Mart N. van der Plas

Pulmonary Endarterectomy Improves Dyspnea by the Relief of Dead Space Ventilation

BACKGROUND In chronic thromboembolic pulmonary hypertension (CTEPH), dyspnea is considered to be related to increased dead space ventilation caused by vascular obstruction. Pulmonary endarterectomy releases the thromboembolic obstruction, thereby improving regional pulmonary blood flow. We hypothesized that pulmonary endarterectomy reduces dead space ventilation and that this reduction contributes to attenuation of dyspnea symptoms. METHODS In this follow-up study we assessed dead space ventilation, hemodynamic severity of disease, and symptomatic dyspnea in 54 consecutive CTEPH patients, before and 1 year after pulmonary endarterectomy. Dead space ventilation was calculated using the Bohr-Enghoff equation. Dyspnea was assessed by Borg scores and the New York Heart Association functional classification. RESULTS Preoperatively, dead space ventilation was increased (0.40 +/- 0.07) and correlated with severity of disease (mean pulmonary artery pressure: r = 0.49, p < 0.001; total pulmonary resistance: r = 0.53, p < 0.001), and resting (r = 0.35, p < 0.05) and post-exercise Borg dyspnea scores (r = 0.44, p < 0.01). Postoperatively, dead space ventilation (0.33 +/- 0.08, p < 0.001) and dyspnea symptoms decreased significantly. Changes in symptomatic dyspnea were independently associated with changes in pulmonary hemodynamics and absolute dead space. CONCLUSIONS Dead space ventilation in CTEPH is increased and correlates significantly with hemodynamic severity of disease and dyspnea symptoms. Pulmonary endarterectomy decreases dead space ventilation. The induced change in dead space upon surgical removal of chronic thromboembolism contributes to the postoperative recovery of symptomatic dyspnea.

Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.

OBJECTIVES The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. BACKGROUND The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. METHODS We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). RESULTS The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 μm vs. 122.0 ± 0.4 μm; p = 0.02) and width (21.9 ± 0.2 μm vs. 25.3 ± 0.3 μm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005). CONCLUSIONS Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV.

Longitudinal Follow-Up of Six-Minute Walk Distance After Pulmonary Endarterectomy

BACKGROUND The 6-minute walk test is a useful tool to assess functional outcome after pulmonary endarterectomy (PEA) in chronic thromboembolic pulmonary hypertension. However, little is known about the longitudinal dynamics in functional improvement. We performed a longitudinal follow-up of 6-minute walk distance, New York Heart Association functional class, and echocardiography after PEA. METHODS We studied 71 patients with chronic thromboembolic pulmonary hypertension who underwent PEA. A 6-minute walk test and echocardiography were performed before PEA, at 3 months after, and at annual follow-up. At the time of this report, 52 patients had returned for 2-year follow-up, 32 for 3-year follow-up, 23 for 4-year follow-up, and 11 for 5-year follow-up. RESULTS Preoperatively, the 6-minute walk distance (6-MWD) correlated with hemodynamic severity of disease (mean pulmonary artery pressure: r = -0.55, p < 0.001); total pulmonary resistance: r = -0.59, p < 0.001) After PEA, 6-MWD increased from 440 ± 109 to 524 ± 83 meters at 1 year (n = 71, p < 0.001). Further improvement was observed from 523 ± 87 meters at 1 year to 536 ± 91 meters at 2 years (n = 52, p < 0.012). After 2 years, no further improvement was observed. At 1 year, the change in 6-MWD from baseline correlated significantly with the change observed in pulmonary hemodynamics. Changes in 6-MWD and hemodynamics were more pronounced in patients with residual pulmonary hypertension after PEA, despite the worse absolute outcome. CONCLUSIONS In patients with chronic thromboembolic pulmonary hypertension, 6-MWD showed a gradual improvement up to 2 years after PEA. Patients with residual pulmonary hypertension benefited most from treatment, despite the worse absolute outcome.

Pulmonary vascular limitation to exercise and survival in idiopathic pulmonary fibrosis

Pulmonary hypertension is frequently observed in advanced idiopathic pulmonary fibrosis (IPF) and is associated with poor prognosis. Cardiopulmonary exercise testing (CPET) can be used to detect less advanced pulmonary vascular impairment, and therefore may be of prognostic use. We studied the predictive value of non‐invasive exercise parameters that were associated with elevated systolic pulmonary artery pressure (sPAP) for survival in IPF patients.

Time course of restoration of systolic and diastolic right ventricular function after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension

BACKGROUND In chronic thromboembolic pulmonary hypertension, right ventricular (RV) pressure overload causes RV remodeling and dysfunction. Successful pulmonary endarterectomy (PEA) initiates restoration of RV remodeling and global function. Little is known on the restoration of systolic and diastolic RV function. Using transthoracic echocardiography, we studied the time course and extent of postoperative restoration of systolic and diastolic RV function. METHODS In chronic thromboembolic pulmonary hypertension (n = 55, 36 women, age 52 ± 14 years), transthoracic echocardiography was performed before PEA (pre-PEA) and 2 weeks, 3 months, and 1 year postoperatively. RESULTS Two weeks postoperatively, RV afterload and dimension had decreased significantly, without further improvement during follow-up. Global RV function, expressed by the myocardial performance index, showed a gradual improvement (from pre-PEA 0.58 ± 0.29 to 0.45 ± 0.38, 0.39 ± 0.19, and 0.37 ± 0.18). In contrast, 2 weeks after PEA systolic RV function, as assessed by tricuspid annular plane systolic velocity excursion and peak tricuspid annular systolic velocity of the RV, had worsened, with a subsequent incomplete restoration during follow-up: tricuspid annular plane systolic velocity excursion from 19.3 ± 5.0 to 12.4 ± 2.5, 15.3 ± 3.0, and 16.8 ± 2.9 mm and systolic velocity of the right ventricle from 11.4 ± 3.0 to 9.6 ± 2.0, 10.0 ± 1.8, and 10.3 ± 1.7 cm/s. Postoperative diastolic RV function also showed a biphasic response: tricuspid inflow-to-annulus ratio from 6.1 ± 3.0 to 9.5 ± 3.5, 6.8 ± 2.4, and 6.3 ± 2.2 cm/s. Dynamics and ultimate level of restoration of systolic and diastolic RV function were similar in patients with and without residual pulmonary hypertension. CONCLUSIONS Postoperative reduction in RV afterload caused an immediate improvement in RV dimension and global function. In contrast, systolic and diastolic RV function deteriorated after PEA with subsequently a gradual yet incomplete restoration during 1-year follow-up.

Bosentan Treatment Is Associated With Improvement of Right Ventricular Function and Remodeling in Chronic Thromboembolic Pulmonary Hypertension

Medical pretreatment before pulmonary endarterectomy (PEA) can optimize right ventricular (RV) function and may improve postoperative outcome in high‐risk patients. Using cardiac magnetic resonance imaging (cMRI), we determined whether the dual endothelin‐1 antagonist bosentan improves RV function and remodeling in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who waited for PEA.

Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients.

Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty‐four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS‐beta thalassemia) with a median age (interquartile range) of 26 (21–41) years underwent pulmonary function tests, CPET, chest x‐ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V′O2‐peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V′O2‐peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x‐ray inversely correlated with FVC (R = −0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better. Am. J. Hematol. 89:819–824, 2014.

Impaired cardiac reserve in asymptomatic patients with moderate pulmonary restenosis late after relief of severe pulmonary stenosis: Evidence for diastolic dysfunction

BACKGROUND Patients with moderate pulmonary valve restenosis late after relief of severe pulmonary stenosis (PS) may show decreased exercise tolerance. To elucidate the mechanism of decreased exercise tolerance, we evaluated cardiac response to physical and pharmacological stress in these patients and compared results with those of patients with native moderate PS. METHODS Twenty asymptomatic patients with moderate PS were divided into 2 groups: Group I (late after relief of severe PS, n=9), and Group II (no previous intervention, n=11). All patients underwent an exercise test, dobutamine stress (DS) MRI, and delayed contrast enhanced MRI. The response to physical and pharmacological stress was compared between both groups. RESULTS Group I showed impaired exercise capacity compared to Group II (VO2max=72.8% ± 3.5% vs. 102.5% ± 16.3%, p<0.001). During DS-MRI, RV-SV increased in Group II, but not in Group I (+13 ± 8 ml, -5 ± 8 ml, p<0.001). RV end-diastolic volume decreased significantly in Group I patients (p=0.006) while it did not significantly change in Group II patients. The amount of RV-SV increase (∆ RV-SV) correlated negatively with the period of moderate PS existence and the current PG in Group I (r=-0.82, p=0.007, and r=-0.68, p=0.04, respectively) but not in Group II (r=0.45, p=0.1, and r=0.40, p=0.2, respectively). Furthermore, ∆ RV-SV correlated negatively with the PG before valvuloplasty (r=-0.76, p=0.02). CONCLUSION Impaired exercise capacity in patients with moderate pulmonary restenosis after relief of severe PS is probably caused by inability to increase RV-SV. Disturbed RV filling properties, worsening in time, might play a role.

Chronic Thromboembolic Pulmonary Hypertension: Effects of Pulmonary Endarterectomy

Chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete resolution of the vascular obstruction associated with pulmonary embolism (PE) (Fedullo et al., 2001; Hoeper et al., 2006). This condition is considered to develop in 1-4 % of patients who survive an acute pulmonary embolism (Becattini et al., 2006; Fedullo et al., 2001; Pengo et al., 2004). Given the worldwide incidence of acute PE, approximately 1:1000, this indicates that even in a small country like the Netherlands, CTEPH may be diagnosed in up to 600 patients yearly. Most CTEPH patients present with gradually progressive exercise intolerance, typically portrayed as exertional dyspnea, fatigue, palpitations and/or on productive cough. In further stages of disease there may be signs of right ventricular failure, chest pain on exertion and syncope. The ensuing progressive right ventricular failure leads to progressive disability and early death ( Hoeper et al., 2004) . If left untreated, CTEPH is a progressive and life-threatening disorder; survival being proportional to the degree of pulmonary hypertension at diagnosis. In CTEPH patients with a mean pulmonary arterial pressure (mPAP) above 30 mmHg at time of diagnosis, 5-years survival is about 30%, whereas in patients with a mPAP above 50 mmHg the 5-years survival may be as low as 10% (Lewczuk et al., 2001; Riedel et al., 1982). Pulmonary endarterectomy (PEA) is the therapy of first choice for CTEPH patients with surgical accessible thrombi (Fedullo et al., 2001; Jamieson et al., 2000, 2003). PEA has been found to improve, and in many cases normalize pulmonary hemodynamics, functional status and long-term survival. PEA, however, does not come without potential risk. Reported periand direct postoperative mortality still ranges between 4.4% and 16% even in experienced centres (Archibald et al., 1999; Auger et al., 2007; Condliffe et al., 2008; Jamieson et al., 2000 ; Rubens et al., 2007). In this chapter we will discuss the pathophysiology of CTEPH. In particular, we will focus on the pathophysiology of the exercise limitation and dyspnea that is observed in these patients. Moreover, the effects of surgical treatment, that is the removal of the obstructing chronic thrombi by pulmonary endarterectomy, on cardiac function and the restoration of exercise tolerance and dyspnea will be discussed.

Decreased exercise capacity in 'asymptomatic' patients late after relief of severe pulmonary stenosis and moderate restenosis: evidence for diastolic dysfunction

Summary We concluded that close and regular follow up of asymptomatic patients with a history of previous intervention for PS and residual moderate PS by stress testing is recommended. This might reveal cardiac functional deterioration, which could be an indicator for the earlier intervention in this group of patients to avoid permanent cardiac dysfunction. Background Little is known about the management of moderate pulmonary restenosis after relief for severe pulmonary valve stenosis (PS).We evaluated cardiac response to physical and pharmacological stress late after relief of severe PS in these patients. Methods Twenty asymptomatic patients with moderate PS were divided into 2 groups: Group I (late after relief of severe PS, n = 9), and Group II (no previous intervention, n = 11). All patients underwent an exercise test, dobutamine stress (DS) MRI, and delayed contrast enhanced MRI. The response to physical and pharmacological stress was compared between both groups. Results Group I showed impaired exercise capacity compared to Group II (VO2max = 72.8 ± 3.5 vs. 103 ± 16%, p = 0.01). At rest, both groups showed normal systolic function. Majority of Group I patients have impaired RV diastolic function (82% vs. 33%, P = 0.004). During DSMRI, right ventricular stroke volume (RV-SV) increased in Group II but not in Group I (+13 ± 8 ml, - 5 ± 8 ml, p < 0.001). In Group I, RV peak flow rate ratio correlated positively with Δ RV-SV (r = 0.58, p = 0.01), and negatively with the period of moderate PS existence (r = -0.77, p = 0.01- Figure 1). VO2max and O2-pulse were correlated with RV-SV response to DS-MRI. Conclusions