Clinical-imaging-pathological correlation in pulmonary hypertension associated with left heart disease.

Pulmonary hypertension (PH) is highly prevalent in patients with left heart disease (LHD) and negatively impacts prognosis. The most common causes of PH associated with LHD (PH-LHD) are left heart failure and valvular heart disease. In LHD, passive backward transmission of increased left-sided filling pressures leads to isolated post-capillary PH. Additional pulmonary vasoconstriction and remodelling lead to a higher vascular load and combined pre- and post-capillary PH. The increased afterload leads to right ventricular dysfunction and failure. Multimodality imaging of the heart plays a central role in the diagnostic work-up and follow-up of patients with PH-LHD. Echocardiography provides information about the estimated pulmonary artery pressure, morphology and function of the left and right side of the heart, and valvular abnormalities. Cardiac magnetic resonance imaging is the gold standard for volumetric measurements and provides myocardial tissue characterisation. Computed tomography of the thorax may show general features of PH and/or LHD and is helpful in excluding other PH causes. Histopathology reveals a spectrum of pre- and post-capillary vasculopathy, including intimal fibrosis, media smooth muscle cell hyperplasia, adventitial fibrosis and capillary congestion. In this paper, we provide an overview of clinical, imaging and histopathological findings in PH-LHD based on three clinical cases.

Treatment response in patients with idiopathic pulmonary arterial hypertension and a severely reduced diffusion capacity.

Patients with idiopathic pulmonary arterial hypertension (IPAH) and a reduced diffusion capacity of the lung for carbon monoxide (DLCO) have a worse survival compared to IPAH patients with a preserved DLCO. Whether this poor survival can be explained by unresponsiveness to pulmonary hypertension (PH)-specific vasodilatory therapy is unknown. Therefore, the aim of this study was to evaluate the hemodynamic and cardiac response to PH-specific vasodilatory therapy in patients with IPAH and a reduced DLCO. Retrospectively, we studied treatment naïve hereditary and IPAH patients diagnosed between January 1990 and May 2015 at the VU University Medical Center. After exclusion of participants without available baseline DLCO measurement or right heart catheterization data and participants carrying a BMPR2 mutation, 166 participants could be included in this study. Subsequently, hemodynamics, cardiac function, exercise capacity, and oxygenation at baseline and after PH-specific vasodilatory therapy were compared between IPAH patients with a preserved DLCO (DLCO >62%), IPAH patients with a moderately reduced DLCO (DLCO 43-62%), and IPAH patients with a severely reduced DLCO (DLCO <43%). Baseline hemodynamics and right ventricular function were not different between groups. Baseline oxygenation was worse in patients with IPAH and a severely reduced DLCO. Hemodynamics and cardiac function improved in all groups after PH-specific vasodilatory therapy without worsening of oxygenation at rest or during exercise. Patients with IPAH and a severely reduced DLCO show a similar response to PH-specific vasodilatory therapy in terms of hemodynamics, cardiac function, and exercise capacity as patients with IPAH and a moderately reduced or preserved DLCO.

Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle.

BACKGROUND: The effect of a mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension is unknown. Therefore, we investigated RV function in patients who have pulmonary arterial hypertension with and without the BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular tissue. METHODS AND RESULTS: In total, 95 patients with idiopathic or familial pulmonary arterial hypertension were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, and 67 patients did not have a BMPR2 mutation. In vivo measurements were assessed using right heart catheterization and cardiac MRI. Despite a similar mean pulmonary artery pressure (noncarriers 54±15 versus mutation carriers 55±9 mm Hg) and pulmonary vascular resistance (755 [483-1043] versus 931 [624-1311] dynes·s(-1)·cm(-5)), mutation carriers presented with a more severely compromised RV function (RV ejection fraction: 37.6±12.8% versus 29.0±9%: P<0.05; cardiac index 2.7±0.9 versus 2.2±0.4 L·min(-1)·m(-2)). Differences continued to exist after treatment. To investigate the role of transforming growth factor ß and bone morphogenetic protein receptor II signaling, human RV and left ventricular tissue were studied in controls (n=6), mutation carriers (n=5), and noncarriers (n=11). However, transforming growth factor ß and bone morphogenetic protein receptor II signaling, and hypertrophy, apoptosis, fibrosis, capillary density, inflammation, and cardiac metabolism, as well, were similar between mutation carriers and noncarriers. CONCLUSIONS: Despite a similar afterload, RV function is more severely affected in mutation carriers than in noncarriers. However, these differences cannot be explained by a differential transforming growth factor ß, bone morphogenetic protein receptor II signaling, or cardiac adaptation.

Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival.

RATIONALE: Patients with pulmonary hypertension due to left heart disease (PH-LHD) and a diastolic pulmonary vascular pressure gradient ≥ 7 mm Hg, representing PH out of proportion to pulmonary arterial wedge pressure, have pulmonary vascular disease and increased mortality. Little information exists on this condition, recently labeled as "combined pre- and post-capillary PH" (Cpc-PH). OBJECTIVES: To investigate epidemiology, risk factors, right ventricular function, and outcomes in patients with chronic heart failure and Cpc-PH. METHODS: The study population was identified from a retrospective chart review of a clinical database of 3,107 stable patients who underwent first diagnostic right heart catheterization and from a prospective cohort of 800 consecutive patients at a national university-affiliated tertiary center. MEASUREMENTS AND MAIN RESULTS: The retrospective cohort had 664 patients with systolic heart failure (SHF) and 399 patients with diastolic heart failure (DHF), 12% of whom were classified as Cpc-PH. The prospective cohort had 172 patients with SHF (14% Cpc-PH) and 219 patients with DHF (12% Cpc-PH). Chronic obstructive pulmonary disease (P = 0.034) and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio (P = 0.015) predicted Cpc-PH in SHF. Younger age (P = 0.004), valvular heart disease (P = 0.046), and the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio predicted Cpc-PH in DHF (P = 0.016). Right ventricular-pulmonary vascular coupling was worse in Cpc-PH patients (end-systolic elastance to effective arterial elastance [Ees/Ea]: SHF: 1.05 ± 0.25; P = 0.002; DHF: 1.17 ± 0.27; P = 0.027) than in those with isolated post-capillary PH (Ees/Ea: SHF: 1.52 ± 0.51; DHF: 1.45 ± 0.29). CONCLUSIONS: Cpc-PH is rare in chronic heart failure. Right ventricular-pulmonary vascular coupling is poor in Cpc-PH and could be one explanation for dismal outcomes.

Clinical relevance of right ventricular diastolic stiffness in pulmonary hypertension.

Right ventricular (RV) diastolic stiffness is increased in pulmonary arterial hypertension (PAH) patients. We investigated whether RV diastolic stiffness is associated with clinical progression and assessed the contribution of RV wall thickness to RV systolic and diastolic stiffness. Using single-beat pressure-volume analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV--arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed) in controls (n=15), baseline PAH patients (n=63) and treated PAH patients (survival >5 years n=22 and survival <5 years n=23). We observed an association between Eed and clinical progression, with baseline Eed >0.53 mmHg·mL(-1) associated with worse prognosis (age-corrected hazard ratio 0.27, p=0.02). In treated patients, Eed was higher in patients with survival <5 years than in patients with survival >5 years (0.91±0.50 versus 0.53±0.33 mmHg·mL(-1), p<0.01). Wall-thickness-corrected Eed values in PAH patients with survival >5 years were not different from control values (0.76±0.47 versus 0.60±0.41 mmHg·mL(-1), respectively, not significant), whereas in patients with survival <5 years, values were significantly higher (1.52±0.91 mmHg·mL(-1), p<0.05 versus controls). RV diastolic stiffness is related to clinical progression in both baseline and treated PAH patients. RV diastolic stiffness is explained by the increased wall thickness in patients with >5 years survival, but not in those surviving <5 years. This suggests that intrinsic myocardial changes play a distinctive role in explaining RV diastolic stiffness at different stages of 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.

Right ventricular diastolic impairment in patients with pulmonary arterial hypertension.

BACKGROUND: The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients. METHODS AND RESULTS: Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean ± SEM. RV diastolic stiffness (ß) was significantly increased in PAH patients (PAH, 0.050 ± 0.005 versus control, 0.029 ± 0.003; P<0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453 ± 31 µm² versus control, 218 ± 21 µm²; P<0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6 ± 0.7% versus control, 7.2 ± 0.6%; P<0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (>200%; Pinteraction <0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78 ± 0.07 versus control, 0.91 ± 0.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16 ± 0.01 arbitrary units versus control, 0.20 ± 0.01 arbitrary units; P<0.05). CONCLUSIONS: RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.

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.

Accurate assessment of load-independent right ventricular systolic function in patients with pulmonary hypertension.

BACKGROUND: End-systolic elastance (E(es)), a load-independent measure of ventricular function, is of clinical interest for studies of the right ventricle (RV) in patients with pulmonary arterial hypertension (PAH). The objective of this study was to determine whether, in PAH patients, E(es) can be estimated from mean pulmonary artery pressure (mPAP) and end-systolic volume (ESV) only. METHODS: Right heart catheterization was used to measure mPAP. Maximal isovolumic pressure (P(iso)) was estimated from RV pressure curves with the so-called single-beat method. Cardiac magnetic resonance imaging (MRI) was used to assess RV end-diastolic and end-systolic volumes (EDV and ESV). E(es) was then calculated as: E(es) = (P(iso)-mPAP) / (EDV-ESV), and as E(es,V0 = 0) = mPAP/ESV (simplified method, with V0 = 0, is negligible volume at zero pressure). Right ventricular volume at zero pressure (V(0)) was then defined as the intercept of the end-systolic pressure-volume relation (single-beat method) with the horizontal axis. RESULTS: E(es,V0 = 0) was significantly lower compared with E(es) (0.61 vs 1.34 mm Hg/ml, respectively, p<0.01). A modified Bland-Altman analysis showed a contractility-dependent difference between E(es,V0 = 0) and E(es). Moreover, V(0) ranged from-8 up to 171 ml, and a moderate and good correlation was found between V(0) and EDV, and V(0) and ESV, respectively (r = 0.65 and r = 0.87, p< 0.01). CONCLUSIONS: These findings show that V(0) is dependent on RV dilation. Therefore, the assumption that V(0) is negligible in PAH is incorrect. Consequently, for an accurate assessment of load-independent RV systolic function, RV volumes and pressure curves are required.

Cardiopulmonary exercise testing reveals onset of disease and response to treatment in a case of heritable pulmonary arterial hypertension.

Patients affected by pulmonary arterial hypertension (PAH) show a typical pattern of abnormalities on cardiopulmonary exercise testing (CPET). However, CPET is not routinely used as a screening method. We discuss a patient with hereditary PAH in whom CPET revealed onset of disease. Furthermore, we show that the abnormalities observed can improve in part by PAH-specific treatment.

Ventilatory and cardiocirculatory exercise profiles in COPD: the role of pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a well-recognized complication of COPD. The impact of PH on exercise tolerance is largely unknown. We evaluated and compared the circulatory and ventilatory profiles during exercise in patients with COPD without PH, with moderate PH, and with severe PH. METHODS: Forty-seven patients, GOLD (Global Initiative for Chronic Obstructive Lung Disease)stages II to IV, underwent cardiopulmonary exercise testing and right-sided heart catheterization at rest and during exercise. Patients were divided into three groups based on mean pulmonary artery pressure (mPAP) at rest: no PH (mPAP, < 25 mm Hg), moderate PH (mPAP, 25-39 mm Hg),and severe PH (mPAP, ≥ 40 mm Hg). Mixed venous oxygen saturation (S VO 2 ) was used for evaluating the circulatory reserve. Pa CO 2 and the calculated breathing reserve were used for evaluation of the ventilatory reserve. RESULTS: Patients without PH (n = 24) had an end-exercise S VO 2 of 48%± 9%, an increasing Pa CO 2 with exercise, and a breathing reserve of 22% ± 20%. Patients with moderate PH (n = 14) had an exercise S VO 2 of 40% ± 8%, an increasing Pa CO 2 , and a breathing reserve of 26% ± 15%. Patients with severe PH (n =9) had a significantly lower end-exercise S VO 2 (30% ± 6%), a breathing reserve of 37% ± 11%, and an absence of Pa CO 2 accumulation. CONCLUSION: Patients with severe PH showed an exhausted circulatory reserve at the end of exercise.A profile of circulatory reserve in combination with ventilatory impairments was found inpatients with COPD and moderate or no PH. The results suggest that pulmonary vasodilation might only improve exercise tolerance in patients with COPD and severe PH.

Right atrial pressure affects the interaction between lung mechanics and right ventricular function in spontaneously breathing COPD patients.

INTRODUCTION: It is generally known that positive pressure ventilation is associated with impaired venous return and decreased right ventricular output, in particular in patients with a low right atrial pressure and relative hypovolaemia. Altered lung mechanics have been suggested to impair right ventricular output in COPD, but this relation has never been firmly established in spontaneously breathing patients at rest or during exercise, nor has it been determined whether these cardiopulmonary interactions are influenced by right atrial pressure. METHODS: Twenty-one patients with COPD underwent simultaneous measurements of intrathoracic, right atrial and pulmonary artery pressures during spontaneous breathing at rest and during exercise. Intrathoracic pressure and right atrial pressure were used to calculate right atrial filling pressure. Dynamic changes in pulmonary artery pulse pressure during expiration were examined to evaluate changes in right ventricular output. RESULTS: Pulmonary artery pulse pressure decreased up to 40% during expiration reflecting a decrease in stroke volume. The decline in pulse pressure was most prominent in patients with a low right atrial filling pressure. During exercise, a similar decline in pulmonary artery pressure was observed. This could be explained by similar increases in intrathoracic pressure and right atrial pressure during exercise, resulting in an unchanged right atrial filling pressure. CONCLUSIONS: We show that in spontaneously breathing COPD patients the pulmonary artery pulse pressure decreases during expiration and that the magnitude of the decline in pulmonary artery pulse pressure is not just a function of intrathoracic pressure, but also depends on right atrial pressure.