treprostinil using a variety of methodologies in different settings with the expectation that patients will improve or at least remain clinically stable.

High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4.

Survival rates for patients with pulmonary hypertension (PH) remain low, and our understanding of the mechanisms involved are incomplete. Here we show in a mouse model of chronic hypoxia (CH)-induced PH that the nuclear protein and damage-associate molecular pattern molecule (DAMP) high mobility group box 1 (HMGB1) contributes to PH via a Toll-like receptor 4 (TLR4)-dependent mechanism. We demonstrate extranuclear HMGB1 in pulmonary vascular lesions and increased serum HMGB1 in patients with idiopathic pulmonary arterial hypertension. The increase in circulating HMGB1 correlated with mean pulmonary artery pressure. In mice, we similarly detected the translocation and release of HMGB1 after exposure to CH. HMGB1-neutralizing antibody attenuated the development of CH-induced PH, as assessed by measurement of right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling and endothelial activation and inflammation. Genetic deletion of the pattern recognition receptor TLR4, but not the receptor for advanced glycation end products, likewise attenuated CH-induced PH. Finally, daily treatment of mice with recombinant human HMGB1 exacerbated CH-induced PH in wild-type (WT) but not Tlr4(-/-) mice. These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH.

Bosentan.

IMPORTANCE TO THE FIELD: Pulmonary arterial hypertension (PAH) is a morbid condition with high mortality if left untreated. Bosentan is an effective treatment option for group 1 pulmonary arterial hypertension. Bosentan improves exercise tolerance and functional class and delays the time to clinical worsening in these patients. Investigation is ongoing to determine its efficacy in other groups of pulmonary hypertension. AREAS COVERED IN THIS REVIEW: This review provides a background on endothelin activity in PAH, as a rationale for the use of bosentan in this disease. It also presents evidence from key clinical trials of bosentan and discusses future directions in the study of bosentan to help the clinician better understand the role of bosentan in PAH management. WHAT THE READER WILL GAIN: i) An understanding of the rationale for using endothelin receptor antagonists in treating PAH; ii) an understanding of the clinical evidence to support bosentan for the treatment of PAH; and iii) an understanding of how to use bosentan optimally in the treatment of PAH. TAKE HOME MESSAGE: Bosentan is an effective and safe treatment for patients with PAH. Patients with suspected PAH should be evaluated carefully as the use of bosentan in non-group 1 pulmonary hypertension is still being investigated. Patients on bosentan should be monitored with monthly liver transaminase testing. Coadministration with other drugs should be reviewed carefully as drug-drug interactions may be important.

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by pulmonary arteriolar remodeling. This investigation aimed to identify genes involved specifically in the pathogenesis of PAH and not other forms of pulmonary hypertension (PH). Using genomewide microarray analysis, we generated the largest data set to date of RNA expression profiles from lung tissue specimens from 1) 18 PAH subjects and 2) 8 subjects with PH secondary to idiopathic pulmonary fibrosis (IPF) and 3) 13 normal subjects. A molecular signature of 4,734 genes discriminated among these three cohorts. We identified significant novel biological changes that were likely to contribute to the pathogenesis of PAH, including regulation of actin-based motility, protein ubiquitination, and cAMP, transforming growth factor-beta, MAPK, estrogen receptor, nitric oxide, and PDGF signaling. Bone morphogenic protein receptor type II expression was downregulated, even in subjects without a mutation in this gene. Women with PAH had higher expression levels of estrogen receptor 1 than normal women. Real-time quantitative PCR confirmed differential expression of the following genes in PAH relative to both normal controls and PH secondary to IPF: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9, cell adhesion molecule with homology to L1CAM, cytochrome b(558) and beta-polypeptide, coagulation factor II receptor-like 3, A-myb myeloblastosis viral oncogene homolog 1, nuclear receptor coactivator 2, purinergic receptor P2Y, platelet factor 4, phospholamban, and tropomodulin 3. This study shows that PAH and PH secondary to IPF are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.

Racial differences in heart failure therapeutics.

Heart failure in African Americans has a phenotype that is distinct from that in non-African Americans and that demonstrates increased importance of hypertensive etiologies. Trial data demonstrate that African Americans receive significant benefit from beta blockade. Despite differences in the heart failure phenotype, therapy of heart failure in African Americans remains largely the same as in white heart failure cohorts, with the notable exception of the added benefits provided by combination of hydralazine and isosorbide dinitrate (HYD-ISDN), now regarded as highly indicated therapy by both the Heart Failure Society of America and the American College of Cardiology/American Heart Association heart failure guideline committees. HYD-ISDN in fixed combination is the first cardiovascular drug approved for a single ethnic or racial subset--self-designated African Americans.

The beta1-adrenergic receptor mediates the pharmacogenetic interaction of the ACE D allele and beta-blockers.

The role of beta-receptor selectivity for the interaction between the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and beta-blocker therapy was investigated in 479 subjects with left ventricular dysfunction. Subjects were separated into no beta-blocker, beta1 -selective, and nonselective beta-blocker treatment groups. The D allele adversely affected transplant-free survival for subjects not on beta-blockers (p= 0.004). Treatment with selective beta1-blockers eliminated the impact of the D allele (p= 0.51) in a manner similar to nonselective beta1,2-blockers (p= 0.80). Treatment with beta1-blockers was sufficient to eliminate the adverse impact of the ACE D allele, suggesting this pharmacogenetic interaction is mediated through the beta1-receptor.