Author Archives: Paul Older

Inhibition of peripheral chemoreceptors improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction – a role of tonic activity and acute reflex response.

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.

Pulmonary vascular disease and exercise hemodynamics in chronic liver disease.

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.

Determinants of exercise capacity in patients with heart failure without left ventricular hypertrophy.

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.

Low Cardiorespiratory Fitness Post-COVID-19: A Narrative Review.

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.

Long-term comprehensive cardiopulmonary phenotyping of COVID-19.

Kimmig LM; Rako ZA; Ziegler S; Richter MJ; G S AT; Roller F; Grimminger F; Vadász I; Seeger W; Herold S; Tello K; Matt U;

Respiratory research [Respir Res] 2022 Sep 21; Vol. 23 (1), pp. 263.
Date of Electronic Publication: 2022 Sep 21.

Background: Persistent symptoms after initial COVID-19 infection are common and are frequently referred to by the umbrella terms “post-COVID syndrome” and “long COVID”. The sheer number of affected patients pose an increasing challenge to healthcare systems worldwide. To date, our understanding of the pathophysiology of the post-COVID syndrome remains poor and the extent to which persistent cardiopulmonary abnormalities contribute to the symptom complex is unclear. We sought to determine the presence and impact of cardiopulmonary sequelae after COVID-19 in longitudinal assessment.
Methods: We report on 71 patients who underwent comprehensive, longitudinal testing in regular intervals for up to 12 months after their initial COVID-19 diagnosis. Testing included pulmonary function testing, cardiopulmonary exercise testing, dedicated left and right heart echocardiography, lung ultrasonography, and cardiac MRI.
Results: Our results demonstrate that subjective quality of life after COVID-19 (EQ-5D visual acuity scale, VAS, 67.4 for patients treated as outpatient, 79.2 for patients admitted to the general floor, 71.8 for patients treated in an ICU) is not related to the severity of the initial infection. Maximal exercise capacity is also reduced (VO 2 max 79% predicted, SD ± 19%); however, this is driven in large parts by patients who had initially required ICU-level of care. The degree of objective reduction in exertion did not correlate with quality of life scores. Pulmonary function testing revealed mild and persistent reduction in D LCO over the first 12 months without significant restrictive or obstructive lung disease. Left and right heart function was intact with good RV function and intact RV/PA coupling, imaging findings suggestive of myocarditis were uncommon (7% of patients).
Conclusion: A reduction in exercise capacity after COVID-19 is common, but is most prominent in patients previously treated in the ICU and more likely related to deconditioning or fatigue than to cardiopulmonary impairment. Subjective quality of life scores are independent of the severity of initial infection and do not correlate with objective measures of cardiopulmonary function. In our cohort, persistent cardiopulmonary impairment after COVID-19 was uncommon. The post-COVID syndrome is unlikely to be the result of cardiopulmonary sequalae and may reflect a post-ICU syndrome in some.

Exertional dyspnoea in patients with mild-to-severe chronic obstructive pulmonary disease: neuromechanical mechanisms.

James MD; Phillips DB; Vincent SG; Abdallah SJ; Donovan AA; de-Torres JP;
Neder JA; Smith BM; Jensen D; O’Donnell DE;

Journal of Physiology. 600(18):4227-4245, 2022 Sep.VI 1

In patients with chronic obstructive pulmonary disease (COPD), exertional
dyspnoea generally arises when there is imbalance between ventilatory
demand and capacity, but the neurophysiological mechanisms are unclear. We
therefore determined if disparity between elevated inspiratory neural
drive (IND) and tidal volume (VT ) responses (neuromechanical
dissociation) impacted dyspnoea intensity and quality during exercise,
across the COPD severity spectrum. In this two-centre, cross-sectional
observational study, 89 participants with COPD divided into tertiles of
FEV1 %predicted (Tertile 1 = FEV1 = 87 +/- 9%, Tertile 2 = 60 +/- 9%,
Tertile 3 = 32 +/- 8%) and 18 non-smoking controls, completed a
symptom-limited cardiopulmonary exercise test (CPET) with measurement of
IND by diaphragm electromyography (EMGdi (%max)). The association between
increasing dyspnoea intensity and EMGdi (%max) during CPET was strong (r =
0.730, P < 0.001) and not different between the four groups who showed
marked heterogeneity in pulmonary gas exchange and mechanical
abnormalities. Significant inspiratory constraints (tidal
volume/inspiratory capacity (VT /IC) >= 70%) and onset of neuromechanical
dissociation (EMGdi (%max):VT /IC > 0.75) occurred at progressively lower
minute ventilation ( V E ${\dot{V}}_{{\rm{E}}}$ ) from Control to Tertile
3. Lower resting IC meant earlier onset of neuromechanical dissociation,
heightened dyspnoea intensity and greater propensity (93% in Tertile 3) to
select qualitative descriptors of ‘unsatisfied inspiration’. We concluded
that, regardless of marked variation in mechanical and pulmonary gas
exchange abnormalities in our study sample, exertional dyspnoea intensity
was linked to the magnitude of EMGdi (%max). Moreover, onset of critical
inspiratory constraints and attendant neuromechanical dissociation
amplified dyspnoea intensity at higher exercise intensities. Simple
measurements of IC and breathing pattern during CPET provide useful
insights into mechanisms of dyspnoea and exercise intolerance in
individuals with COPD.

KEY POINTS: Dyspnoea during exercise is a common
and troublesome symptom reported by patients with chronic obstructive
pulmonary disease (COPD) and is linked to an elevated inspiratory neural
drive (IND). The precise mechanisms of elevated IND and dyspnoea across
the continuum of airflow obstruction severity in COPD remains unclear. The
present study sought to determine the mechanisms of elevated IND (by
diaphragm EMG, EMGdi (%max)) and dyspnoea during cardiopulmonary exercise
testing (CPET) across the continuum of COPD severity. There was a strong
association between increasing dyspnoea intensity and EMGdi (%max) during
CPET across the COPD continuum despite significant heterogeneity in
underlying pulmonary gas exchange and respiratory mechanical impairments.
Critical inspiratory constraints occurred at progressively lower
ventilation during exercise with worsening severity of COPD. This was
associated with the progressively lower resting inspiratory capacity with
worsening disease severity. Earlier critical inspiratory constraint was
associated with earlier neuromechanical dissociation and greater
likelihood of reporting the sensation of ‘unsatisfied inspiration’.


Pellegrino A; Casatori L; Messineo A; Ghionzoli M;Facchini F; Modesti A; Modesti PA;

Journal of hypertension [J Hypertens] 2022 Jun 01; Vol. 40 (Suppl 1), pp. e294.

Objective: Exercise training increases muscle VO2 by increasing O2 transport and O2 uptake positively affecting cardiac output. In subjects with pectus excavatum cardiac output increase during exercise might be limited by the conformation of the chest. In this condition, the psychological impact of the deformity can further reduce the propensity to physical activity, leading to a sedentary lifestyle. Surgery is the preferred choice in severe cases. However, many patients with milder deformities can benefit from exercise-based treatment. The choice of the therapeutic strategy is fundamental, but the functional parameters on which to base this choice are not yet well defined. Therefore, we investigated the relationships between habitual physical activity and functional physiological parameters obtained from the cardiopulmonary exercise test (exercise performance and stroke volume at peak exercise) in pectus excavatum.
Design and Method: A cohort of adolescents (15 with pectus excavatum and 15 age- and sex-matched healthy controls) underwent Cardiopulmonary Exercise Test to estimate exercise performance (VO2 max) and stroke volume at peak exercise (VO2/HR, O2 pulse). Habitual weekly physical activity, estimated with International Physical Activity Questionnaire – Short Form (IPAQ-SF), was expressed as METs h-1·week-1. Determinants of exercise performance and stroke volume at peak exercise were investigated in the whole group with multivariable linear regression analysis adjusted for sex, body mass index, forced expiratory volume in the first second, and presence of pectus excavatum.
Results: When compared to healthy controls, subjects with pectus excavatum had lower VO2 max (37.2 ± 6.6 vs 45.4 ± 6.4 mL·kg-1·min-1, p < 0.05), and O2 pulse (12.1 ± 2.4 vs 16.2 ± 3.6 mL·min-1·bpm-1, p < 0.05). Importantly, physical activity level was a predictor of VO2 max (B = 0.085; 95% Cl 0.010 to 0.160) while it did not affect O2 pulse (B = 0.035; 95% Cl -0.004 to 0.074).
Conclusions: Training programs should be encouraged to increase cardiopulmonary performance in subjects with pectus excavatum. A marked reduction in O2 pulse at peak exercise might be considered as a criteria to address a subject towards surgery.


Kariori M; Fragoulis C;Chrysochoou C;Leontsinis I;Mantzouranis E;Iliakis P;Konstantinidis D;Konstantinou K;Andrikou I;Kalos T;Grigoriou K;Tsioufis K

Journal of hypertension [J Hypertens] 2022 Jun 01; Vol. 40 (Suppl 1), pp. e176.

Objective: There is little data concerning the impact of arterial hypertension (HTN) on the cardiopulmonary status and right ventricle (RV) function of patients with SARS-Cov-2 infection. The purpose of our study was to investigate whether HTN affects the functional status of hospitalized for SARS-Cov-2 patients, using cardiopulmonary test and echocardiographic parameters, 3 months after the first day of infection.
Design and Method: Subjects who were hospitalized and survived Covid-19 infection were divided into two groups according to history of HTN. All subjects underwent cardiorespiratory exercise using Bruce or modified Bruce protocol evaluating all parameters. Echocardiographic findings including right ventricle strain were analyzed using an offline program.
Results: A total population of 52 hospitalized Sars-Cov-2 patients with a mean age of 57 ± 11.5 years were evaluated 3 months after the symptoms onset. Males amounted to 51.9 %. History of coronary artery disease was recorded in 15.4% of them. In hypertensive subjects, age (63 ± 8 vs. 52 ± 11 years, p < 0.001), BMI (29.9 ± 4.6 vs. 27.1 ± 5.8 kg/m2, p:0.03) and BSA (2.1 ± 0.25 vs. 2 ± 0.9 m2, p:0.04) were significantly higher. When analyzing cardiopulmonary test parameters, only maximum systolic blood pressure ((SBP, mmHg), 190 ± 21 vs.171 ± 26, p: 0.02) at peak and during the 1st minute of recovery (180 ± 23 vs. 157 ± 27 mmHg, p: 0.005) were higher comparing to normotensive subjects. Furthermore, diameter of left atrium ((LA, mm), 42 ± 6 vs.38 ± 6 p: 0.009), left ventricle ejection fraction ((LVEF,%), 48 ± 11 vs. 57 ± 6, p:0.004) and the absolute mean value of right ventricle strain ((RVLS, %), 9.1 ± 4 vs. 12.7 ± 5.4, p:0.04) differed significantly between two groups. Using linear regression analysis adjusted for age, gender, HTN, coronary heart disease and LVEF, HTN.
Conclusions: Our study highlighted negative impact of HTN both in right and left ventricle functionality, implying HTN as a negative independent predictive factor for right ventricle strain in patients hospitalized for SARS-Cov-2.

Effects of Exercise on Heart Failure with Preserved Ejection Fraction: An Updated Review of Literature.

Crisci G; De Luca M; D’Assante R; Ranieri B; D’Agostino A; IValente V; Giardino F;Capone V; Chianese S; Rega S; Cocchia R; Israr MZ; Debiek R; Heaney LM; Salzano A;

Journal of cardiovascular development and disease [J Cardiovasc Dev Dis] 2022 Jul 28; Vol. 9 (8).
Date of Electronic Publication: 2022 Jul 28.

Heart failure with preserved ejection fraction (HFpEF) represents the most common HF phenotype of patients aged &gt; 65 years, with an incidence and a prevalence that are constantly growing. The HFpEF cardinal symptom is exercise intolerance (EI), defined as the impaired ability to perform physical activity and to reach the predicted age-related level of exercise duration in the absence of symptoms-such as fatigue or dyspnea-and is associated with a poor quality of life, a higher number of hospitalizations, and poor outcomes. The evidence of the protective effect between exercise and adverse cardiovascular outcomes is numerous and long-established. Regular exercise is known to reduce cardiovascular events and overall mortality both in apparently healthy individuals and in patients with established cardiovascular disease, representing a cornerstone in the prevention and treatment of many cardio-metabolic conditions. Several studies have investigated the role of exercise in HFpEF patients. The present review aims to dwell upon the effects of exercise on HFpEF. For this purpose, the relevant data from a literature search (PubMed, EMBASE, and Medline) were reviewed. The analysis of these studies underlines the fact that exercise training programs improve the cardiorespiratory performance of HFpEF patients in terms of the increase in peak oxygen uptake, the 6 min walk test distance, and the ventilatory threshold; on the other hand, diastolic or systolic functions are generally unchanged or only partially modified by exercise, suggesting that multiple mechanisms contribute to the improvement of exercise tolerance in HFpEF patients. In conclusion, considering that exercise training programs are able to improve the cardiorespiratory performance of HFpEF patients, the prescription of exercise training programs should be encouraged in stable HFpEF patients, and further research is needed to better elucidate the pathophysiological mechanisms underpinning the beneficial effects described.

Muscle strength, aerobic capacity, and exercise tolerance are impaired in left ventricular assist devices recipients: A pilot study.

Gobbo S; Favro F; Bullo V; Cugusi L; Blasio AD; Bortoletto A; Bocalini DS; Gasperetti A;Ermolao A; Bergamin M;

Frontiers in physiology [Front Physiol] 2022 Aug 08; Vol. 13, pp. 967817.
Date of Electronic Publication: 2022 Aug 08 (Print Publication: 2022).

Background: Left ventricular assist devices (LVAD) are increasingly being used as a therapy for advanced heart failure, both as a bridge to heart transplant and, given the rapid advances in the LVAD’s functionality and safety, and constant lack in availability of donor organs, as long-term destination therapy. With the diffusion of such therapy, it is crucial to assess patients’ muscle strength, aerobic capacity and exercise tolerance, to improve their functional capacity.
Methods: 38 LVAD recipients (33 men and five women) were included. Exercise testing including a maximal cardiopulmonary exercise test (CPET), handgrip, isometric and isokinetic strength testing of knee and ankle flexion/extension, and Romberg balance test in three conditions (eyes open, eyes closed, double task). Given the small and heterogeneous final sample size, a mostly descriptive statistical approach was chosen.
Results: 12 participants were classified as “Obese” (BMI>29.9). The most common comorbidities were type II diabetes and chronic kidney disease. Only 12 participants were able to successfully complete all the assessments. CPET and isokinetic strength trials were the least tolerated tests, and the handgrip test the best tolerated. Mean VO 2 peak was 12.38 ± 3.43 ml/kg/min, with 15 participants below 50% of predicted VO 2 max, of which 6 below 30% VO 2 max. Mean handgrip strength was 30.05 ± 10.61 Kg; 25 participants were below the 25° percentile of their population’s normative reference values for handgrip strength, 10 of which were below the 5° percentile. Issues with the management of the external pack of the LVAD and its influence on the test limited the validity of the balance tests data, therefore, no solid conclusions could be drawn from them. VO 2 peak did not correlate with handgrip strength or with any of the lower limb strength measures.
Conclusion: LVAD recipients show greatly reduced functional capacity and tolerance to exercise and exercise testing, with low overall strength levels. As strength variables appear to be independent from VO 2 peak, different lower limbs strength tests should be explored to find a tolerable alternative in this population, which is subjected to muscle wasting due to old age, reduced tissue perfusion, side effects from the pharmacological therapies, and prolonged periods of bedrest.