Elbehairy AF; Geneidy NM; Elhoshy MS; Elsanhoury D; Elfeky MK; Abd-Elhameed A; Horsley A; O’Donnell DE;
Abd-Elwahab NH; Mahmoud MI;

Chest [Chest] 2022 Sep 29.
Date of Electronic Publication: 2022 Sep 29.

Background: Reduced exercise capacity has been previously reported in patients with obstructive sleep apnea hypopnea syndrome (OSAHS); though the underlying mechanisms are unclear.
Research Question: What are the underlying mechanisms of reduced exercise capacity in untreated patients with OSAHS? Is there a role for systemic or pulmonary vascular abnormalities?
Study Design and Methods: This is a cross-sectional observational study in which 14 patients with moderate-severe OSAHS and 10 control subjects (matched for age, body mass index (BMI), smoking history and FEV ₁ ) underwent spirometry, incremental cycle cardiopulmonary exercise test (CPET) with arterial line, resting echocardiogram and assessment of arterial stiffness (pulse wave velocity (PWV) and augmentation index (AIx)).
Results: Patients (age:50±11 years, BMI: 30.5±2.7kg/m ² , smoking: 2.4±4.0 pack-years, FEV ₁ /FVC: 0.78±0.04%, FEV ₁ :85±14 %predicted; mean±SD) had apnea hypopnea index of 43±19/hour. At rest, PWV, AIx, and mean pulmonary artery pressure (mPAP) were higher in patients vs. control subjects, P<.05. During CPET, patients had lower peak work rate (WR) and oxygen uptake; and greater dyspnea ratings compared with control subjects, all P<.05. Minute ventilation (V _E ), ventilation/CO ₂ output (V _E /VCO ₂ ), and dead space/tidal volume (V _D /V _T ) were greater in patients vs. control subjects during exercise (all P<.05). Reduction in V _D /V _T from rest to peak exercise was greater in control subjects compared with patients (0.24±0.08 vs. 0.04±0.14, P=.001). Dyspnea intensity at the highest equivalent WR correlated with corresponding values of V _E /VCO ₂ (r=0.65, P=.002), and dead space ventilation (r=0.70, P=.001). Age, PWV and mPAP explained ∼70% of the variance in peak WR, while predictors of dyspnea during CPET were rest-to-peak change in V _D /V _T and PWV (Rsqr=0.50, P<.001).
Interpretation: Patients with OSAHS had evidence of pulmonary gas exchange abnormalities during exercise (in the form of increased dead space) and resting systemic vascular dysfunction which may explain reduced exercise capacity and increased exertional dyspnea intensity.

Bayonas-Ruiz A; Muñoz-Franco FM; Sabater-Molina M; Oliva-Sandoval MJ; Gimeno JR; Bonacasa B;

ESC heart failure [ESC Heart Fail] 2022 Oct 01.
Date of Electronic Publication: 2022 Oct 01.

Aims: The aim of this study was to synthesize the evidence on the effect of the current therapies over the pathophysiological and clinical characteristics of patients with hypertrophic cardiomyopathy (HCM).
Methods and Results: A systematic review and meta-analysis of 41 studies identified from 1383 retrieved from PubMed, Web of Science, and Cochrane was conducted. Therapies were grouped in pharmacological, invasive and physical exercise. Pharmacological agents had no effect on functional capacity measured by VO2max (1.11 mL/kg/min; 95% CI: -0.04, 2.25, P < 0.05). Invasive septal reduction therapies increased VO2max (+3.2 mL/kg/min; 95% CI: 1.78, 4.60, P < 0.05). Structured physical exercise programmes did not report contraindications and evidenced the highest increases on functional capacity (VO2max + 4.33 mL/kg/min; 95% CI: 0.20, 8.45, P < 0.05). Patients with left ventricular outflow tract (LVOT) obstruction at rest improved their VO2max to a greater extent compared with those without resting LVOT obstruction (2.82 mL/kg/min; 95% CI: 1.97, 3.67 vs. 1.18; 95% CI: 0.62, 1.74, P < 0.05). Peak LVOT gradient was reduced with the three treatment options with the highest reduction observed for invasive therapies. Left ventricular ejection fraction was reduced in pharmacological and invasive procedures. No effect was observed after physical exercise. Symptomatic status improved with the three options and to a greater extent with invasive procedures.
Conclusions: Invasive septal reduction therapies increase VO2max, improve symptomatic status, and reduce resting and peak LVOT gradient, thus might be considered in obstructive patients. Physical exercise emerges as a coadjuvant therapy, which is safe and associated with benefits on functional capacity. Pharmacological agents improve reported NYHA class, but not functional capacity.

Kulej-Lyko K; Niewinski P; Tubek S; Krawczyk M; Kosmala W; Ponikowski P;

Frontiers in physiology [Front Physiol] 2022 Aug 30; Vol. 13, pp. 911636.
Date of Electronic Publication: 2022 Aug 30 (Print Publication: 2022).

Peripheral chemoreceptors (PChRs) play a significant role in maintaining adequate oxygenation in the bloodstream. PChRs functionality comprises two components: tonic activity (PChT) which regulates ventilation during normoxia and acute reflex response (peripheral chemosensitivity, PChS), which increases ventilation following a specific stimulus. There is a clear link between augmented PChS and exercise intolerance in patients with heart failure with reduced ejection fraction. It has been also shown that inhibition of PChRs leads to the improvement in exercise capacity. However, it has not been established yet: 1) whether similar mechanisms take part in heart failure with preserved ejection fraction (HFpEF) and 2) which component of PChRs functionality (PChT vs. PChS) is responsible for the benefit seen after the acute experimental blockade. To answer those questions we enrolled 12 stable patients with HFpEF. All participants underwent an assessment of PChT (attenuation of minute ventilation in response to low-dose dopamine infusion), PChS (enhancement of minute ventilation in response to hypoxia) and a symptom-limited cardiopulmonary exercise test on cycle ergometer. All tests were placebo-controlled, double-blinded and performed in a randomized order. Under resting conditions and at normoxia dopamine attenuated minute ventilation and systemic vascular resistance ( p = 0.03 for both). These changes were not seen with placebo. Dopamine also decreased ventilatory and mean arterial pressure responses to hypoxia ( p < 0.05 for both). Inhibition of PChRs led to a decrease in V˙E/V˙CO ₂ comparing to placebo (36 ± 3.6 vs. 34.3 ± 3.7, p = 0.04), with no effect on peak oxygen consumption. We found a significant relationship between PChT and the relative decrement of V˙E/V˙CO ₂ on dopamine comparing to placebo (R = 0.76, p = 0.005). There was a trend for correlation between PChS (on placebo) and V˙E/V˙CO ₂ during placebo infusion (R = 0.56, p = 0.059), but the relative improvement in V˙E/V˙CO ₂ was not related to the change in PChS (dopamine vs. placebo). We did not find a significant relationship between PChT and PChS. In conclusion, inhibition of PChRs in HFpEF population improves ventilatory efficiency during exercise. Increased PChS is associated with worse (higher) V˙E/V˙CO ₂ , whereas PChT predicts an improvement in V˙E/V˙CO ₂ after PChRs inhibition. This results may be meaningful for patient selection in further clinical trials involving PChRs modulation.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Douschan P; Kovacs G; Sassmann T; Stadlbauer V; Avian A; Foris V;Tatscher E; Durchschein F; Rainer F; Spindelboeck W; Wagner M; Kniepeiss D; Zollner G; Bachmaier G; Fickert P;Olschewski H; Stauber RE;

Respiratory medicine [Respir Med] 2022 Sep 12; Vol. 202, pp. 106987.
Date of Electronic Publication: 2022 Sep 12.

Background & Aims: Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are severe pulmonary vascular complications of chronic liver disease and strongly associated with morbidity and mortality. The prevalence of these complications is relatively high in patients evaluated for liver transplantation, however it is virtually unknown in patients with stable chronic liver disease.
Methods: We assessed the pulmonary hypertension (PH) and HPS prevalence in a prospective registry study of our liver out-patient clinic in a tertiary center. Between 2011 and 2016, consecutive patients with cirrhosis or non-cirrhotic portal hypertension were prospectively enrolled after written informed consent. We excluded patients with acute decompensation of liver disease and other causes of PH like severe chronic heart or lung diseases and chronic thromboembolic PH. HPS was diagnosed using contrast enhanced echocardiography and blood gas analysis. Patients were screened for PH using an algorithm implementing severity of dyspnea, echocardiography, cardiopulmonary exercise testing and exercise echocardiography employing a threshold of systolic pulmonary arterial pressure (SPAP) = 50 mmHg at peak exercise. If the algorithm indicated an increased PH risk, patients were invited for invasive investigations by means of right heart and hepatic vein catheter. We defined POPH as resting mPAP≥21 mmHg and PVR>3WU and PAWP<15 mmHg, mild PH as resting mPAP = 21-24 mmHg, and exercise PH as mPAP>30 mmHg and TPR >3 WU at peak exercise.
Results: Two-hundred-five patients were enrolled (male 75%; cirrhosis 96%; median age 57 yrs). Sixty-seven patients (33%) fulfilled HPS criteria but only two (1.0%) for severe (PaO2:50-60 mmHg) or very severe HPS (PaO2<50 mmHg). In 18/77 patients (23%) undergoing exercise echocardiography, SPAP at peak exercise exceeded 50 mmHg. Finally, n = 3 (1.5%) patients were invasively diagnosed with POPH, n = 4 (2.9%) with mild PH and n = 2 with exercise PH.
Conclusion: In chronic liver disease, excluding acute decompensation and other causes of PH, POPH and severe HPS are rare findings while mild to moderate HPS and mild PH or exercise PH are more frequent.
Competing Interests: Declaration of competing interest R.S. and H·O.: research grant from Glaxo Smith Kline, Vienna, Austria; all other authors declare no conflicts of interest related to the study.

Ishizaka S; Iwano H; Tsujinaga S;Murayama M; Tsuneta S; Aoyagi H; Tamaki Y; Motoi K;Chiba Y; Tanemura A; Nakabachi M; Yokoyama S; Nishino H; Okada K; Meyers BA;Vlachos PP; Sato T; Kamiya K; Watanabe M; Kaga S; Nagai T; Oyama-Manabe N; Anzai T;

Journal of cardiology [J Cardiol] 2022 Sep 16.
Date of Electronic Publication: 2022 Sep 16.

Background: Determinants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated.
Methods: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO ₂ ). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s’) and early diastolic mitral annular velocities (e’), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s’) were measured at rest and exercise. E/e’ and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively.
Results: During exercise, CO, LV-s’, RV-s’, e’, and SPAP were significantly increased (p < 0.05 for all), whereas E/e’ remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO ₂ . In univariable analyses, LV-s’ (R = 0.35, p = 0.022), SPAP (R = -0.40, p = 0.008), RV-s’ (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO ₂ . In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO ₂ even after the adjustment for clinically relevant parameters.
Conclusions: In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure.

Schwendinger F; Knaier R; Radtke T; Schmidt-Trucksäss A;

Sports medicine (Auckland, N.Z.) [Sports Med] 2022 Sep 17.
Date of Electronic Publication: 2022 Sep 17.

Patients recovering from COVID-19 often report symptoms of exhaustion, fatigue and dyspnoea and present with exercise intolerance persisting for months post-infection. Numerous studies investigated these sequelae and their possible underlying mechanisms using cardiopulmonary exercise testing. We aimed to provide an in-depth discussion as well as an overview of the contribution of selected organ systems to exercise intolerance based on the Wasserman gears. The gears represent the pulmonary system, cardiovascular system, and periphery/musculature and mitochondria. Thirty-two studies that examined adult patients post-COVID-19 via cardiopulmonary exercise testing were included. In 22 of 26 studies reporting cardiorespiratory fitness (herein defined as peak oxygen uptake-VO _2peak ), VO _2peak was < 90% of predicted value in patients. VO _2peak was notably below normal even in the long-term. Given the available evidence, the contribution of respiratory function to low VO _2peak seems to be only minor except for lung diffusion capacity. The prevalence of low lung diffusion capacity was high in the included studies. The cardiovascular system might contribute to low VO _2peak via subnormal cardiac output due to chronotropic incompetence and reduced stroke volume, especially in the first months post-infection. Chronotropic incompetence was similarly present in the moderate- and long-term follow-up. However, contrary findings exist. Peripheral factors such as muscle mass, strength and perfusion, mitochondrial function, or arteriovenous oxygen difference may also contribute to low VO _2peak . More data are required, however. The findings of this review do not support deconditioning as the primary mechanism of low VO _2peak post-COVID-19. Post-COVID-19 sequelae are multifaceted and require individual diagnosis and treatment.