Symptomatic post COVID patients have impaired alveolar capillary membrane function and high VE/VCO2.

BACKGROUND: Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients' reported symptomatology is still unclear. METHODS: Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. RESULTS: We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102-123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. CONCLUSIONS: In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

Do Androgenic Pattern, Insulin State and Growth Hormone Affect Cardiorespiratory Fitness and Strength in Young Women with PCOS?

In this study, cardiorespiratory fitness (CRF) and strength level were assessed in women with and without polycystic ovary syndrome (PCOS), matched for age, body composition, androgenic pattern and insulinemic pattern. Patients with and without PCOS were evaluated at the Endocrinology Unit and Sport Medicine Division to assess endocrinological (insulinemic, androgenic pattern and growth hormone), anthropometric (with DEXA) and functional parameters (with cardiopulmonary exercise test and handgrip test), as well as physical activity level (with the Global Physical Activity Questionnaire). A total of 31 patients with PCOS and 13 controls were included. No statistically significant differences were found between groups in terms of age, body mass index, body composition, androgenic pattern, insulin state, growth hormone and physical activity level. The PCOS group demonstrated significantly better cardiorespiratory fitness (VO2max per kg (30.9 ± 7.6 vs. 24.8 ± 4.1 mL/kg/min; p = 0.010), VO2max per kg of fat-free mass (52.4 ± 8.9 vs. 45.3 ± 6.2 mL/kg/min; p = 0.018)), strength levels (handgrip per kg (0.36 ± 0.09 vs. 0.30 ± 0.08; p = 0.009), handgrip per kg of fat-free mass (13.03 ± 2.32 vs. 11.50 ± 1.91; p = 0.001)) and exercise capacity (METs at test (14.4 ± 2.72 vs. 12.5 ± 1.72 METs; p = 0.019)). In this study, women with PCOS showed a better cardiorespiratory fitness and strength than the control group. The only determinant that could explain the differences observed seems to be the presence of the syndrome itself. These results suggest that PCOS per se does not limit exercise capacity and does not exclude good functional capacity.

The double anaerobic threshold in heart failure: MECKI score database overview.

AIMS: In heart failure (HF), anaerobic threshold (AT) may be indeterminable but its value held a relevant prognostic role. AT is evaluated joining three methods: V-slope, ventilatory equivalent, and end-tidal methods. The possible non-concordance between the V-slope (met AT) and the other two methods (vent AT) has been highlighted in healthy individuals and named double threshold (DT). METHODS AND RESULTS: We reanalysed 1075 cardiopulmonary exercise tests of HF patients recruited in the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score database. We identified DT in 43% of cases. Met AT precedes vent AT being met-ventΔVO2 221 (interquartile range: 129-319) mL/min. Peak VO2 , 1307 ± 485 vs. 1343 ± 446 mL/min (63 ± 17 vs. 63 ± 17 percentage of predicted), was similar between DT+ and DT- patients. Differently, DT+ showed a lower ventilatory vs. carbon dioxide production (VE/VCO2 ) slope (29.6 ± 6.1 vs. 31.0 ± 6.3), a lower peak exercise end-tidal oxygen tension (PetO2 ) 115.3 (111.5-118.9) vs. 116.4 (112.4-120.2) mmHg, and a higher carbon dioxide tension (PetCO2 ) 34.2 (30.9-37.1) vs. 32.4 (28.7-35.5) mmHg. Vent AT showed a significant higher VO2 , 957 ± 318 vs. 719 ± 252 mL/min, VCO2 , 939 ± 319 vs. 627 ± 226 mL/min, ventilation, 31.0 ± 8.3 vs. 22.5 ± 6.3 L/min, respiratory exchange ratio, 0.98 ± 0.08 vs. 0.87 ± 0.07, PetO2 , 108 (104-112) vs. 105 (101-109) mmHg, PetCO2 , 37 (34-40) vs. 36 (33-39) mmHg, and VE/VO2 ratio, 33.5 ± 6.7 vs. 32.6 ± 6.9, but lower VE/VCO2 ratio, 33 (30-37) vs. 36 (32-41), compared with met AT. At 2 year survival by Kaplan-Meier analysis, even adjusted for confounders, DT resulted not associated with survival. CONCLUSIONS: Double threshold is frequently observed in HF patients. DT+ is associated to a decreased ventilatory response during exercise.

Exercise oxygen pulse kinetics in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Reduced cardiac output (CO) has been considered crucial in symptoms' genesis in hypertrophic cardiomyopathy (HCM). Absolute value and temporal behaviour of O2-pulse (oxygen uptake/heart rate (VO2/HR)), and the VO2/work relationship during exercise reflect closely stroke volume (SV) and CO changes, respectively. We hypothesise that adding O2-pulse absolute value and kinetics, and VO2/work relationship to standard cardiopulmonary exercise testing (CPET) could help identify more exercise-limited patients with HCM. METHODS: CPETs were performed in 3 HCM dedicated clinical units. We retrospectively enrolled non-end-stage consecutive patients with HCM, grouped according to left ventricle outflow tract obstruction (LVOTO) at rest or during Valsalva manoeuvre (72% of patients with LVOTO <30; 10% between 30 and 49 and 18% ≥50 mm Hg). We evaluated the CPET response in HCM focusing on parameters strongly associated with SV and CO, such as O2-pulse and VO2, respectively, considering their absolute values and temporal behaviour during exercise. RESULTS: We included 312 patients (70% males, age 49±18 years). Peak VO2 (percentage of predicted), O2-pulse and ventilation to carbon dioxide production (VE/VCO2) slope did not change across LVOTO groups. Ninety-six (31%) patients with HCM presented an abnormal O2-pulse temporal behaviour, irrespective of LVOTO values. These patients showed lower peak systolic pressure, workload (106±45 vs 130±49 W), VO2 (21.3±6.6 vs 24.1±7.7 mL/min/kg; 74%±17% vs 80%±20%) and O2-pulse (12 (9-14) vs 14 (11-17) mL/beat), with higher VE/VCO2 slope (28 (25-31) vs 27 (24-31)) (p<0.005 for all). Only 2 patients had an abnormal VO2/work slope. CONCLUSION: None of the frequently used CPET parameters, either as absolute values or dynamic relationships, were associated with LVOTO. Differently, an abnormal temporal behaviour of O2-pulse during exercise, which is strongly related to inadequate SV increase, correlates with reduced functional capacity (peak and anaerobic threshold VO2 and workload) and increased VE/VCO2 slope, identifying more advanced disease irrespectively of LVOTO.

The double anaerobic threshold in heart failure.

BACKGROUND: Cardiopulmonary exercise test (CPET) has an important role in assessing heart failure (HF) patients. Among CPET parameters, a pivotal role is attributed to the anaerobic threshold (AT), normally determined by V-slope, ventilatory equivalent and end-tidal methods. In about 10% of healthy subjects, a lack of concordance between these methods has been reported. This event was named double AT (DT). We hypothesized that DT was due to a delay in chemoreflex response. METHODS: We reanalyzed CPET data of two cross-over studies in which we compared CPET in stable HF patients treated for two months with bisoprolol and carvedilol. In chronic HF, carvedilol has a greater sympathetic inhibition than bisoprolol, as shown by a lower chemoreflex response. RESULTS: In 87 patients, we identified DT in 46% and 66% of cases during bisoprolol and carvedilol treatment, respectively (p < 0.01). Compared with bisoprolol, carvedilol treatment was associated to a lower peak oxygen uptake (from 17.4 ± 4.3 to 16.4 ± 4.1 mL/min/kg) and oxygen pulse (from 11.8 ± 2.9 to 11.1 ± 2.9 mL/min/kg) suggestive of lower peak cardiac output. CONCLUSIONS: DT is frequent in HF and more often with carvedilol than bisoprolol treatment, may be due to a greater inhibition of sympathetic tone and prolonged circulatory time. These findings open an unexplored research field.

Evidence of a double anaerobic threshold in healthy subjects.

AIMS: The anaerobic threshold (AT) is an important cardiopulmonary exercise test (CPET) parameter both in healthy and in patients. It is normally determined with three approaches: V-slope method, ventilatory equivalent method, and end-tidal method. The finding of different AT values with these methods is only anecdotic. We defined the presence of a double threshold (DT) when a ΔVO2 > 15 mL/min was observed between the V-slope method (met AT) and the other two methods (vent AT). The aim was to identify whether there is a DT in healthy subjects. METHODS AND RESULTS: We retrospectively analysed 476 healthy subjects who performed CPET in our laboratory between 2009 and 2018. We identified 51 subjects with a DT (11% of cases). Cardiopulmonary exercise test data at rest and during the exercise were not different in subjects with DT compared to those without. Met AT always preceded vent AT. Compared to subjects without DT, those with DT showed at met AT lower carbon dioxide output (VCO2), end-tidal carbon dioxide tension (PetCO2) and respiratory exchange ratio (RER), and higher ventilatory equivalent for carbon dioxide (VE/VCO2). Compared to met AT, vent AT showed a higher oxygen uptake (VO2), VCO2, ventilation, respiratory rate, RER, work rate, and PetCO2 but a lower VE/VCO2 and end-tidal oxygen tension. Finally, subjects with DT showed a higher VO2 increase during the isocapnic buffering period. CONCLUSION: Double threshold was present in healthy subjects. The presence of DT does not influence peak exercise performance, but it is associated with a delayed before acidosis-induced hyperventilation.

Exercise Dynamic of Patients with Chronic Heart Failure and Reduced Ejection Fraction.

PURPOSE OF REVIEW: Exercise causes various dynamic changes in all body parts either in healthy subject or in heart failure (HF) patients. The present review of current knowledge about HF patients with reduced ejection fraction focuses on dynamic changes along a "metabo-hemodynamic" perspective. RECENT FINDINGS: Studies on the dynamic changes occurring during exercise span many years. Thanks to the availability of advanced methods, it is nowadays possible to properly characterize respiratory, hemodynamic, and muscular function adjustments and their mismatch with the pulmonary and systemic circulations. Exercise is a dynamic event that involves several body functions. In HF patients, it is important to know at what level the limitation takes place in order to better manage these patients and to optimize therapeutic strategies.

Sacubitril/valsartan use in a real-world population of patients with heart failure and reduced ejection fraction.

AIMS: Practice guidelines recommend sacubitril/valsartan for heart failure with reduced ejection fraction. The aim of our study was to describe the use of sacubitril/valsartan in real-world clinical practice to help identify patients best able to tolerate titration to higher doses. METHODS: We retrospectively analyzed clinical data for 201 patients with heart failure with reduced ejection fraction prescribed sacubitril/valsartan at our heart failure clinic (Centro Cardiologico Monzino) between September 2016/December 2018. Patients had a mean age of 67.2 years, mean left ventricular ejection fraction of 30.1%, New York Heart Association class II (65%), class III (35%), and poor cardiopulmonary exercise capacity. Median 2-year risk of death/urgent cardiac transplantation was 8.9% [Metabolic Exercise Cardiac Kidney Index (MECKI) score]. RESULTS: After a median follow-up of 230 (interquartile interval: 105-366) days, 57 patients achieved higher-dose sacubitril/valsartan, 103 tolerated medium/low doses, nine died, and 20 interrupted treatment. The highest dose of sacubitril/valsartan was reached by younger patients with better hemoglobin (Hb) levels, renal function, and blood pressure (BP). Patients continuing on sacubitril/valsartan had significantly higher serum Hb and sodium, better BP, and lower MECKI scores than patients who discontinued treatment or died during follow-up. Our patients were older and frailer than those in the pivotal PARADIGM-HF trial. CONCLUSION: In our experience, more than one-third of the patients were able to tolerate the higher dose of sacubitril/valsartan, and these patients were younger, had higher Hb, and better BP and renal function. MECKI score stratification was useful to discriminate patients who continued treatment from those who did not. Future prospective studies should test if these clinical variables can guide the up-titration of sacubitril/valsartan.

Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction.

AIMS: Ventilation vs. carbon dioxide production (VE/VCO2 ) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. METHODS AND RESULTS: We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13-83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2-year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). CONCLUSIONS: The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.

Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-range ejection fraction.

AIMS: Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (<40%, HFrEF) and with HF with preserved ejection fraction (>50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40-49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients. METHODS AND RESULTS: We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF, respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV- patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV- patients. Kaplan-Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV- of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18 months of follow-up. CONCLUSION: Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV- patients diverged only after 18 months.

Unsafe workout: a weak and painful shoulder in a professional volleyball player.

A 29-year-old professional volleyball player started complaining of a dull ache in the right lateral base of the neck. This pain arose during a preseasonal athletic training intense session. After 3 days, he presented deficiency of right scapula adduction, limitation of scapula elevation, right shoulder weakness and local mild pain. He had asymmetrical neckline with drooping of the affected shoulder, lateral displacement and minimal winging of the right scapula. After 1 week, hypothrophy of superior trapezius appeared. An electromyography of right upper limb showed a denervation in the upper, middle and lower components of the right trapezius muscle, due to axonotmesis of spinal accessory nerve (SAN). A subsequent MRI was consistent with muscular suffering caused by early denervation. This case shows idiopathic SAN palsy, likely secondary to an inappropriate use of a weight-lifting machine, where the athlete recovered after an adequate rest and rehabilitation period.

Do rebreathing manoeuvres for non-invasive measurement of cardiac output during maximum exercise test alter the main cardiopulmonary parameters?

BACKGROUND: Inert gas rebreathing has been recently described as an emergent reliable non-invasive method for cardiac output determination during exercise, allowing a relevant improvement of cardiopulmonary exercise test clinical relevance. For cardiac output measurements by inert gas rebreathing, specific respiratory manoeuvres are needed which might affect pivotal cardiopulmonary exercise test parameters, such as exercise tolerance, oxygen uptake and ventilation vs carbon dioxide output (VE/VCO2) relationship slope. METHOD: We retrospectively analysed cardiopulmonary exercise testing of 181 heart failure patients who underwent both cardiopulmonary exercise testing and cardiopulmonary exercise test+cardiac output within two months (average 16 ± 15 days). All patients were in stable clinical conditions (New York Heart Association I-III) and on optimal medical therapy. RESULTS: The majority of patients were in New York Heart Association Class I and II (78.8%), with a mean left ventricular ejection fraction of 31 ± 10%. No difference was found between the two tests in oxygen uptake at peak exercise (1101 (interquartile range 870-1418) ml/min at cardiopulmonary exercise test vs 1103 (844-1389) at cardiopulmonary exercise test-cardiac output) and at anaerobic threshold. However, anaerobic threshold and peak heart rate, peak workload (75 (58-101) watts and 64 (42-90), p < 0.01) and carbon dioxide output were significantly higher at cardiopulmonary exercise testing than at cardiopulmonary exercise test+cardiac output, whereas VE/VCO2 slope was higher at cardiopulmonary exercise test+cardiac output (30 (27-35) vs 33 (28-37), p < 0.01). CONCLUSION: The similar anaerobic threshold and peak oxygen uptake in the two tests with a lower peak workload and higher VE/VCO2 slope at cardiopulmonary exercise test+cardiac output suggest a higher respiratory work and consequent demand for respiratory muscle blood flow secondary to the ventilatory manoeuvres. Accordingly, VE/VCO2 slope and peak workload must be evaluated with caution during cardiopulmonary exercise test+cardiac output.