Exercise-induced Pulmonary Hypertension Research Articles

Association between lung ultrasound B-lines and exercise-induced pulmonary hypertension in patients with connective tissue disease.

Identification of elevation in pulmonary pressures during exercise may provide prognostic and therapeutic implications in patients with connective tissue disease (CTD). Interstitial lung disease (ILD) is common in CTD patients and subtle interstitial abnormalities detected by lung ultrasound could predict exercise-induced pulmonary hypertension (PH). Echocardiography and lung ultrasound were performed at rest and bicycle exercise in CTD patients (n=41) and control subjects without CTD (n=24). Ultrasound B-lines were quantified by scanning four intercostal spaces in the right hemithorax. We examined the association between total B-lines at rest and the development of exercise-induced PH during ergometry exercise. Compared to controls, the number of total B-lines at rest was higher in CTD patients (0 [0, 0] vs 2 [0, 9], P<.0001) and was correlated with radiological severity of ILD assessed by computed tomography (fibrosis score, r=.70, P<.0001). Pulmonary artery systolic pressure (PASP) was increased with ergometry exercise in CTD compared to controls (48 ± 14vs 35 ± 13mm Hg, P=.0006). The number of total B-lines at rest was highly correlated with higher PASP (r=.52, P<.0001) and poor right ventricular pulmonary artery coupling (tricuspid annular plane systolic excursion/PASP ratio, r=-.31, P=.01) during peak exercise. The number of resting B-lines predicted the development of exercise-induced PH with an area under the curve .79 (P=.0003). These data may suggest the value of a simple resting assessment of lung ultrasound as a potential tool for assessing the risk of exercise-induced PH in CTD patients.

Exercise-induced pulmonary hypertension in HIV patients: Association with poor clinical and immunological status

Background and aimExercise-induced pulmonary hypertension (Ex-PH) may represent the earliest sign of pulmonary arterial hypertension (PAH) in human immunodeficiency virus (HIV) patients. We investigated its association with clinical and immunological status, virologic control, and response to antiviral therapy. MethodsIn 32 consecutive HIV patients with either low (n = 29) or intermediate probability (n = 3) of PH at rest, we evaluated the association of isolated ExPH with: time to HIV diagnosis; CD4+ T-cell count; clinical progression to acquired immunodeficiency syndrome (AIDS); development of resistance to antiretroviral therapy (ART); HIV RNA levels; time to beginning of ART; current use of protease inhibitors; combination of ART with boosters (ritonavir or cobicistat); immuno-virologic response to ART; and ART discontinuation.Isolated ExPH at stress echocardiography (ESE) was defined as absence of PH at rest and systolic pulmonary arterial pressure (sPAP) >45 mmHg or a >20 mmHg increase during low-intensity exercise cardiac output (<10 L/min). ResultsIn our cohort, 22% (n = 7) of the enrolled population developed ExPH which was inversely related to CD4+ T-cell count (p = 0.047), time to HIV diagnosis (p = 0.014) and time to onset of ART (p = 0.041). Patients with ExPH had a worse functional class than patients without ExPH (p < 0.001). ExPH and AIDS showed a trend (p = 0.093) to a direct relationship. AIDS patients had a higher pulmonary vascular resistance compared to patients without ExPH (p = 0.020) at rest echocardiography. ConclusionsThe presence of isolated ExPH associates with a worse clinical status and poor immunological control in HIV patients. Assessment of ExPH by ESE may help identify subgroups of HIV patients with a propensity to develop subclinical impairment of pulmonary circulation following poor control of HIV infection.

Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

Salutary Acute Effects of Exercise on Central Hemodynamics in Heart Failure With Preserved Ejection Fraction

BackgroundA warmup period of priming exercise has been shown to improve peripheral oxygen transport in older adults. We sought to determine the acute effects of priming exercise on central hemodynamics at rest and during a repeat exercise in heart failure with preserved ejection fraction (HFpEF). Methods and ResultsThis is a post hoc analysis from 3 studies. Patients with HFpEF (n = 42) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise (20 W for 5 minutes, priming exercise). Measurements were then repeated at rest and during a second bout of exercise at a 20-W workload (second exercise). During the priming exercise, patients with HFpEF displayed dramatic increases in biventricular filling pressures and exercise-induced pulmonary hypertension. After the priming exercise at rest, biventricular filling pressures and pulmonary artery (PA) pressures were lower and lung tidal volume was increased. During the second bout of exercise, biventricular filling (PA wedge pressure, 29 ± 8 mm Hg at second exercise vs 32 ± 7 mm Hg at first exercise, P = .0003) and PA pressures were lower, and PA compliance increased. ConclusionsThis study shows that short duration, submaximal priming exercise attenuates the pathologic increases in filling pressures, improving pulmonary vascular hemodynamics at rest and during repeat exercise in patients with HFpEF.

Reduction in Pulmonary Arterial Pressure at Rest and During Exercise and Improvement in Gas Exchange Efficiency Following Percutaneous Closure of Patent Foramen Ovale

PURPOSE The patent foramen ovale (PFO) is a source of intracardiac right-to-left shunt and is present in ~1/3rd of the adult population. Deficits in pulmonary gas exchange efficiency associated with PFO have been well-documented (Lovering et al, J Appl Physiol 2016). However, changes in pulmonary artery pressure and total pulmonary resistance (TPR) following closure have not previously been reported. METHODS Four candidates (3F, 1M) for closure of PFO were identified by local cardiologists and referred to our laboratory as subjects. 3 subjects (3F) received physician clearance to participate in the exercise trials. 1 subject (1M) was not cleared for exercise so only resting measures were taken. Presence and size of PFO was confirmed utilizing transthoracic saline contrast echocardiography (TTSCE). A radial arterial catheter was placed utilizing aseptic technique. Subjects exercised at 4 sub-maximal workloads (25%, 50%, 75% and 90% of pre-closure VO2Max), with arterial blood drawn anaerobically during the last 30 seconds of each workload and immediately analyzed in duplicate for gas content. Transthoracic ultrasound measures of cardiac output (QT) and pulmonary arterial systolic pressure (PASP) were taken prior to exercise and during the final minute of each workload. TPR was calculated as PASP/ QT. Subjects then underwent percutaneous closure of PFO utilizing a commercially available closure device (Amplatzer PFO Occluder, Abbott, Illinois; Cardioform Septal Occluder, GORE, Arizona). All measures were repeated in the laboratory 3-6 months after closure of PFO following confirmation of endothelialization of the closure device with TTSCE. RESULTS Data were analyzed by a 2-way (Closure x Workload) RMANOVA. There was a main effect of closure on PASP F(1, 11) = 21.05, p = 0.0008, and a main effect of closure on TPR F(1, 11) = 9.899, p = 0.0093, with reductions in both following closure. There was a main effect of workload, but not closure, on cardiac output F(4, 11) = 60.18, p < 0.0001. There were main effects of both workload F(4,11) = 73665, p = .0033 and closure F(1,11) = 28.31, p = .0002 on pulmonary gas exchange efficiency. CONCLUSION Improvements in pulmonary gas exchange efficiency are expected with removal of the intracardiac right-to-left shunt. However, our results demonstrating a significantly reduced pulmonary artery pressure, due to a significantly reduced TPR, are intriguing and deserve more attention to better understand the contributing factors of a PFO to exercise-induced pulmonary hypertension.

Exercise Right Heart Catheterisation in Cardiovascular Diseases: A Guide to Interpretation and Considerations in the Management of Valvular Heart Disease

The use of exercise right heart catheterisation for the assessment of cardiovascular diseases has regained attention recently. Understanding physiologic haemodynamic exercise responses is key for the identification of abnormal haemodynamic patterns. Exercise total pulmonary resistance >3 Wood units identifies a deranged haemodynamic response and when total pulmonary resistance exceeds 3 Wood units, an exercise pulmonary artery wedge pressures/cardiac output slope >2 mmHg/l/min indicates the presence of underlying exercise-induced pulmonary hypertension related to left heart disease. In the evolving field of transcatheter interventions for valvular heart disease, exercise right heart catheterisation may objectively unmask symptoms and underlying haemodynamic abnormalities. Further studies are needed on the use of the procedure to inform the selection of patients who might receive the most benefit from transcatheter interventions for valvular heart diseases.

Left atrial filling index in prediction of exercise induced pulmonary hypertension in patients with asymptomatic primary mitral regurgitation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. In patients with chronic mitral regurgitation (MR), left atrium (LA) is one of the first cardiac structures, that are affected by progressive volume overload. Previous studies have shown that higher LA filling index (FI) could be a potential negative prognostic marker and it may provide additional information in cases where surgical valve correction is considered. Purpose. The aim of this study was to evaluate the connection between the LA FI and exercise–induced pulmonary hypertension (EIPH) in patients with asymptomatic primary moderate to severe MR. Methods. The study sample consisted of 50 patients (age 61.88 ± 12.88 years) with asymptomatic primary moderate to severe MR and preserved left ventricular (LV) ejection fraction (EF) (&amp;gt;60%). All of the patients underwent resting and stress (bicycle–ergometry as per protocol 25 + 25W every 3 minutes) echocardiography. The ratio of the early–diastolic mitral inflow peak velocity (E) and LA reservoir strain was calculated as the LA FI. EIPH was considered as systolic pulmonary artery pressure (SPAP) ≥60 mmHg during peak stress. Results. EIPH was identified in 13 (26%) patients with primary asymptomatic MR. LA FI at rest, during initial and peak stress was higher in patients with EIPH (p = 0.041, p = 0.023 and p = 0.036, respectively). LA FI at rest (r = 0.334; p = 0.044), during initial (25W) stress (r = 0.371; p = 0.037) and during recovery phase (r = 0.408; p = 0.023), weakly correlated with SPAP during maximal achieved workload. In univariate logistic regression analysis, LA FI during initial and peak stress was significantly related to EIPH (Table 1). According to ROC analysis, LA FI &amp;gt;6.46 during initial stress could predict EIPH with 70.0% sensitivity and 75.0% specificity (p = 0.023). LA FI &amp;gt;9.59 during peak stress could distinguish the possibility of underlying EIPH with 60.0% sensitivity and 94.3% specificity (p = 0.036). Conclusions. Resting and exercise LA FI was higher in subjects with EIPH. LA FI during stress could be the potential predictor of EIPH in patients with asymptomatic primary MR and preserved LV EF. Table 1 Parameter β Chi-Square Odds ratio Standard error 95% CI p value LA FI at rest 1.21 3.549 3.271 0.106 0.984 - 1.489 0.071 LA FI during initial (25 W) stress 1.535 6.056 4.812 0.195 1.047 - 2.250 0.028 LA FI during peak stress 1.662 7.364 4.646 0.236 1.047 - 2.638 0.031 LA FI during recovery phase 1.257 3.998 3.139 0.129 0.976 - 1.619 0.076 LA - left atrium FI - filling index Abstract Figure. Picture 1

Echocardiographic predictors of exercise induced pulmonary hypertension in patients with asymptomatic moderate to severe mitral regurgitation and preserved left ventricular ejection fraction.

The significant role of mitral regurgitation (MR) in development of pulmonary hypertension (PH) has been proved in previous studies. Experts suggest systolic pulmonary arterial pressure (SPAP) ⩾60 mmHg during exercise as a significant threshold of negative prognostic value in patients with MR. The aim of this study was to evaluate the changes of SPAP and to ascertain the determinants of exercise induced pulmonary hypertension (EIPH) in patients with asymptomatic primary MR. We performed a prospective study that included 50 patients with asymptomatic primary moderate to severe MR with preserved left ventricular ejection fraction (LV EF ⩾60%) at rest. They were divided into two groups according to the presence (PH group; n = 13) or absence (non-PH group; n = 37) of EIPH. Rest and stress (bicycle ergometry) echocardiography and speckle-tracking offline analysis were performed. An increment of SPAP from rest to peak stress was higher in PH group (p < 0.001). Multivariate regression analysis showed that MR effective regurgitation orifice area (EROA; p = 0.008) and regurgitant volume (RVol; p = 0.006) contributed significantly to SPAP at rest. Higher increment of MR EROA during stress and worse parameters of LV diastolic function at rest (E, A, E/e') correlated significantly with higher SPAP during peak stress and they had a major role in predicting EIPH according to univariate logistic regression analysis. In ROC analysis SPAP >33.1 mmHg at rest could predict EIPH with 84.6% sensitivity and 87.1% specificity (95%CI 0.849-1.000; p < 0.001). Parameters of MR severity (EROA and RVol) were significant determinants of SPAP at rest, while the increment of MR EROA during stress and parameters of resting LV diastolic function were the best predictors of significant EIPH.

Diagnostic Application of Invasive Cardiopulmonary Exercise Test in Patients with Unexplained Dyspnea

To explore the clinical diagnostic application of invasive cardiopulmonary exercise test (iCPET) in patients with unexplained dyspnea. A retrospective analysis was conducted, covering patients with a chief complaint of exertional dyspnea between May 5, 2017 and October 1, 2020. Right cardiac catheterization examination was performed on patients whose cause had not been identified through routine examination, and further iCPET was performed on patients if no clear etiology was identified through right cardiac catheterization. According to the results and the diagnostic criteria of iCPET, patients showing no obvious abnormalities in the right cardiac catheterization examination were divided into four subgroups: exercise-induced pulmonary arterial hypertension (eiPAH), exercise-induced heart failure with preserved ejection fraction (eiHFpEF), preload failure, and oxidative myopathy. By comparing the lab test, echocardiography, right heart catheter and iCPET peak exercise data of the subgroups, the disease distribution and exercise hemodynamic characteristics of patients with unexplained dyspnea examined by iCPET were described. Of the 1 046 patients with exertional dyspnea, 771 were diagnosed with routine examination, while among the remaining 275 patients, 131 (47.6%) were diagnosed with right cardiac catheterization and 144 (52.4%) showed no clear etiology after routine examination and right cardiac catheterization. Of these 144 patients, 49 (34.0%) received iCPET with a median exercise time of 375 s. A total of 47 patients completed the examination, with a male-to-female ratio of 0.27∶1 and an average age of (47.9±14.4) years old. Among the 47 patients, 76.6% (36/47) aged between 20 and 59 and 78.7% (36/47) lived in urban areas. The preload failure group ( n=27) showed low right atrium pressure at peak exercise intensity. The eiHFpEF group ( n=9) showed high wedge pressure of pulmonary capillaries at peak of exercise intensity. The eiPAH group ( n=8) showed high average pulmonary artery pressure at peak exercise intensity. The oxidative myopathy group ( n=3) was characterized by impairment of tissue uptake and/or utilization of oxygen during exercise. According to the comparison among the three subgroups of the preload failure, eiHFpEF and eiPAH, the eiPAH group had the highest blood K + level in routine examination, while the preload failure group had the lowest blood K + level ( P=0.014). The iCPET of the three subgroups showed statistically significant ( P=0.001) difference in right atrial pressure increase during exercise. Among the three, the eiHFpEF group had the highest increase and the preload failure group had the lowest increase. Conclusion In unexplained dyspnea patients showing no abnormal results in right cardiac catheterization examination, the main cause was preload failure, which manifested as low right atrial pressure at peak exercise intensity. The study showed that iCPET was of important value for dyspnea cases when the cause of the condition was not revealed with right cardiac catheterization.

Prolonged Elevation of Tricuspid Regurgitation Pressure Gradient After Exercise in Patients With Exercise-induced Pulmonary Hypertension

It is necessary to measure the peak tricuspid regurgitation pressure gradient (TRPG) that is recorded at maximum exercise intensity when diagnosing exercise-induced pulmonary hypertension (ePH) on exercise stress echocardiography (ESE). However, it is difficult to measure maximum TRPG during the treadmill exercise. If ePH induced TRPG elevation continues during recovery period after exercise termination, this elevation will serve as a practical diagnostic standard. We aimed to assess whether the elevation of postexercise peak TRPG prolong soon after finishing exercise in patients with ePH. Seventy-four patients underwent symptom-limited ESE by using a semirecumbent bicycle ergometer. ePH was defined as peak TRPG > 50 mm Hg at maximum exercise. We measured peak TRPG during exercise and until 5 minutes afterward. Thirty-five patients were diagnosed with ePH; their median TRPG was 57 mm Hg [interquartile range: 52-62 mm Hg] at maximum exercise. Peak TRPG in patients with ePH was > 40 mm Hg until 2 minutes after exercise. The cut-off values of peak TRPG to detect ePH were 43 mm Hg just after exercise and 41 mm Hg at 1 minute afterward (areas under the curve: 0.98, 0.92, respectively; both p < 0.001). In conclusion, elevated peak TRPG persisted for at least 2 minutes after finishing exercise, and this time frame will therefore provide a new window for diagnosing ePH by ESE.

Metabolic syndrome contributes to the pulmonary arterial dysfunction in pulmonary hypertension in heart failure with preserved ejection fraction

Abstract Background Many Heart Failure with preserved Ejection Fraction (HFpEF) patients have metabolic syndrome and develop Exercise Induced Pulmonary Hypertension (EIPH). The pathogenesis of EIPH in HFpEF remains unclear as there is no rodent model. As the SGLT2 inhibitor Empagliflozin improves clinical outcome in patients with type 2 diabetes and cardiovascular risk, we tested its effect on EIPH in a novel rat model of HFpEF. Methods Obese ZSF1 (HFpEF model) with leptin receptor mutation have metabolic syndrome and received the VEGF-inhibitor SU5416 to stimulate PH (Obese + Sugen). Half also received Empagliflozin (0.2 mg/kg/day) in drinking water from 8 to 22 weeks old. Lean ZSF1 lacking the mutation served as controls. During treadmill exercise, right/left ventricle (RV/LV) hemodynamics were evaluated via catheters. Pulmonary artery vascular smooth muscle cells (PAVSMC) prepared from normal or diabetic patients were cultured in standard media, or with Palmitate acid, Glucose and Insulin (PGI) to induce metabolic stress. Flow cytometry was used to evaluate reactive oxygen species (ROS) in mitochondria (Mitosox) or cytoplasm (CellROX). Results Relative to Lean, Obese + Sugen had increased body weight and HgA1C (Fig. 1A). Relative to Lean and at rest, Obese + Sugen showed mildly elevated RVSP and LVEDP. After exercise, LVSP and LVEDP rose similarly in Lean and Obese + Sugen. However, after exercise, Obese + Sugen showed a markedly greater increase in RVSP and exercise intolerance consistent with EIPH (Fig. 1B). In MR imaging of PA, Lean showed dobutamine (5 μg/kg/min)-induced PA dilation, which was not seen in Obese + Sugen (Fig. 1C). Protein levels of sGCβ1 (key regulator of PA relaxation) and its transcription factor (NFYA) both were decreased in PA from Obese + Sugen relative to Lean (Fig. 1D). Obese + Sugen + SGLT2 inhibitor treated rats showed marked improvements metabolic syndrome (body weight, HgA1c), exercise induced increase in RVSP, PA response to dobutamine, and increased NFYA and sGCβ1 expression (Fig. 1A–D). We observed greater ROS-induced DNA damage (8-OHdG staining) (Fig. 1E) and mitochondrial complex I, III, and IV activity in Obese + Sugen PA that was normalized in Obese + Sugen + SGLT2 inhibitor (Fig. 1F), suggesting a role of ROS in EIPH. Control human PAVSMC treated with PGI media showed elevated cytoplasmic and mitochondrial ROS, associated with increased mitochondrial complex I, III, IV and V activity (Fig. 1F, G). PGI media also accelerated the degradation of NFYA RNA and protein level in a manner mimicked by H2O2, and prevented by catalase/SOD (Fig. 1H, I), suggesting PGI-induced ROS enhanced NFYA degradation. Diabetic human PAVSMCs cultured in normal media resembled PGI-treated normal cells with respect to sGCb1 and NFYA expression, and in response to catalase/SOD (Fig. 1H, I). Conclusions In this PH-HFpEF model, metabolic syndrome contributes to PA dysfunction and EIPH through mitochondrial dysfunction and enhanced ROS, which were improved by Empagliflozin treatment. Figure 1 Funding Acknowledgement Type of funding source: None

Prognostic relevance of exercise pulmonary hypertension for new-onset atrial fibrillation in primary mitral regurgitation

Abstract Background/Introduction New-onset of atrial fibrillation (AF) portends poor prognosis in patients with primary mitral regurgitation (MR). However less is known about prognostic indicator for new-onset AF. Purpose The purpose of this study was to identify the prognostic relevance of exercise pulmonary hypertension for the new-onset AF in patients with primary MR. Methods Total of 114 consecutive patients with primary MR who underwent symptom-limited exercise echocardiography using supine-cycle ergometer were followed for new-onset AF over mean follow-up time of 3.6±2.6 years. Those with prevalent AF and pulmonary hypertension (estimated systolic pulmonary artery pressure ≥50mmHg) prior to exercise echocardiography were excluded from our analysis. We defined exercise-induced pulmonary hypertension (ExPHT) as those with peak estimated systolic pulmonary artery pressure (SPAP) ≥60mmHg or delta SPAP defined as differences between rest and peak SPAP ≥20mmHg. Results The mean age was 61±15 years old and 70 (61%) were male. Of those, 8 (7.8%) had mild MR, 32 (31.1%) had moderate MR, and 63 (61.2%) had severe MR. 60 (52.2%) patients had ExPHT. A total of 27 cases of new-onset AF were found during follow-up where the ExPHT group had higher prevalence of new-onset AF than the non-ExPHT group (35% vs. 11%, p=0.002). Those with ExPHT had significantly stronger association with shorter event-free survival time of new-onset AF (log-rank p&amp;lt;0.001, Figure). When adjusted for age, sex, body surface area, the American Society of Echocardiography MR grade, left atrial dimension, peak systolic blood pressure and heart rate, the multivariable Cox regression analysis showed that those with ExPHT had a hazard risk of 3.1 ([95% CI 1.1–9.1], p=0.039) for new-onset of AF. Conclusions Exercise-induced pulmonary hypertension predicted incident of new-onset AF in those with primary MR. Exercise echocardiography is expected to play an important role in decision making with regards to the optimal timing for surgical intervention in primary MR. Figure 1 Funding Acknowledgement Type of funding source: None

Impact of obstructive sleep apnea on cardiopulmonary performance, endothelial dysfunction, and pulmonary hypertension during exercise

RationaleOSA has been associated with reduced exercise capacity. Endothelial dysfunction and exercise-induced pulmonary hypertension (ePH) may be mediators of this impairment. We hypothesized that OSA severity would be associated with impaired exercise performance, endothelial dysfunction, and ePH. MethodsSubjects with untreated OSA were recruited. Subjects underwent endothelial function, and cardiopulmonary exercise testing with an echocardiogram immediately before and following exercise. Results22 subjects were recruited with mean age 56 ± 8 years, 74 % male, BMI 29 ± 3 kg/m2, and AHI 22 ± 12 events/hr. Peak V˙O2 did not differ from normal (99.7 ± 17.3 % predicted; p = 0.93). There was no significant association between OSA severity (as AHI, ODI) and exercise capacity, endothelial function, or pulmonary artery pressure. However, ODI, marker of RV diastolic dysfunction, and BMI together explained 59.3 % of the variability of exercise performance (p < 0.001) via our exploratory analyses. ConclusionsExercise capacity was not impaired in this OSA cohort. Further work is needed to elucidate mechanisms linking sleep apnea, obesity, endothelial dysfunction and exercise impairment.

Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients - A Randomized Controlled Trial.

This prospective randomized multicenter open-label trial evaluated whether sodium-glucose cotransporter-2 inhibitor (SGLT2-i) improves left ventricular (LV) pump function and suppresses elevation of LV filling pressure (LVFP) and right ventricular systolic pressure (RVSP) during exercise in type 2 diabetes mellitus (T2DM) patients. Based on HbA1c and LV ejection fraction, 78 patients with poorly controlled T2DM were randomly assigned to D-group (dapagliflozin 5 mg/day add-on) or C-group (conventional therapy add-on). Physical examination, home and office blood pressure examination, blood tests, and echocardiography at rest and during ergometer exercise were performed at baseline and at 1.5 and 6 months after treatment. The primary endpoint was defined as the change in RVSP (mmHg) between baseline and 6-month follow up. The secondary endpoints were changes in LVFP (ratio), stroke volume index (SVi; mL/m2), and cardiac index (CI; L/min/m2). Both RVSP and LVFP during exercise significantly decreased from baseline to 6 months after starting treatment in the D-group (P<0.001). No changes to either parameter was observed in the C-group. The SVi and CI did not improve in either group. Both home and office blood pressure significantly decreased in the D-group. Decreases in HbA1c were somewhat greater in the C-group. Dapagliflozin significantly improved RVSP and LVFP during exercise in patients with T2DM and cardiovascular risk, which may contribute to favorable effects on heart failure.

Cardiopulmonary Exercise Testing in Patients With Interstitial Lung Disease.

Interstitial lung disease (ILD) is a heterogeneous group of conditions characterized by fibrosis and/or inflammation of the lung parenchyma. The pathogenesis of ILD consistently results in exertional dyspnea and exercise intolerance. Cardiopulmonary exercise testing (CPET) provides important information concerning the pathophysiology of ILD that can help inform patient management. Despite the purported benefits of CPET, its clinical utility in ILD is not well defined; however, there is a growing body of evidence that provides insight into the potential value of CPET in ILD. Characteristic responses to CPET in patients with ILD include exercise-induced arterial hypoxemia, an exaggerated ventilatory response, a rapid and shallow breathing pattern, critically low inspiratory reserve volume, and elevated sensations of dyspnea and leg discomfort. CPET is used in ILD to determine cause(s) of symptoms such as exertional dyspnea, evaluate functional capacity, inform exercise prescription, and determine the effects of pharmacological and non-pharmacological interventions on exercise capacity and exertional symptoms. However, preliminary evidence suggests that CPET in ILD may also provide valuable prognostic information and can be used to ascertain the degree of exercise-induced pulmonary hypertension. Despite these recent advances, additional research is required to confirm the utility of CPET in patients with ILD. This brief review outlines the clinical utility of CPET in patients with ILD. Typical patterns of response are described and practical issues concerning CPET interpretation in ILD are addressed. Additionally, important unanswered questions relating to the clinical utility of CPET in the assessment, prognostication, and management of patients with ILD are identified.

Isolated Exercise-Induced Pulmonary Hypertension Associates with Higher Cardiovascular Risk in Scleroderma Patients.

Background and Aim: Isolated exercise-induced pulmonary hypertension (ExPH) associates with cardiovascular (CV) events in patients with left heart disease. We investigated its prognostic significance in scleroderma patients at risk for pulmonary arterial hypertension (PAH). Methods: In 26 consecutive scleroderma female patients with either low (n = 13) or intermediate probability (n = 13) of pulmonary hypertension (PH) at rest, we evaluated, both at time 0 and 1 year, prognostic determinants of CV risk: onset or progression of heart failure/syncope; worsening of functional class; functional performance at the 6-minute walking test and at cardiopulmonary exercise test; right atrial area; and pericardial effusion. We assigned a severity score 1–3 to each prognostic determinant, derived an overall CV risk score, and its 0–1 year change. Isolated ExPH during the cardiopulmonary exercise test (CPET) was defined as absence of PH at rest, reduced peak VO2, VE/VCO2 >30 at anaerobic threshold, reduced O2 pulse, and ΔVO2/ΔW <9 mL/min/W. We then correlated ExPH at time 0 with clinical worsening (risk score increase >20% after 1 year). Results: ExPH was strongly associated with clinical worsening compared to patients without ExPH (p = 0.005). In patients without ExPH, none had > 20% increased CV risk score after 1 year. Conversely, about 50% of patients with ExPH had such an increase, suggesting a worsening of prognosis. Conclusions: Isolated ExPH associates with higher cardiovascular risk and thus clinical worsening in scleroderma patients. The assessment of ExPH by CPET can thus contribute to a better risk stratification and the planning of a more adequate follow-up.

Exercise intolerance in heart failure: The important role of pulmonary hypertension

What is the topic of this review? This review concerns the negative impact of pulmonary hypertension (PH) on the pulmonary haemodynamic and gas exchange responses to exercise, considering the mechanisms by which PH plays a role in exercise intolerance in heart failure (HF) patients. What advances does it highlight? The hallmark limited pulmonary vascular 'reserve' and impaired pulmonary gas exchange responses to exercise in HF are worsened by the development of PH; these are key determinants of exercise intolerance. Even HF patients who present with 'normal' pulmonary vascular function experience exercise-induced PH, which plays a role in exercise intolerance. Patients with heart failure universally complain of exertional intolerance, but the underlying cause(s) of this intolerance may differ between patients with different disease phenotypes. Exercise introduces an impressive stress to the lungs, where elevations in venous return and cardiac output engender substantial increases in pulmonary blood volume and flow. Relative to healthy individuals, the pulmonary vascular reserve to accept this increase in pulmonary perfusion is compromised in heart failure, with a growing body of evidence suggesting that the development of pulmonary hypertension (PH), and in particular a precapillary component of PH, worsens the pulmonary haemodynamic response to exercise in these patients. Characterized by an exaggerated increase in pulmonary arterial pressure and an elevation in pulmonary vascular resistance, this dysfunctional pulmonary haemodynamic response plays a role in exercise intolerance, probably through an impairment of right ventricular function, underperfusion of the pulmonary circulation and a subsequent reduction in systemic blood flow and oxygen delivery. The hallmark abnormalities in ventilatory and pulmonary gas exchange that accompany heart failure, including a greater ventilatory equivalent for carbon dioxide, are also worsened by the development of PH. This raises the possibility that measures of exercise pulmonary gas exchange might help to 'describe' underlying PH in heart failure; however, several fundamental issues and questions need to be addressed before such gas exchange measures could truly be considered efficacious measures used to differentiate the type of PH and track the severity of PH in heart failure. exercise intolerance, heart failure, pulmonary gas exchange, pulmonary haemodynamics, pulmonary hypertension.

Pulmonary Artery Systolic Pressure Response to Exercise in Patients with Rheumatic Mitral Stenosis: Determinants and Prognostic Value

Pulmonary hypertension in response to exercise is a marker of the hemodynamic severity of mitral stenosis (MS). However, the factors related to elevated pulmonary pressure with exercise are not well defined. The aim of this study was to assess the parameters associated with the pulmonary pressure response to exercise in patients with pure rheumatic MS. An additional aim was to determine the impact of exercise-induced pulmonary hypertension on clinical outcome. One hundred thirty patients with MS (94% women; mean age, 45±11years) underwent exercise echocardiography. A range of echocardiographic parameters were obtained at rest and at peak exercise. Symptom-limited graded ramp bicycle exercise was performed in the supine position. The primary end point was mitral valve intervention, either percutaneous or surgical. In the overall population, systolic pulmonary artery pressure (SPAP) increased from 38.3±13.4mm Hg at rest to 65.8±20.7mm Hg during exercise. Increases in mean mitral gradient, right ventricular function, left atrial volume, and net atrioventricular compliance were independently associated with SPAP at peak exercise, after adjusting for changes in heart rate. During the follow-up period (median, 17months; range, 1-45months), 46 adverse clinical events were observed. By multivariate Cox proportional-hazards analysis adjusted for age and sex, SPAP achieved at peak exercise was an important predictor of adverse outcome (adjusted hazard ratio, 1.025; 95% CI, 1.010-1.040; P=.001). New York Heart Association functional class (adjusted hazard ratio, 2.459; 95% CI, 1.509-4.006; P<.001) and the interaction between valve area and net atrioventricular compliance (P=.001) were also significant predictors of adverse events. Time-dependent areas under the receiver operating characteristic curve for the model with SPAP during exercise were better than for the model with SPAP at rest, with a significant improvement from 3years onward. In patients with MS, the pulmonary artery pressure response to exercise is determined by a combination of factors, including transmitral mean gradient at exercise, net atrioventricular compliance, left atrial volume, and right ventricular function. Pulmonary artery pressure at peak exercise is a predictor of clinical outcomes and adds incremental prognostic value beyond that provided by standard resting measurements, including valve area.

P942 Outcome prediction by exercise stress echocardiography and cardiopulmonary exercise testing assessment in patients with heart failure

Abstract Background Cardiopulmonary exercise testing (CPX) is essential to the assessment of functional impairment and prognosis in patients with heart failure (HF). Peak oxygen consumption (peak VO2) continues to be considered the gold standard for assessing prognosis in HF. The minute ventilation-carbon dioxide production (VE-VCO2) slope has recently demonstrated prognostic significance in patients with HF. Ergometer stress echocardiography (Erg-Echo) is useful to evaluate the exercise-induced pulmonary hypertension and the potential cardiac dysfunction that are difficult to evaluate in the resting state. Objective The aim of this study is to evaluate the relationship between CPX and Erg-echo indices, and the usefulness of Erg-echo to determine the severity of cardiac dysfunction and the prognosis in patients with HF. Methods We studied 58 patients with HF (age 65.2 ± 11.9 years) and performed CPX and Erg-Echo. The peak VO2 and the VE-VCO2 slope were measured by CPX. Cardiac output (CO) and estimated mean pulmonary artery pressure (mPAP) were measured by Erg-Echo at rest and peak exercise load, and the change ratio (ΔmPAP / ΔCO) were calculated. We evaluated the clinical outcome during a1 year period. Results The ΔmPAP / ΔCO was significantly correlated with the peak VO2 (R = -0.6767, P &amp;lt;0.0001) and the VE-VCO2 slope (R = 0.6809, P &amp;lt;0.0001). Cardiovascular events (1 patient of cardiovascular death, 8 patients of re-hospitalization due to HF, 4 patients of myocardial ischemia, 2 patients of Cardiac Resynchronization Therapy (CRT) devices implantation, 1 patient of ventricular tachycardia) developed in 16 of the 58 patients (27.5%: Group CE) during the 1 year. The peak VO2 was significantly lower (12.1 ± 2.5 vs. 16.1 ± 3.1ml/min/kg, P &amp;lt;0.0001) and the VE-VCO2 slope was significantly higher (41.1 ±. 12.3 vs. 31.8 ± 6.1ml/ml, P &amp;lt;0.0001) in Group CE compared to the other 42 patients (Group N). The ΔmPAP was significantly higher (19.1 ± 4.4 vs. 14.9 ± 6.4, P = 0.0408) and the ΔCO was significantly lower (2.4 ± 1.2 vs. 4.1 ± 2.0, P = 0.0078), and the ΔmPAP / ΔCO was significantly higher (9.7 ± 4.6 vs. 4.4 ± 2.4, P &amp;lt;0.0001) in Group CE compared to Group N. Conclusions The ΔmPAP/ ΔCO by Erg-Echo is useful to evaluate the severity of cardiac dysfunction and the prognosis of HF patients.

Noninvasive evaluation of pulmonary artery pressure during exercise: the importance of right atrial hypertension.

Identification of elevated pulmonary artery pressures during exercise has important diagnostic, prognostic and therapeutic implications. Stress echocardiography is frequently used to estimate pulmonary artery pressures during exercise testing, but data supporting this practice are limited. This study examined the accuracy of Doppler echocardiography for the estimation of pulmonary artery pressures at rest and during exercise. Simultaneous cardiac catheterisation-echocardiographic studies were performed at rest and during exercise in 97 subjects with dyspnoea. Echocardiography-estimated pulmonary artery systolic pressure (ePASP) was calculated from the right ventricular (RV) to right atrial (RA) pressure gradient and estimated RA pressure (eRAP), and then compared with directly measured PASP and RAP. Estimated PASP was obtainable in 57% of subjects at rest, but feasibility decreased to 15-16% during exercise, due mainly to an inability to obtain eRAP during stress. Estimated PASP correlated well with direct PASP at rest (r=0.76, p<0.0001; bias -1 mmHg) and during exercise (r=0.76, p=0.001; bias +3 mmHg). When assuming eRAP of 10 mmHg, ePASP correlated with direct PASP (r=0.70, p<0.0001), but substantially underestimated true values (bias +9 mmHg), with the greatest underestimation among patients with severe exercise-induced pulmonary hypertension (EIPH). Estimation of eRAP during exercise from resting eRAP improved discrimination of patients with or without EIPH (area under the curve 0.81), with minimal bias (5 mmHg), but wide limits of agreement (-14-25 mmHg). The RV-RA pressure gradient can be estimated with reasonable accuracy during exercise when measurable. However, RA hypertension frequently develops in patients with EIPH, and the inability to noninvasively account for this leads to substantial underestimation of exercise pulmonary artery pressures.