Dana McGlothlin

World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.

Circulating Endothelial Microparticle Levels Predict Hemodynamic Severity of Pulmonary Hypertension

RATIONALE Circulating microparticles (MPs) are submicron membrane fragments shed from damaged or activated vascular cells. Endothelial MPs are a biological marker of dysfunctional endothelium. Vascular remodeling and endothelial dysfunction are involved in pulmonary hypertension (PH). OBJECTIVES We tested the hypothesis that circulating MPs are increased in patients with PH and that identifiable subgroups of MPs predict the hemodynamic severity of this condition progression. METHODS Patients (n = 24; age, 54 +/- 4 yr) undergoing right heart catheterization for precapillary PH without any endothelium-active vasodilator therapy participated in the study. Age- and sex-matched healthy control subjects (n = 20) were included. Endothelial (PECAM(+) [CD31(+)]/ CD41(-), VE-cadherin(+) [CD144(+)], and E-selectin(+) [CD62e(+)]), platelet (CD41(+)), leukocyte-derived (CD45(+)), and annexin V(+) MPs were measured by flow cytometry in platelet-free plasma from venous blood. MEASUREMENTS AND MAIN RESULTS Levels of circulating endothelial PECAM(+), VE-cadherin(+), E-selectin(+), and leukocyte-derived MPs, but not platelet and annexin V(+) MPs, were increased in subjects with PH compared with control subjects (P < 0.01 each). PECAM(+) and VE-cadherin(+) MP levels significantly correlated with mean pulmonary artery pressure (r = 0.92 and r = 0.87, respectively), pulmonary vascular resistance (r = 0.78 and r = 0.73), and mean right atrial pressure (r = 0.43, and r = 0.46) and correlated inversely with cardiac index (r = -0.59 and r = -0.52). These relationships were not observed for other MP subgroups, and persisted in multivariate analysis after adjustment for confounding factors. CONCLUSIONS In subjects with precapillary PH, levels of circulating endothelial and leukocyte MPs were increased compared with control subjects. In addition, levels of PECAM(+) and VE-cadherin(+), but not E-selectin(+), endothelial MPs predicted hemodynamic severity of the disease.

Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: Analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database

BACKGROUND Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressure > or = 25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > or = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure. METHODS This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality. RESULTS Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P < .001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups. CONCLUSIONS Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

Increased CD62e+ Endothelial Microparticle Levels Predict Poor Outcome in Pulmonary Hypertension Patients

BACKGROUND Endothelial and leukocytes-derived microparticles (EMPs and LMPs, respectively) are increased in patients with pulmonary hypertension (PH). We hypothesized that the levels of circulating EMPs and LMPs could predict outcome in these patients. METHODS Patients undergoing right heart catheterization for untreated pre-capillary PH were eligible for the study. Baseline hemodynamics and biologic and clinical parameters were measured at the time of enrollment. Measurements of CD62e(+), CD144(+) and CD31(+)/CD41(-) EMPs and CD45(+) LMPs were performed using flow cytometry in venous platelet-free plasma samples. After inclusion, patients were treated at the discretion of the physician and prospectively followed for 12 months. The primary end-point was the combined occurrence of death and re-admission for right heart failure (RHF) or worsening of RHF symptoms. RESULTS Seven of 21 patients (mean age 54.1 +/- 3.5 years, 62% female) experienced the primary end-point during the study period. These patients had higher baseline levels of CD62e(+) EMPs, LMPs and hsCRP (high sensitivity C-reactive protein) compared to patients without events (p < 0.05), whereas no difference was observed for other microparticles and functional and hemodynamics parameters. Receiver operating curve analysis showed that baseline CD62e(+) EMPs levels of >353 events/microl predicted clinical complications. Kaplan-Meier analysis revealed that patients with baseline CD62e(+) EMPs above this cut-off value had a significantly worse prognosis compared with those subjects who had levels below this cut-off (p = 0.02, log-rank statistics). CONCLUSIONS Elevated levels of circulating CD62e(+) EMPs but not LMPs in PH patients prior to treatment are associated with adverse clinical events. Assessment of CD62e(+) EMPs levels may represent a new tool for stratification of PH patients.

Furthering the Link Between the Sarcomere and Primary Cardiomyopathies: Restrictive Cardiomyopathy Associated with Multiple Mutations in Genes Previously Associated With Hypertrophic or Dilated Cardiomyopathy

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patients mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patients parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non‐hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Association of CYP2C9*2 With Bosentan‐Induced Liver Injury

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug‐induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29−∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan‐induced liver injury and warrants investigation for the optimization of bosentan treatment.

Transplantation in adults with congenital heart disease.

Considerable progress in pediatric cardiac surgery has led to more patients with congenital heart disease surviving into adulthood. However, progressive cardiopulmonary dysfunction often occurs late after palliative or corrective surgeries to the point where transplantation becomes the only treatment option. Adult congenital heart disease represents a growing population of patients being referred for heart, lung, and combined heart-lung transplantation. This group of patients presents multiple unique surgical and medical challenges to transplantation owing to their complex anatomy, multiple prior palliative and corrective procedures, frequently increased pulmonary vascular resistance, and often debilitated condition. Consequently, transplantation in adults with congenital heart disease is associated with a relatively high operative mortality secondary to increased bleeding, infection, and graft failure rates compared with noncongenital heart disease transplant recipients. However, those who survive of the first posttransplant year enjoy an excellent long-term prognosis.

Anesthesia and pulmonary hypertension.

Anesthesia and surgery are associated with significantly increased morbidity and mortality in patients with pulmonary hypertension due mainly to right ventricular failure, arrhythmias, postoperative hypoxemia, and myocardial ischemia. Preoperative risk assessment and successful management of patients with pulmonary hypertension undergoing cardiac surgery involve an understanding of the pathophysiology of the disease, screening of patients at-risk for pulmonary arterial hypertension, analysis of preoperative and operative risk factors, thorough multidisciplinary planning, careful intraoperative management, and early recognition and treatment of postoperative complications. This article will cover each of these aspects with particular focus on the anesthetic approach for non-cardiothoracic surgeries.

Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival

BACKGROUND The Registry to Evaluate Early and Long-Term Pulmonary Arterial (PAH) Hypertension Disease Management (REVEAL) model was designed to predict 1-year survival in patients with PAH. Multivariate prediction models need to be evaluated in cohorts distinct from the derivation set to determine external validity. In addition, limited data exist on the utility of this model in the prediction of long-term survival. METHODS REVEAL model performance was assessed to predict 1-year and 5-year outcomes, defined as survival or composite survival or freedom from lung transplant, in 140 patients with PAH. RESULTS The validation cohort had a higher proportion of human immunodeficiency virus (7.9% vs 1.9%, p < 0.0001), methamphetamine use (19.3% vs 4.9%, p < 0.0001), and portal hypertension PAH (16.4% vs 5.1%, p < 0.0001) compared with the development cohort. The C-index of the model to predict survival was 0.765 at 1 year and 0.712 at 5 years of follow-up. The C-index of the model to predict composite survival or freedom from lung transplant was 0.805 and 0.724 at 1 and 5 years of follow-up, respectively. Prediction by the model, however, was weakest among patients with intermediate-risk predicted survival. CONCLUSIONS The REVEAL model had adequate discrimination to predict 1-year survival in this small but clinically distinct validation cohort. Although the model also had predictive ability out to 5 years, prediction was limited among patients of intermediate risk, suggesting our prediction methods can still be improved.

The Clinical Pharmacology of Intranasal l-Methamphetamine

BackgroundWe studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.Methods12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 μg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.ResultsPlasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 ± 56.1, 124.7 ± 106.6, and 268.1 ± 220.5 μg for ascending exposures (mean 4.2 ± 3.3 μg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.ConclusionInhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.