Maxim Hardziyenka

Right Ventricular Failure Following Chronic Pressure Overload Is Associated With Reduction in Left Ventricular Mass : Evidence for Atrophic Remodeling

OBJECTIVES We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. BACKGROUND The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. METHODS We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. RESULTS At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. CONCLUSIONS RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.

Clinical ResearchHeart FailureRight Ventricular Failure Following Chronic Pressure Overload Is Associated With Reduction in Left Ventricular Mass: Evidence for Atrophic Remodeling

OBJECTIVES We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy. BACKGROUND The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction. METHODS We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization. RESULTS At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV. CONCLUSIONS RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.

How valid are animal models to evaluate treatments for pulmonary hypertension

Various animal models of pulmonary hypertension (PH) exist, among which injection of monocrotaline (MCT) and exposure to hypoxia are used most frequently. These animal models have not only been used to characterize the pathophysiology of PH and its sequelae such as right ventricular hypertrophy and failure, but also to test novel therapeutic strategies. This manuscript summarizes the available treatment studies in animal models of PH, and compares the findings to those obtained in patients with PH. The analysis shows that all approaches which have proven successful in patients, most notably prostacyclin and its analogs and endothelin receptor antagonists, are also effective in various animal models. However, the opposite it not always true. Therefore, promising results in animals have to be interpreted carefully until confirmed in clinical studies.

Early inflammatory response during the development of right ventricular heart failure in a rat model

Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression.

Right ventricular pacing improves haemodynamics in right ventricular failure from pressure overload: an open observational proof-of-principle study in patients with chronic thromboembolic pulmonary hypertension

AIMS Right ventricular (RV) failure in patients with chronic thromboembolic pulmonary hypertension (CTEPH), and other types of pulmonary arterial hypertension is associated with right-to-left ventricle (LV) delay in peak myocardial shortening and, consequently, the onset of diastolic relaxation. We aimed to establish whether RV pacing may resynchronize the onsets of RV and LV diastolic relaxation, and improve haemodynamics. METHODS AND RESULTS Fourteen CTEPH patients (mean age 63.7 ± 12.0 years, 10 women) with large (≥60 ms) RV-to-LV delay in the onset of diastolic relaxation (DIVD, diastolic interventricular delay) were studied. Temporary RV pacing was performed by atrioventricular (A-V) sequential pacing with incremental shortening of A-V delay to advance RV activation. Effects were assessed using tissue Doppler echocardiography and LV pressure-conductance catheter measurements in a subset of patients. Compared with right atrial pacing, RV pacing at optimal A-V delay (average 140 ± 22 ms, range 120-180 ms) resulted in significant DIVD reduction (59 ± 19 to 3 ± 22 ms, P < 0.001), and increase in LV stroke volume as measured by LV outflow tract velocity-time integral (14.9 ± 2.8 to 16.9 ± 3.0 cm, P < 0.001), along with enhanced global RV contractility and LV diastolic filling. CONCLUSION Right-to-left ventricle resynchronization of the onset of diastolic relaxation results in stroke volume increase in CTEPH patients. Whether RV pacing may be a novel therapeutic target in RV failure following chronic pressure overload remains to be investigated.

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.

Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

Right ventricular (RV) function is the major determinant of survival in patients with pulmonary hypertension. Yet, the pathophysiologic basis of RV disease is unresolved. We aimed to study the role of apoptosis in RV disease by monitoring it serially during disease progression using in vivo 99mTc-annexin-V (99mTc-annexin) scintigraphy and study whether the reduction in apoptosis resulting from chronic treatment with valsartan can be detected by 99mTc-annexin scintigraphy. Methods: RV disease after pulmonary hypertension was induced by monocrotaline injection in rats. The following 3 groups were studied: rats treated with monocrotaline (monocrotaline rats), rats treated with monocrotaline plus valsartan (valsartan rats), and age-matched controls (control rats). Serial echocardiography and in vivo 99mTc-annexin scintigraphy were performed. Apoptosis was confirmed by 99mTc-annexin autoradiography and terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling. Fibrosis was assessed by picrosirius red staining. Results: In monocrotaline rats, in vivo 99mTc-annexin uptake peaked early and declined thereafter but remained elevated, compared with baseline. These stage-dependent changes of in vivo 99mTc-annexin uptake were paralleled by changes in autoradiography and terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling. Valsartan rats had longer RV failure–free survival than did monocrotaline rats and had reduced apoptosis. These changes were accompanied by commensurate delays in RV hypertrophy and RV dilation. Valsartan rats also had less fibrosis than monocrotaline rats at all disease stages. Conclusion: RV disease progression is associated with an early increase in RV apoptosis, as monitored using serial in vivo 99mTc-annexin scintigraphy. Delay in RV disease progression by valsartan is accompanied by reduction in RV apoptosis. Apoptosis plays a role in RV disease progression and may be assessed by serial in vivo 99mTc-annexin scintigraphy.

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.

Duration of right ventricular contraction predicts the efficacy of bosentan treatment in patients with pulmonary hypertension.

AIMS In patients with pulmonary hypertension (PH), elevated endothelin-1 levels are associated with prolonged duration of right ventricular (RV) contraction, which induces leftward ventricular septal bowing with impaired left diastolic filling. We hypothesized that baseline RV contraction duration predicts efficacy of endothelin receptor antagonist, bosentan. METHODS AND RESULTS Eighteen PH patients (age 57, range 35-79 years, 33% male) received bosentan. Six minute walk distance (6-MWD) and echocardiography were performed at baseline and after 1 year follow-up. After 1 year of treatment, 6-MWD increased (mean 60 +/- 41 m) in 67% of patients (responders). Baseline RV contraction duration was longer in responders, compared with non-responders (612 +/- 66 vs. 514 +/- 23 ms; P < 0.01). A baseline RV contraction duration >550 ms was associated with improved 6-MWD (sensitivity 83%, specificity 83%; P < 0.01). CONCLUSION An improvement of 6-MWD during bosentan treatment was associated with a decrease in RV contraction duration and could be predicted by a baseline RV contraction duration >550 ms.

Echocardiographic determinants of the clinical condition in patients with a systemic right ventricle.

Background: Ventricular systolic and diastolic function, as measured by echocardiography, are diminished in patients with a systemic right ventricle (RV). As the clinical implications of these finding remained unknown, we aimed to identify echocardiographic parameters of systolic and diastolic ventricular function that are independent determinants of the clinical condition in these patients. Methods: Forty‐six adult patients (61% male; mean age 33 [range 18–69] years) with a systemic RV underwent echocardiography to assess qualitative and quantitative systolic and diastolic function of the systemic RV and the subpulmonary left ventricle (LV). Uni‐ and multivariate linear regression analyses were performed to identify independent echocardiographic determinants for NYHA class, maximal exercise capacity (V’O2peak) and NT‐proBNP levels. Results: We found qualitative assessment of RV and LV function to be significantly associated with NYHA class (RV: β= 0.26; P = 0.05 and LV: β= 0.82; P < 0.01), V’O2peak (RV: β=−10.4; P < 0.05 and LV: β=−18.4; P < 0.05) and NT‐proBNP levels (RV: β= 0.58; P < 0.01 and LV: β= 1.40; P < 0.001). Tricuspid annulus plane systolic excursion (TAPSE) was significantly associated with NYHA class (β=−0.92; P = 0.001), V’O2peak (β= 18.5; P = 0.05), and serum NT‐proBNP levels (β=−1.00; P < 0.05). Associations between quantitative parameters of systolic subpulmonary LV function and clinical parameters were less distinct. We found no associations between RV and LV diastolic function and clinical parameters. Conclusions: Qualitative function of the systemic RV and the subpulmonary LV, and TAPSE, are determinants of clinical condition in patients with a systemic RV. These patients’ clinical condition could not be determined by echocardiographically measured diastolic RV function, and systolic and diastolic LV function. (Echocardiography 2010;27:1247‐1255)