Harm-Jan Bogaard

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Progressive Changes in Right Ventricular Geometric Shortening and Long-term Survival in Pulmonary Arterial Hypertension

BACKGROUND Until now, many investigators have focused on describing right ventricular (RV) dysfunction in groups of patients with pulmonary arterial hypertension (PAH), but very few have addressed the deterioration of RV function over time. The aim of this study was to investigate time courses of RV geometric changes during the progression of RV failure. METHODS Forty-two patients with PAH were selected who underwent right-sided heart catheterization and cardiac MRI at baseline and after 1-year follow-up. Based on the survival after this 1-year run-in period, patients were classified into two groups: survivors (26 patients; subsequent survival of > 4 years) and nonsurvivors (16 patients; subsequent survival of < 4 years). Four-chamber cine imaging was used to quantify RV longitudinal shortening (apex-base distance change), RV transverse shortening (septum-free wall distance change), and RV fractional area change (RVFAC) between end diastole and end systole. RESULTS Longitudinal shortening, transverse shortening, and RVFAC measured at the beginning of the run-in period and 1 year later were significantly higher in subsequent survivors than in nonsurvivors (P < .05). Longitudinal shortening did not change during the run-in period in either patient group. Transverse shortening and RVFAC did not change during the run-in period in subsequent survivors but did decrease in subsequent nonsurvivors (P < .05). This decrease was caused by increased leftward septal bowing. CONCLUSIONS Progressive RV failure in PAH is associated with a parallel decline in longitudinal and transverse shortening until a floor effect is reached for longitudinal shortening. A further reduction of RV function is due to progressive leftward septal displacement. Because transverse shortening incorporates both free wall and septum movements, this parameter can be used to monitor the decline in RV function in end-stage PAH.

The Right Ventricle Explains Sex Differences in Survival in Idiopathic Pulmonary Arterial Hypertension

BACKGROUND Male sex is an independent predictor of worse survival in pulmonary arterial hypertension (PAH). This finding might be explained by more severe pulmonary vascular disease, worse right ventricular (RV) function, or different response to therapy. The aim of this study was to investigate the underlying cause of sex differences in survival in patients treated for PAH. METHODS This was a retrospective cohort study of 101 patients with PAH (82 idiopathic, 15 heritable, four anorexigen associated) who were diagnosed at VU University Medical Centre between February 1999 and January 2011 and underwent right-sided heart catheterization and cardiac MRI to assess RV function. Change in pulmonary vascular resistance (PVR) was taken as a measure of treatment response in the pulmonary vasculature, whereas change in RV ejection fraction (RVEF) was used to assess RV response to therapy. RESULTS PVR and RVEF were comparable between men and women at baseline; however, male patients had a worse transplant-free survival compared with female patients (P = .002). Although male and female patients showed a similar reduction in PVR after 1 year, RVEF improved in female patients, whereas it deteriorated in male patients. In a mediator analysis, after correcting for confounders, 39.0% of the difference in transplant-free survival between men and women was mediated through changes in RVEF after initiating PAH medical therapies. CONCLUSIONS This study suggests that differences in RVEF response with initiation of medical therapy in idiopathic PAH explain a significant portion of the worse survival seen in men.

The Effects of Exercise on Right Ventricular Contractility and Right Ventricular–Arterial Coupling in Pulmonary Hypertension

RATIONALE Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility. OBJECTIVES To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV-arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP). METHODS We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure-volume loop analysis. MEASUREMENTS AND MAIN RESULTS Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate. CONCLUSIONS In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

BACKGROUND After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. OBJECTIVES The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. METHODS LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. RESULTS Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (~30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (~25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ~30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. CONCLUSIONS The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.

Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses

A subgroup of patients with idiopathic pulmonary arterial hypertension (IPAH) has severely reduced diffusing capacity of the lung for carbon monoxide (DLCO) and poor prognosis. Their characteristics are currently unknown. The aim of this study is to contrast clinical characteristics and treatment responses of IPAH-patients with a severely reduced and more preserved DLCO. Retrospectively, 166 IPAH patients were included and grouped based on a DLCO cut-off value of 45% pred (IPAH<45% and IPAH≥45%). Clinical characteristics, treatment responses and survival were compared. IPAH<45% were older, more often male, had a more frequent history of coronary disease and a higher tobacco exposure. Forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, total lung capacity and alveolar volume values were slightly lower and computed tomography scan abnormalities more prevalent in patients with a low DLCO. Age and number of pack years were independently associated with DLCO <45% pred. IPAH<45% showed no different haemodynamic profile, yet worse exercise performance and a worse survival rate, which were both related to age, sex and the presence of coronary disease. To conclude, a severely reduced DLCO in IPAH is associated with advanced age and a greater tobacco exposure. These patients have a worse exercise performance despite a similar hemodynamic profile. We confirm the decreased survival in this patient group and now show that this poor outcome is related to age, sex and the presence of coronary disease. Severely reduced DLCO in IPAH is associated with advanced age and a greater tobacco exposure http://ow.ly/pkQ5F

Diaphragm muscle fiber weakness in pulmonary hypertension.

RATIONALE Recently it was suggested that patients with pulmonary hypertension (PH) suffer from inspiratory muscle dysfunction. However, the nature of inspiratory muscle weakness in PH remains unclear. OBJECTIVES To assess whether alterations in contractile performance and in morphology of the diaphragm underlie inspiratory muscle weakness in PH. METHODS PH was induced in Wistar rats by a single injection of monocrotaline (60 mg/kg). Diaphragm (PH n = 8; controls n = 7) and extensor digitorum longus (PH n = 5; controls n = 7) muscles were excised for determination of in vitro contractile properties and cross-sectional area (CSA) of the muscle fibers. In addition, important determinants of protein synthesis and degradation were determined. Finally, muscle fiber CSA was determined in diaphragm and quadriceps of patients with PH, and the contractile performance of single fibers of the diaphragm. MEASUREMENTS AND MAIN RESULTS In rats with PH, twitch and maximal tetanic force generation of diaphragm strips were significantly lower, and the force-frequency relation was shifted to the right (i.e., impaired relative force generation) compared with control subjects. Diaphragm fiber CSA was significantly smaller in rats with PH compared with controls, and was associated with increased expression of E3-ligases MAFbx and MuRF-1. No significant differences in contractility and morphology of extensor digitorum longus muscle fibers were found between rats with PH and controls. In line with the rat data, studies on patients with PH revealed significantly reduced CSA and impaired contractility of diaphragm muscle fibers compared with control subjects, with no changes in quadriceps muscle. CONCLUSIONS PH induces selective diaphragm muscle fiber weakness and atrophy.

Signs of Right Ventricular Deterioration in Clinically Stable Patients With Pulmonary Arterial Hypertension

BACKGROUND Even after years of stable response to therapy, patients with idiopathic pulmonary arterial hypertension (IPAH) may show an unexpected clinical deterioration due to progressive right ventricular (RV) failure. Therefore, the aim of this study was to assess in 5-year clinically stable patients with IPAH whether initial differences or subsequent changes in RV volumes precede late clinical progression. METHODS Included were 22 clinically stable patients with IPAH as reflected by stable or improving New York Heart Association functional class II-III and exercise capacity during 5 years of follow-up. Twelve patients subsequently remained stable during a total follow-up of 10 years, whereas 10 other patients showed late progression leading to death or lung transplantation after a follow-up of 8 years. All patients underwent right-sided heart catheterization and cardiac MRI at baseline and at 1½, 3½, 6½, and, if still alive, 10 years follow-up. RESULTS Baseline hemodynamics were comparable in both groups and remained unchanged during the entire follow-up period. Baseline RV end-systolic volume (RVESV) was higher and RV ejection fraction (RVEF) was lower in late-progressive patients. Late-progressive patients demonstrated a gradually increased RV end-diastolic volume and RVESV and a decline in RVEF, whereas long-term stable patients did not show any RV changes. CONCLUSIONS In patients with stable IPAH for 5 years, subsequent late disease progression is preceded by changes in RV volumes. The results indicate that monitoring RV volumes anticipates clinical worsening, even at a time of apparent clinical stability.

Treatment of Group I Pulmonary Arterial Hypertension with Carvedilol Is Safe

The principal treatment strategy for patients with pulmonary artery hypertension (PAH) is the use of medications targeting the pulmonary vasculature (1, 2). Despite several classes of available therapy for the treatment of PAH, some of which can improve cardiac function, patients continue to die of right heart failure (RHF) (3) and additional therapies are needed. We have previously proposed that the dysfunctional right ventricle (RV) should be a treatment target in patients with PAH (3, 4). b-Adrenergic receptor (BAR) blockade has been a mainstay of congestive left heart failure treatment for years and yet, despite some initial prospective safety data (5), BAR blockers are infrequently used in patients with PAH and RV dysfunction. On the basis of experimental data obtained in an animal model of severe angio-obliterative PAH and RHF (6, 7) we designed a single-arm open-label pilot study (clinicaltrials.gov; NCT00964678) to evaluate the feasibility and safety of add-on treatment with carvedilol in patients with stable PAH and RV dysfunction (functional classes II and III) in a prospective study using cardiac magnetic resonance (CMR) to measure interval changes in RV dimensions and systolic function, using a threedimensional reconstruction of the RV cavity (CVI 42 software; Circle Cardiovascular Imaging, Calgary, AB, Canada). Carvedilol was chosen because it is the preferred BAR in congestive left heart failure, and was found to improve RV ejection fraction (RVEF) in patients with biventricular failure (8). Here we report our findings from this pilot study. The study was initially registered at clinicaltrials.gov in August 2009; however, enrollment was delayed by needed changes in principal investigator and study design, leading to initiation in March 2011. Ten consecutive patients signed an institutional review board–approved consent form and enrolled in the study. Of these, four were excluded (two unable to tolerate CMR, one required titration of PAH therapy before initiation, and one had pulmonary hypertension other than PAH). After the screening CMR study, the remaining six patients were started on carvedilol at a dose of 3.25 mg twice daily, and up-titrated every 2 weeks as tolerated, based on evaluation of vital signs, electrocardiogram, and symptoms (including dizziness, fatigue, diarrhea, palpitations, edema, or change in breathlessness). A second CMR was completed after 6 months. Baseline characteristics and changes over time of the study for the six patients are presented in Table 1 and Figure 1. All patients were stable on PAH therapy for 3 months before study entry and throughout the study. All patients had normal left ventricular function assessed by echocardiogram and CMR on study entry. The titration rate differed among patients, but no patient required cessation or downtitration. Reasons for slow titration included asymptomatic bradycardia (n = 1), asymptomatic hypotension (n = 1), and mild fatigue (n = 1). None of the patients experienced worsening dyspnea. Carvedilol add-on treatment (median tolerated dose, 18.75 mg twice daily; with three patients reaching 25 mg twice daily) led to a statistically significant improvement in RVEF and RV stroke volume, due to a reduction in RV end-systolic volume and without changes in RV end-diastolic volume. There was a significant increase in brain natriuretic peptide (BNP) levels (P = 0.046), which correlated with the improvement in RVEF (R = 10.83, P = 0.042). There was a nonsignificant trend (P = 0.22) toward increase in 6-minute walk distance (6MWD). One patient could not complete 6MWD testing at study completion because of an orthopedic injury, and one patient could not be scheduled for echocardiography at study completion despite multiple attempts. Figure 1 reports changes for each patient, as well as median change and interquartile range in RVEF, RV end-diastolic volume, RV end-systolic volume, and RV stroke volume. Figure E1 (see the online supplement) provides individual changes in LV ejection fraction, LV end-diastolic volume, LV stroke volume (all measured during CMR), tricuspid annular plane systolic excursion at M-mode echocardiography, 6MWD, and BNP plasma levels. The statistical analysis was performed with SPSS 19.0 (IBM, Armonk, NY), using the Wilcoxon test for paired data or the Spearman rank test for correlations. The initial data from this first pilot study suggest that treatment with carvedilol in patients with PAH receiving standard vasodilator drug therapy is feasible and safe. A major limitation of our study is the exclusion of four patients from the analysis, as explained previously. Our study suggests that treatment with carvedilol leads to significant improvement in RVEF and stroke volume, without changes in LV ejection fraction. There were no associated adverse events. Of the clinical marker measures, there was a nonsignificant trend toward an

Protein changes contributing to right ventricular cardiomyocyte diastolic dysfunction in pulmonary arterial hypertension.

Background Right ventricular (RV) diastolic function is impaired in patients with pulmonary arterial hypertension (PAH). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca2+ sensitivity underlie diastolic dysfunction in PAH. This study investigates protein modifications contributing to cellular diastolic dysfunction in PAH. Methods and Results RV samples from PAH patients undergoing heart‐lung transplantation were compared to non‐failing donors (Don). Titin stiffness contribution to RV diastolic dysfunction was determined by Western‐blot analyses using antibodies to protein‐kinase‐A (PKA), Cα (PKCα) and Ca2+/calmoduling‐dependent‐kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (P<0.0001). To test the functional relevance of PKA‐, PKCα‐, and CamKIIδ‐mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness while CamKIIδ had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca2+ sensitivity is mediated by sarcomeric troponin I (cTnI) phosphorylation. We observed increased unphosphorylated cTnI in PAH compared with donors (P<0.05) and reduced PKA‐mediated cTnI phosphorylation (Ser22/23) (P<0.001). Finally, alterations in Ca2+‐handling proteins contribute to RV diastolic dysfunction due to insufficient diastolic Ca2+ clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (P<0.05). Conclusions Increased titin stiffness, reduced cTnI phosphorylation, and altered levels of phosphorylation of Ca2+ handling proteins contribute to RV diastolic dysfunction in PAH.