Exercise Capacity In Pulmonary Hypertension Research Articles

Reduced exercise capacity occurs before intrinsic skeletal muscle dysfunction in experimental rat models of pulmonary hypertension.

Reduced exercise capacity in pulmonary hypertension (PH) significantly impacts quality of life. However, the cause of reduced exercise capacity in PH remains unclear. The objective of this study was to investigate whether intrinsic skeletal muscle changes are causative in reduced exercise capacity in PH using preclinical PH rat models with different PH severity. PH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats with one dose of SU5416 (20 mg/kg) injection, followed by 3 weeks of hypoxia and additional 0-4 weeks of normoxia exposure. Control s rats were injected with vehicle and housed in normoxia. Echocardiography was performed to assess cardiac function. Exercise capacity was assessed by VO2 max. Skeletal muscle structural changes (atrophy, fiber type switching, and capillary density), mitochondrial function, isometric force, and fatigue profile were assessed. In SD rats, right ventricular systolic dysfunction is associated with reduced exercise capacity in PH rats at 7-weektimepoint in comparison to control rats, while no changes were observed in skeletal muscle structure, mitochondrial function, isometric force, or fatigue profile. CDF rats at 4-weektimepoint developed a more severe PH and, in addition to right ventricular dysfunction, the reduced exercise capacity in these rats is associated with skeletal muscle atrophy; however, mitochondrial function, isometric force, and fatigue profile in skeletal muscle remain unchanged. Our data suggest that cardiopulmonary impairments in PH are the primary cause of reduced exercise capacity, which occurs before intrinsic skeletal muscle dysfunction.

Abstract P3030: Reduced Exercise Capacity Occurs Before Intrinsic Changes In Skeletal Muscle In Experimental Rat Models Of Pulmonary Hypertension

Background: Pulmonary Hypertension (PH) is defined with mean pulmonary arterial pressure greater than 20 mmHg at rest. Reduced exercise capacity in PH significantly impacts quality of life. While the cause of reduced exercise capacity in PH remains unclear, it is suggested that regional skeletal muscle adaptions may play a role. The objective of this study was to investigate whether intrinsic changes in skeletal muscle determine exercise capacity in PH using preclinical PH rat models with different PH severity. Methods and Results: PH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats with one dose of SU5416 (20 mg/kg) injection, followed by 3 weeks of hypoxia and additional 1-4 weeks of normoxia exposure. Rats injected with vehicle and housed in normoxia were used as controls. Echocardiography and hemodynamics were performed to assess PH and cardiac function. Exercise capacity was assessed by VO 2 max. Skeletal muscle structural changes (atrophy, fiber type switch, and capillary density), mitochondrial function, isometric force, and fatigue profile were assessed in soleus muscles. In SD rats, right ventricular systolic dysfunction is associated with reduced exercise capacity in PH rats at 7 weeks timepoint in comparison to control rats, while no changes were observed in skeletal muscle structure, mitochondrial function, isometric force, or fatigue profile. CDF rats at 4 weeks timepoint developed a more severe PH and, in addition to right ventricular dysfunction, the reduced exercise capacity in these rats is associated with skeletal muscle atrophy; however, mitochondrial function, isometric force, and fatigue profile in skeletal muscle remain unchanged. Conclusions: Our study demonstrated that reduced exercise capacity in PH occurs before intrinsic changes in skeletal muscle, suggesting that alterations in skeletal muscle are not causative to exercise intolerance in PH, while they may worsen exercise capacity collaboratively with primary factors in the late stage of PH. In addition, our study supports the notion that improving central cardiopulmonary impairments at the early stage of PH may be critical in preventing or delaying the occurrence of exercise limitation in settings of PH.

The effects of pulmonary hypertension on skeletal muscle oxygen pressures in contracting rat spinotrapezius muscle.

What is the central question of this study? Does impairment in the dynamics of O2 transport in skeletal muscle during a series of contractions constitute a potential mechanism underlying reduced exercise capacity in pulmonary hypertension? What is the main finding and its importance? Pulmonary hypertension compromises the dynamic matching of skeletal muscle O2 delivery-to-utilization following contraction onset in the rat spinotrapezius muscle. These results implicate a role for vascular dysfunction in the slow kinetics and exercise intolerance present in pulmonary hypertension. Pulmonary hypertension (PH) is characterized by pulmonary vascular dysfunction and exercise intolerance due, in part, to compromised pulmonary and cardiac function. We tested the hypothesis that there are peripheral (i.e., skeletal muscle) aberrations in O2 delivery ( )-to-O2 utilization ( ) matching and vascular control that might help to explain poor exercise tolerance in PH. Furthermore, we investigated the peripheral effects of nitric oxide (NO) in attenuating these decrements. Male Sprague-Dawley rats (n=21) were administered monocrotaline (MCT; 50mg/kg, i.p.) to induce PH. Disease progression was monitored via echocardiography. Phosphorescence quenching determined the O2 partial pressure in the interstitial space ( ) in the spinotrapezius muscle at rest and during contractions under control (SNP-) and NO-donor (sodium nitroprusside, SNP+) conditions. MCT rats displayed right ventricular (RV) hypertrophy (right ventricle/(left ventricle + septum): 0.44 (0.13) vs. 0.28 (0.05)), pulmonary congestion, increased RV systolic pressure (48 (18) vs. 20 (8) mmHg) and arterial hypoxaemia ( : 64 (9) vs. 82 (9) mmHg) compared to healthy controls (HC) (P<0.05). was significantly lower in MCT rats during the first 30s of SNP- contractions. SNP superfusion elevated in both groups; however, MCT rats demonstrated a lower throughout SNP+ contractions versus HC (P<0.05). Thus, for small muscle mass exercise in MCT rats, muscle oxygenation is impaired across the rest-to-contractions transition and exogenous NO does not raise the -to- ratio in contracting muscle to the same levels as HC. These data support muscle -to- mismatch as a potential contributor to slow kinetics and therefore exercise intolerance in PH and suggest peripheral vascular dysfunction or remodelling as a possible mechanism.

Impact of grip strength and balance function on the exercise capacity in pulmonary hypertension

Abstract Funding Acknowledgements Type of funding sources: None. 【Background】 Patients with pulmonary hypertension (PH) suffer from poor exercise capacity due to impaired oxygenation or reduced cardiac output. However, the relationship between exercise capacity and physical functions remains unclear. 【Purpose】 The purpose of this study is to investigate the relationship between exercise capacity and physical functions in pulmonary hypertension. 【Methods】 From February 2018 to June 2020, 94 patients (61.3 ± 14.7 years old, 69.1% females) with group 1/3/4/5 PH underwent cardiac catheterization, 6-minute walking distance (6MWD), and physical function measurements simultaneously. The physical functions was measured using muscle strength (grip strength, knee extension muscle strength), balance function (one leg standing time), and short physical performance battery (SPPB). Exercise capacity was measured by 6MWD. 【Results】 The study cohort consists of 22/8/60/4 (23.4%/8.5%/63.8%/4.3%) patients with group 1/3/4/5 PH, respectively. The average age of each group was 50.7/64.7/63.1/66.0 years old, respectively. A total of 194 measurements of physical functions were evaluated from 94 patients and employed in multivariate logistic regression analysis using adaptive-LASSO methods with the 6MWD (476.2 ± 107.5m) as a dependent variable. WHO functional class (class II: standardized β=-0.35, 95% confidence interval (CI) [-0.54 - -0.16], p &amp;lt; 0.001), class III: β=-0.60, 95%CI [-0.90 - -0.30], p &amp;lt; 0.001), mixed venous oxygen saturation (SvO2: β=0.11, 95%CI [0.03 - 0.19], p = 0.008), pulmonary vascular resistance (PVR: β=-0.16, 95%CI [-0.25 - -0.07], p &amp;lt; 0.001), grip strength (β=0.20, 95%CI [0.09 - 0.31], p &amp;lt; 0.001), one leg standing time (β=0.10, 95%CI [0.00 - 0.20], p = 0.049) , and 4m gait speed test (β=-0.28, 95%CI [-0.36 - -0.19], p &amp;lt; 0.001) were associated with 6MWD. 【Conclusions】 Grip strength and balance function, as well as SvO2 and PVR, were associated with the exercise capacity in pulmonary hypertension.

Two-dimensional speckle tracking echocardiography assessed right ventricular function and exercise capacity in pre-capillary pulmonary hypertension.

Resting two-dimensional speckle tracking echocardiography (2D-STE) identified right ventricular (RV) systolic function were reported to predict exercise capacity in pulmonary hypertension (PH) patients, but little attention had been payed to 2D-STE detected RV diastolic function. Therefore, we aim to elucidate and compare the relations between 2D-STE identified RV diastolic/systolic functions and peak oxygen consumption (PVO2) determined by cardiopulmonary exercise testing (CPET) in pre-capillary PH. 2D-STE was performed in 66 pre-capillary PH patients and 28 healthy controls. Linear correlation and multivariate regression analyses were performed to evaluate and compare the relations between RV 2D-STE parameters and PVO2. Receiver operating characteristic curves were used to compare the predictive value of 2D-STE parameters in predicting the cut-off-PVO2 < 11ml/min/kg. There were significant differences of all the 2D-STE parameters between PH patients and healthy controls. In patients, RV-peak global longitudinal strain (GLS, rs = - 0.498, P < 0.001), RV- peak systolic strain rate (GSRs, rs = - 0.537, P < 0.001) and RV- peak early diastolic strain rate (GSRe, rs = 0.527, P < 0.001) significantly correlated with PVO2, but no significant correlation was observed between RV- peak late diastolic strain rate (GSRa, rs = 0.208, P = 0.093) and PVO2. The first multivariate regression analysis of clinical data without echocardiographic parameters identified WHO functional class, NT-proBNP and BMI as independent predictors of PVO2 (Model-1, adjusted r2 = 0.421, P < 0.001); Then we added conventional echocardiographic parameters and 2D-STE parameters to the clinical data, identified S,(Model-2,adjusted r2 = 0.502, P < 0.001), RV-GLS (Model-3, adjusted r2 = 0.491, P < 0.001), RV-GSRe (Model-4, adjusted r2 = 0.500, P < 0.001) and RV-GSRs (Model-5, adjusted r2 = 0.519, P < 0.001) as independent predictors of PVO2, respectively. The predictive power was increased, and Model-5 including RV-GSRs showed the highest predictive capability. ROC curves found RV-GSRs expressed the strongest predictive value (AUC = 0.88, P < 0.001), and RV-GSRs > - 0.65/s had a 88.2% sensibility and 82.2% specificity to predict PVO2 < 11ml/min/kg. 2D-STE assessed RV function improves the prediction of exercise capacity represented by PVO2 in pre-capillary PH.

Echocardiography during preload stress for evaluation of right ventricular contractile reserve and exercise capacity in pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by marked and sustained elevation of pulmonary vascular resistance and pulmonary artery pressure, and subsequent right-sided heart failure. Right ventricular (RV) function and exercise capacity have been recognized as important prognostic factors for PH. Our aim was to investigate RV contractile reserve and exercise capacity during a leg-positive pressure (LPP) maneuver. The study population comprised 43 PH patients and 17 normal controls. All patients underwent echocardiography at rest and during LPP stress. Exercise capacity was assessed by 6-minute walk distance for PH patients. RV relative wall thickness was calculated from dividing by RV free wall thickness by basal RV linear dimensions at end-diastole. RV function was calculated by averaging peak speckle-tracking longitudinal strain from the RV free wall. RV contractile reserve was assessed as the difference in RV free wall strain at rest and during LPP stress. Changes in left ventricular stroke volume (ΔSV) during LPP stress were also calculated. ΔSV and RV contractile reserve of PH patients were significantly lower than of controls (3.6±6.0mL vs 8.5±2.3mL, and 8.2±11.9% vs 14.5±6.6%; both P<0.01). RV contractile reserve of PH patients with ΔSV <3.3mL was significantly lower than of PH patients with ΔSV >3.3mL (3.9±13.2% vs 12.3±8.9%; P=0.02). ΔSV had also significant correlation with 6-minute walk distance (r=0.42, P=0.006). Multivariate regression analysis showed that RV relative wall thickness was an independent determinant parameter of ΔSV during LPP stress for PH patients (β=3.2, P=0.003). Preload stress echocardiography in response to LPP maneuver, a noninvasive and easy-to-use procedure for routine clinical use, proved to be useful for the assessment of RV contractile reserve and exercise capacity of PH patients.

Hypoxia induced mitogenic factor (HIMF) triggers angiogenesis by increasing interleukin-18 production in myoblasts

Inflammatory myopathy is a rare autoimmune muscle disorder. Treatment typically focuses on skeletal muscle weakness or inflammation within muscle, as well as complications of respiratory failure secondary to respiratory muscle weakness. Impaired respiratory muscle function contributes to increased dyspnea and reduced exercise capacity in pulmonary hypertension (PH), a debilitating condition that has few treatment options. The initiation and progression of PH is associated with inflammation and inflammatory cell recruitment and it is established that hypoxia-induced mitogenic factor (HIMF, also known as resistin-like molecule α), activates macrophages in PH. However, the relationship between HIMF and inflammatory myoblasts remains unclear. This study investigated the signaling pathway involved in interleukin-18 (IL-18) expression and its relationship with HIMF in cultured myoblasts. We found that HIMF increased IL-18 production in myoblasts and that secreted IL-18 promoted tube formation of the endothelial progenitor cells. We used the mouse xenograft model and the chick chorioallantoic membrane assay to further explore the role of HIMF in inflammatory myoblasts and angiogenesis in vivo. Thus, our study focused on the mechanism by which HIMF mediates IL-18 expression in myoblasts through angiogenesis in vitro and in vivo. Our findings provide an insight into HIMF functioning in inflammatory myoblasts.

S48 Inefficient ventriculo-arterial coupling contributes to reduced exercise capacity in pulmonary hypertension

IntroductionVentriculo-arterial (VA) coupling (Ees/Ea) in the right heart is defined by RV end-systolic elastance (Ees) and pulmonary arterial effective elastance (Ea) with Ees/Ea representing the mechanical efficiency of forward flow...

Bosentan improves exercise capacity in pulmonary hypertension

Bosentan improves exercise capacity in pulmonary hypertension