Exercise Pulmonary Hemodynamics Research Articles

Mechanisms and treatment of pulmonary arterial hypertension.

Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.

The prognostic relevance of exercise pulmonary hypertension in cardiac and pulmonary diseases.

In this review, we provide an overview of the prognostic implications of exPH in patients with various common cardiac and pulmonary diseases. Exercise pulmonary hypertension (exPH) has been recently re-introduced in the current European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Accordingly, exPH is defined as a mean pulmonary arterial pressure (mPAP)/cardiac output ( CO ) slope greater than 3 mmHg/l/min. Key considerations for this re-introduction included increasing understanding on normal pulmonary hemodynamics during exercise and the broadly available evidence on the association of an abnormal mPAP/ CO slope with poor survival in the general population and in different disease entities. Exercise (patho-)physiology has opened a new field for clinical research facilitating recognition of cardiovascular and pulmonary vascular diseases in an early stage. Such early recognition with significant prognostic and possibly therapeutic relevance, but being undetectable at rest, makes exercise pulmonary hemodynamics particularly interesting for common diseases, such as valvular heart disease, left heart disease, and chronic pulmonary disease.

Better efficacy of sequential combination with balloon pulmonary angioplasty after long-term riociguat for patients with inoperable chronic thromboembolic pulmonary hypertension.

The present study aimed to evaluate the efficacy of long-term riociguat sequentially combined with balloon pulmonary angioplasty (BPA) for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Eight inoperable CTEPH patients were enrolled in this study, who have been administrated riociguat 2.5 mg three times daily for about 8 years, then underwent several sessions of BPA procedures. Data are prospectively collected to evaluate clinical outcomes, hemodynamics, exercise capacity, and right heart size and function by echocardiography at baseline, 8 years after riociguat, and 3 months after the final BPA. Eight patients (mean age 54.9 ± 11.4 years) were treated with riociguat 2.5 mg three times daily for 95.0 ± 10.7 months. Cardiac index (CI) (1.5 ± 0.5 L/min/m2 to 2.4 ± 0.6 L/min/m2, p = 0.005), 6 min walking distance (6MWD) (329.6 ± 87.5 m to 418.1 ± 75.8 m, p = 0.016), and pulmonary vascular resistance (PVR) (1336.9 ± 320.2 dyn·s·cm-5 to 815.4 ± 195.6 dyn·s·cm-5, p = 0.008) were significant improvement after riociguat treatment. Mean 4.1 ± 1.6 additional combinational BPA sessions and mean 18.8 ± 8.1 balloon dilations were performed. Mean pulmonary artery pressure (54.1 ± 11.1 mmHg to 33.6 ± 7.7 mmHg, p = 0.002) and PVR (815.4 ± 195.6 dyn·s·cm-5 to 428.3 ± 151.2 dyn·s·cm-5, p＜0.001) were further decreased. CI (2.4 ± 0.6 L/min/m2 to 2.7 ± 0.7 L/min/m2, p = 0.028) and 6MWD (418.1 ± 75.8 m to 455.7 ± 100.0 m, p = 0.038) were increased significantly. After long-term riociguat treatment, sequential combination with BPA delivered considerably incremental benefits on exercise capacity and pulmonary hemodynamics, as well as right heart size and function of technically inoperable CTEPH patients.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

The Paradox of Pulmonary Vascular Resistance: Restoration of Pulmonary Capillary Recruitment as a Sine Qua Non for True Therapeutic Success in Pulmonary Arterial Hypertension.

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension therapies that have mainly antiproliferative properties are being developed to try and diminish proliferative cellular obstruction in precapillary arterioles. If effective, those agents should restore capillary recruitment and, during exercise testing, pulmonary arterial pressure should remain low despite increasing pulmonary blood flow. The effectiveness of every novel therapy for pulmonary arterial hypertension should be evaluated not only at rest, but with measurement of exercise pulmonary hemodynamics during clinical trials.

Beneficial Effects of Pulmonary Vasodilators on Pre-Capillary Pulmonary Hypertension in Patients with Chronic Kidney Disease on Hemodialysis.

Background: In patients with chronic kidney disease (CKD) on hemodialysis, comorbid pulmonary hypertension (PH) aggravates exercise tolerance and eventually worsens the prognosis. The treatment strategy for pre-capillary PH, including combined pre- and post-capillary PH (Cpc-PH), has not been established. Objectives: This study aimed to evaluate the impact of pulmonary vasodilators on exercise tolerance and pulmonary hemodynamics in patients with CKD on hemodialysis. Methods and Results: The medical records of 393 patients with suspected PH who underwent right heart catheterization were reviewed. Of these, seven patients had isolated pre-capillary PH and end-stage CKD on hemodialysis. Pulmonary vasodilators decreased pulmonary vascular resistance from 5.9 Wood units (interquartile range (IQR), 5.5–7.6) at baseline to 3.1 Wood units (IQR, 2.6–3.3) post-treatment (p = 0.02) as well as increased pulmonary capillary wedge pressure from 10 mmHg (IQR, 7–11) to 11 mmHg (IQR, 8–16) (p = 0.04). Pulmonary vasodilators increased the World Health Organization functional class I or II from 0% to 100% (p = 0.0002) and the 6 min walk distance from 273 m (IQR, 185–365) to 490 m (IQR, 470–550) (p = 0.03). Conclusions: Pulmonary vasodilators for PH in patients with CKD on hemodialysis decrease pulmonary vascular resistance and eventually improve exercise tolerance. Pulmonary vasodilators may help hemodialysis patients with pre-capillary PH, although careful management considering the risk of pulmonary edema is required.

Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity? Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. Twenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4mL/min vs-40.2 ± 21.3mL/min; P< .05). The treatment effect of pyridostigmine was 53.6mL/min (95%CI, -105.2 to -2.0). Peak vsrest Vo2 (25.9 ± 15.3mL/min vs-60.8 ± 25.6mL/min; P< .01), cardiac output (-0.2 ± 0.6 L/min vs-1.9 ± 0.6 L/min; P< .05), and right atrial pressure (1.0 ± 0.5mmHg vs-0.6 ± 0.5mmHg; P< .05) were greater in the pyridostigmine group compared with placebo. Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ClinicalTrials.gov; No.: NCT03674541; URL: www. gov.

Influence of Upright Versus Supine Position on Resting and Exercise Hemodynamics in Patients Assessed for Pulmonary Hypertension.

BackgroundThe aim of the present work was to study the influence of body position on resting and exercise pulmonary hemodynamics in patients assessed for pulmonary hypertension (PH).Methods and ResultsData from 483 patients with suspected PH undergoing right heart catheterization for clinical indications (62% women, age 61±15 years, 246 precapillary PH, 48 postcapillary PH, 106 exercise PH, 83 no PH) were analyzed; 213 patients (main cohort, years 2016–2018) were examined at rest in upright (45°) and supine position, such as under upright exercise. Upright exercise hemodynamics were compared with 270 patients (historical cohort) undergoing supine exercise with the same protocol. Upright versus supine resting data revealed a lower mean pulmonary artery pressure 31±14 versus 32±13 mm Hg, pulmonary artery wedge pressure 11±4 versus 12±5 mm Hg, and cardiac index 2.9±0.7 versus 3.1±0.8 L/min per m2, and higher pulmonary vascular resistance 4.1±3.1 versus 3.9±2.8 Wood P<0.001. Exercise data upright versus supine revealed higher work rates (53±26 versus 33±22 watt), and adjusting for differences in work rate and baseline values, higher end‐exercise mean pulmonary artery pressure (52±19 versus 45±16 mm Hg, P=0.001), similar pulmonary artery wedge pressure and cardiac index, higher pulmonary vascular resistance (5.4±3.7 versus 4.5±3.4 Wood units, P=0.002), and higher mean pulmonary artery pressure/cardiac output (7.9±4.7 versus 7.1±4.1 Wood units, P=0.001).ConclusionsBody position significantly affects resting and exercise pulmonary hemodynamics with a higher pulmonary vascular resistance of about 10% in upright versus supine position at rest and end‐exercise, and should be considered and reported when assessing PH.

Abstract 6991: Impaired Systemic Oxygen Extraction Relates to Reduced Exercise Capacity in Post-COVID-19 Long Hauler Syndrome

Introduction: Following acute coronavirus 2019 (COVID-19) disease, at least 10% of patients report some form of residual limitation, most commonly dyspnea and fatigue. These COVID-19 “long haulers” experience symptoms that are largely unexplained by pulmonary function testing (PFT), echocardiogram and chest computed tomography (CT). Using invasive cardiopulmonary exercise testing, this pilot study characterized exercise limitation in 5 patients with persistent symptoms 1 year following mild COVID-19 illness. Methods: Following written informed consent, data were obtained in accordance with an IRB-approved protocol entailing placement of radial and pulmonary arterial catheters for pressure monitoring and blood sampling prior to and during maximum upright incremental exercise. Rest and exercise pulmonary hemodynamics, ventilation and gas exchange were recorded. Aerobic exercise capacity was estimated by peak O 2 consumption (VO 2 ). Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance &lt;3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO 2 &lt;80% predicted). Reduced peak VO 2 was associated with impaired systemic O 2 extraction as indicated by an arterial-venous O 2 content difference (adjusted for hemoglobin) of &lt;80% ( Figure 1 ). Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O 2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.

Exercise Hemodynamic Profiling Is Associated With Outcome in Patients Undergoing Percutaneous Mitral Valve Repair

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Efficacy and safety of riociguat in the treatment of chronic thromboembolic pulmonary arterial hypertension: A meta-analysis.

Background:Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH.Methods:Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test.Results:Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = −0.24, 95%CI −0.35 to −0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = −0.31, 95%CI −0.51 to −0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=−0.23, 95%CI −0.42 to −0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = −0.24, 95%CI −0.61 to −0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed.Conclusions:We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.

High-intensity interval training and pulmonary hemodynamics in COPD with hypoxemia

ABSTRACT Background Exercise is recommended for all patients with COPD. Evidence for its benefit is considerably weaker in the more severe stages of the disease. The aim of this study was to investigate whether high-intensity interval training could improve exercise capacity, pulmonary hemodynamics and cardiac function in patients with severe COPD and hypoxemia. Methods Stable patients with COPD GOLD stage III or IV and hypoxemia were included. They underwent extensive cardiopulmonary testing including right heart catheterization, lung function tests, echocardiography and 6-minute walk test before and after completion of 10 weeks of high-intensity interval training performed with supplemental oxygen. Primary endpoint was change in pulmonary artery pressure measured by right heart catheterization. Results Ten patients with very severe airflow obstruction, mean FEV1 28.7% predicted and mean FEV1/VC 0.39 completed the exercise programme. Pulmonary artery pressure remained unchanged following the intervention (26,3 mmHg vs. 25,8 mmHg at baseline, p 0.673). Six-minute walk distance improved by a mean of44.8 m (p 0.010), which is also clinically significant. We found marginally improved left ventricular ejection fraction on echocardiography (54.6% vs 59.5%, p 0.046). Conclusion High-intensity interval training significantly improved exercise capacity while pulmonary hemodynamics remained unchanged. The improvement may therefore be due to mechanisms other than altered pulmonary artery pressure. The increase in ejection fraction is of uncertain clinical significance. The low number of patients precludes firm conclusions.

P4685Validation of noninvasive pulmonary artery pressure/flow relationship: echocardiography vs right heart catheterization

Abstract Background Invasive pressure-flow (P/Q) relationship of the pulmonary circulation can detect the presence of pulmonary hypertension (PH) during exercise and provide information on patients' symptoms and assess disease severity. Doppler-echocardiography was reported to provide accurate but imprecise noninvasive estimates of both resting and exercise pulmonary haemodynamics. However, data on the direct comparison of invasive vs noninvasive approaches to build pressure-flow relationship are scarce. Purpose To compare echocardiographic estimates with invasive measurements of P/Q relationship of the pulmonary circulation during exercise. Methods Patients undergoing a clinically indicated right heart catheterization and echocardiography were studied at rest and during exercise. The ratio between mean pulmonary artery pressure and cardiac output at peak exercise (TPR), as well as P/Q slope throughout exercise were calculated. Both TPR and P/Q slope are abnormal when ≥3 mmHg/L/min. Echocardiographic estimates were compared with invasive measurements. Results Sixty patients were included (mean age 65±14 years, 73% female). PH was present at rest in 38 cases (63%), of precapillary origin in 23 (61%). Heart failure with preserved ejection fraction was diagnosed in 23 patients, of which 17 had no PH at rest. TPR at peak exercise and P/Q slope were abnormal (≥3 mmHg/L/min) in the majority of patients (56 and 45 subjects, respectively). Echocardiographic estimates of P/Q slope and TPR correlated significantly although weakly with invasive measurements (R2=0.38 and 0.56, respectively, p&lt;0.001). Bias of echocardiography for P/Q slope and TPR was 1.1±4.2 and 0.4±2.9 mmHg/L/min, respectively (figure). Sensitivity of echocardiography to detect an abnormal TPR or P/Q slope (i.e. ≥3 mmHg/L/min) was 100 and 98%, respectively, faced by low specificity (0 and 33%, respectively). Figure 1 Conclusions Doppler-echocardiography can provide rather accurate and sensitive but imprecise estimates of pressure-flow relationships of the pulmonary circulation during exercise. This intrinsic imprecision may limit its use in clinical practice.

Balloon pulmonary angioplasty vs riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension: A systematic review and meta‐analysis

BackgroundsNo previous meta‐analyses have compared the efficacy and safety of BPA with riociguat therapy in inoperable CTEPH patients.MethodsRelevant published studies were searched in the PubMed, Embase and ClinicalTrial.gov databases.ResultsTwenty‐three clinical trials including 1454 patients (631 underwent BPA; 823 underwent riociguat therapy) were analyzed. BPA was associated with a greater improvement in RAP (mean difference (MD) = −3.53 mmHg, 95% CI: [−4.85, −2.21] vs MD = −1.05 mmHg, 95% CI: [−1.82, −0.29]); mPAP (MD = −15.02 mmHg, 95% CI: [−17.32, −12.71] vs MD = −4.19 mmHg, 95% CI: [−5.58, −2.80]); PVR (standard MD = −1.32 woods, 95% CI: [−1.57, −1.08] vs standard MD = −0.65 woods, 95% CI: [−0.79, −0.50]); NYHA functional class (RR = 6.78, 95% CI: [3.14, 14.64] vs RR = 1.49, 95% CI: [1.07, 2.07]); and 6MWD (MD = 71.66 m, 95% CI: [58.34, 84.99] vs MD = 45.25 m, 95% CI: [36.51, 53.99]) than riociguat treatment. However, the increase in CO was greater with riociguat (MD = 0.78 L/min, 95% CI: [0.61, 0.96]) than with BPA (MD = 0.33 L/min, 95% CI: [0.06, 0.59]). No significant difference in cardiac index (CI) was found between BPA (MD = 0.40 L/min/m2, 95% CI: [0.21, 0.58]) and riociguat (MD = 0.40 L/min/m2, 95% CI: [0.26, 0.54]). The most common complications of BPA were pulmonary injury (0.3%‐5.6%) and pulmonary edema (0.8%‐28.6%). The most common adverse events of riociguat were headache, dizziness, hypotension and nasopharyngitis.ConclusionsOur meta‐analysis indicates that BPA might be associated with greater improvements in exercise tolerance and pulmonary hemodynamics except for cardiac output and cardiac index than riociguat therapy. However, both of them were well tolerated.

USE OF PAH SPECIFIC THERAPY IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: A META-ANALYSIS

SESSION TITLE: Pulmonary Vascular Disease 1 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Pulmonary endarterectomy (PEA) is the definitive treatment for chronic thromboembolic pulmonary hypertension (CTEPH). However, not all patients are surgical candidates and some may be left with residual pulmonary hypertension after PEA. Treatment options for such patients are limited. The microvasculopathy of CTEPH and pulmonary arterial hypertension (PAH) are similar. A few randomized controlled trials (RCTs) have reported on the use of PAH specific therapy in CTEPH but not all have shown improvement in exercise capacity and/or pulmonary hemodynamics. METHODS: PUBMED was searched for articles published between January 1996 and February 2018, using the term “chronic thromboembolic pulmonary hypertension” and applying the filters: English language, Humans and Clinical Trials. Studies were included if they met the following criteria: randomized, placebo controlled, clinical trial AND pulmonary hypertension (PH) confirmed by right heart catheterization, AND baseline and follow up six minute walk distance (6MWD) AND baseline and follow up pulmonary hemodynamic data. RevMan 5.3 was used to perform the meta-analysis. RESULTS: Five RCTs met our inclusion criteria. There was a total of 293 patients treated for 12-16 weeks with placebo or one of the three drug classes of PAH specific therapy: Riociguat (n= 173), Endothelin receptor antagonist (n= 118), and Phosphodiesterase 5 inhibitor (n= 9). The majority of the cases was inoperable CTEPH. Overall, the placebo corrected mean change in 6MWD was 24.73 meters (95%CI 14.24, 35.21). The mean change in mean pulmonary artery pressure was -4.78 mm Hg (95%CI-6.42, -3.14), in pulmonary vascular resistance -194 dynes.sec/cm5 (95%CI -233.30, -155.09) and in cardiac index 0.39 L/min/m2 (95%CI 0.16, 0.61). CONCLUSIONS: The use of PAH specific therapy in patients with CTEPH results in significant improvement in 6MWD and pulmonary hemodynamics. CLINICAL IMPLICATIONS: PAH specific therapy is beneficial in patients with inoperable CTEPH or persistent CTEPH following PEA. DISCLOSURES: No relevant relationships by Jason Filopei, source=Web Response No relevant relationships by Adil Shujaat, source=Web Response No relevant relationships by David Steiger, source=Web Response

Metformin added to bosentan therapy in patients with pulmonary arterial hypertension associated with congenital heart defects: a pilot study.

Pulmonary arterial hypertension (PAH) is a common complication of a congenital heart defect (CHD). Recent studies suggest metformin may be a potential drug to improve cardiac function in PAH. A pilot study was conducted to investigate the efficacy of short-term treatment with a combination regimen consisting of bosentan and metformin in PAH-CHD patients as compared with bosentan monotherapy in a prospective, randomised study.Patients with PAH-CHD were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily).93 patients were enrolled to bosentan monotherapy (n=48) or bosentan/metformin combination treatment (n=45). After 3 months, both treatments significantly improved World Health Organization functional class, 6-min walking distance (6MWD), N-terminal pro-brain natriuretic peptide and right heart haemodynamic parameters. The improvements in 6MWD and pulmonary vascular resistance index were significantly greater in patients treated with combination therapy than in those who received monotherapy (mean±sd 95±136 versus 48±119 m (p=0.017) and −1.8±1.2 versus −1.2±1.3 Wood units per m2 (p<0.001), respectively). Pulmonary endothelin (EDN)1 was significantly decreased after combination therapy (p=0.006). However, plasma EDN1 levels were not affected.Combination therapy with bosentan and metformin in PAH-CHD patients provides improvements in important outcomes such as exercise capacity and pulmonary haemodynamics, compared with bosentan alone.

Therapeutic benefits of phosphodiesterase-5 inhibition in chronic heart failure: A meta-analysis.

BackgroundPhosphodiesterase-5 inhibitors (PDE5i) have been shown to be beneficial for patients with pulmonary arterial hypertension. However, several studies would have documented a useful effect of PDE5i even for pulmonary hypertension secondary to left-sided chronic heart failure (CHF).MethodsWe performed a meta-analysis including randomized controlled trials (RCTs) which had compared PDE5i (mostly sildenafil) and placebo in CHF patients.ResultsFourteen studies enrolling a total of 928 patients were incorporated in the meta-analysis. In heart failure with reduced left ventricular ejection fraction (HFREF), PDE5i, compared to placebo, significantly improved the composite of death and hospitalization (OR = 0.28; 95% CI: 0.10–0.74). They also improved peak VO2 [difference in means (MD): 3.76; 95% CI: 3.27–4.25], six-minute walking distance test (MD: 22.7 m; 95% CI: 8.19–37.21), and pulmonary arterial systolic pressure (MD: −11.52 mmHg; 95% CI: −15.56 to −7.49). Conversely, in CHF with preserved left ventricular ejection fraction (HFpEF), PDE5i proved not to yield any significant improvement of the investigated outcomes.ConclusionsIn HFREF, PDE5i showed beneficial effects on the composite of death and hospitalization, as well as on exercise capacity and pulmonary hemodynamics. Conversely, in HFpEF, no significant clinical, spiroergometric, or hemodynamic improvement was achieved using PDE5i therapy.

Changes in pulmonary exercise haemodynamics in scleroderma: a 4-year prospective study.

Pulmonary arterial hypertension (PAH) is a feared complication of systemic sclerosis. In this prospective cohort study, we monitored the changes in resting and exercise pulmonary haemodynamics of scleroderma patients without initial PAH over a mean follow-up period of ∼4 years.All patients underwent exercise echocardiography and cardiopulmonary exercise testing at baseline and follow-up. A subgroup underwent exercise right heart catheter (RHC) investigations. The primary end-point was the echocardiographic systolic pulmonary arterial pressure at 50 W exercise (sPAP50).We included 99 patients, of whom 58 had a complete dataset. Three out of 99 patients developed RHC-confirmed PAH (0.75 cases per 100 patient-years). sPAP50 increased (p<0.001) and peak oxygen uptake (secondary end-point) decreased significantly (p=0.001) during follow-up, but there was no significant change in resting sPAP (p=0.38). In the RHC subgroup (n=28), mean (m)PAP and pulmonary vascular resistance at 50 W increased significantly (p=0.02 and p=0.002, respectively), but resting mPAP was unchanged.Scleroderma patients without PAH develop a mild but significant deterioration of pulmonary exercise haemodynamics and exercise capacity over a 4-year follow-up period, indicating a progression of pulmonary vascular disease. The manifestation rate of RHC-confirmed PAH was 0.75 cases per 100 patient-years.

Open label study of ambrisentan in patients with exercise pulmonary hypertension.

A growing body of evidence suggests that exercise pulmonary hypertension (ePH) is an early form of pulmonary arterial hypertension (PAH). Identifying the disease at an early, potentially more responsive phase, and initiating treatment may improve functional status and prevent progression to severe forms of PAH. This was a single-center, open-label six-month treatment trial to evaluate the effect of ambrisentan on pulmonary hemodynamics and exercise capacity in ePH utilizing invasive cardiopulmonary exercise testing (iCPET). After six months of treatment with ambrisentan, patients repeated iCPET; exercise capacity, symptoms, and pulmonary hemodynamics were reassessed. Twenty-two of 30 patients completed the treatment phase and repeat iCPET. After six months of treatment there was a significant decline in peak exercise mPAP (−5.2 ± 5.6 mmHg, P = 0.001), TPG (−7.1 ± 8.0 mmHg, P = 0.001), PVR (−0.9 ± 0.7 Woods units, P = 0.0002), and Ca-vO2 (−1.8 ± 2.3 mL/dL, P = 0.0002), with significant increases in peak PCWP (+2.9 ± 5.6 mmHg, P = 0.02), PVC (+0.8 ± 1.4 mL/mmHg, P = 0.03), and CO (+2.3 ± 1.4 L/min, P = 0.0001). A trend toward increased VO2max (+4.4 ± 2.6% predicted, P = 0.07) was observed. In addition, there were improvements in 6MWD and WHO FC after 24 weeks. Our findings suggest that treatment of ePH with ambrisentan results in improved pulmonary hemodynamics and functional status over a six-month period. Treatment of ePH may prevent the progression of vascular remodeling and development of established PAH.

Abstract 12981: Long-term Efficacy of Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension

Background: Balloon pulmonary angioplasty (BPA) has been shown to markedly improve both exercise capacity and pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CETPH). Since 2009, we have adopted BPA as a first-line treatment strategy for inoperable CTEPH. The aim of this study was to evaluate the long-term efficacy of BPA in patients with inoperable CTEPH. Methods and Results: From 1992 to 2014, we treated a total of 110 patients with inoperable CTEPH at our Hospital. Among them, we excluded 11 patients from the present analysis due to advanced cancer or multiple organ failure at admission. We divided the remaining 99 patients into 2 groups; the historical control (HC) group (N=35; mean age, 62 years; M/F = 30/5) who were admitted from 1992 to 2008 and the BPA group (N= 64; mean age, 64 years; M/F= 49/15) who were admitted from 2009 to 2014. We compared baseline characteristics, hemodynamics and long-term survival between the 2 groups. There was no significant difference in baseline parameters, including age, sex, WHO functional class or serum BNP levels between the 2 groups. Regarding hemodynamic parameters, the BPA group had significantly higher pulmonary capillary wedge pressure compared with the HC group (9±0.4 vs. 7±0.6 mmHg, P&lt;0.01). The median follow-up period was 53 months (IQR 26-80 months) for the HC group and 23 months (IQR 13-39 months) for the BPA group. Kaplan-Meier analysis showed that the survival rate was significantly better in the BPA group compared with the HC group (log-rank P=0.02), with the estimated 5-year survival probability of 98% for the BPA group and 73% for the HC group ( Figure ). The multiple Cox hazard analysis showed that both age (hazard ratio 1.07, P=0.02) and the HC group (hazard ratio 9.2, P=0.01) were independent predictor of mortality. Conclusions: These results indicate that BPA has a beneficial impact on long-term survival in patients with inoperable CTEPH.