Ikoma T; Narumi T; Akita K; Sato R; Masuda T; Kaneko H; Toda M; Mogi S; Sano M; Suwa K; Naruse Y; Ohtani H; Saotome M; Maekawa Y;

Internal medicine (Tokyo, Japan) [Intern Med] 2022 Nov 30.
Date of Electronic Publication: 2022 Nov 30.

Objective The cardiac function, blood distribution, and oxygen extraction in the muscles as well as the pulmonary function determine the oxygen uptake (VO ₂ ) kinetics at the onset of exercise. This factor is called the VO ₂ time constant, and its prolongation is associated with an unfavorable prognosis for heart failure (HF). The mitochondrial function of skeletal muscle is known to reflect exercise tolerance. Morphological changes and dysfunction in cardiac mitochondria are closely related to HF severity and its prognosis. Although mitochondria play an important role in generating energy in cardiomyocytes, the relationship between cardiac mitochondria and the VO ₂ time constant has not been elucidated.
Methods We calculated the ratio of abnormal cardiac mitochondria in human myocardial biopsy samples using an electron microscope and measured the VO ₂ time constant during cardiopulmonary exercise testing. The VO ₂ time constant was normalized by the fat-free mass index (FFMI). Patients Fifteen patients with non-ischemic cardiomyopathy (NICM) were included. Patients were divided into two groups according to their median VO ₂ time constant/FFMI value. Results Patients with a low VO ₂ time constant/FFMI value had a lower abnormal mitochondria ratio than those with a high VO ₂ time constant/FFMI value. A multiple linear regression analysis revealed that the ratio of abnormal cardiac mitochondria was independently associated with a high VO ₂ time constant/FFMI.
Conclusions An increased abnormal cardiac mitochondria ratio might be associated with a high VO ₂ time constant/FFMI value in patients with NICM.

Sherman AE; Saggar R;

Heart failure clinics [Heart Fail Clin] 2023 Jan; Vol. 19 (1), pp. 35-43.

Cardiopulmonary exercise testing (CPET) is a comprehensive methodology well studied in pulmonary arterial hypertension (PAH) with roles in diagnosis, treatment response, and prognosis. Submaximal and maximal exercise data is a valuable tool in detecting abnormal hemodynamics associated with exercise-induced and resting pulmonary hypertension as well as right ventricular dysfunction. The increased granularity of CPET may help further risk stratify patients to inform prognosis and better individualize treatment decisions. This article reviews the most commonly implicated variables from CPET in PAH literature and summarizes the latest developments in CPET and exercise testing.

Jae SY; Kim HJ; Kurl S; Kunutsor SK; Laukkanen JA;

American journal of hypertension [Am J Hypertens] 2022 Dec 15.
Date of Electronic Publication: 2022 Dec 15.

Background: We tested the hypothesis that an exaggerated systolic blood pressure (ESBP) at maximal exercise workload would be associated with an increased risk of cardiovascular disease (CVD) mortality, and that high cardiorespiratory fitness (CRF) attenuates this risk.
Methods: This prospective study was based on the general population sample of 1,481 men (aged 42-61 years) who did not have a history of CVD at baseline and were followed up in the Kuopio Ischemic Heart Disease cohort study. Exercise blood pressure and CRF were measured during cardiopulmonary exercise testing, and an ESBP was defined by a peak SBP ≥210mmHg and CRF categorized as tertiles and unfit and fit groups.
Results: During a 26-year median follow-up, 231 CVD deaths occurred. After adjusting for potential confounding factors, an ESBP was associated with an increased risk of CVD mortality (hazard ratio (HR) 1.43, 95% Confidence Interval (CI): 1.06-1.94), while the highest tertile of CRF was associated with a lower risk of CVD mortality (HR 0.64, 0.43-0.95). In the joint association analyses of ESBP and CRF, ≥210mmHg-unfit group had a higher risk of CVD mortality (HR 1.70, 1.02-2.83), but also ≥210mmHg-fit group had an increased risk of CVD death (HR 1.95, 1.20-3.18) compared with their <210mmHg-fit counterparts.
Conclusions: These results indicate that an ESBP is independently associated with an increased risk of CVD death, but moderate-to-high levels of CRF does not attenuate CVD mortality risk in those with ESBP.

Babity M; Zamodics M; Konig A; Kiss AR; Horvath M; Gregor Z; Rakoczi R; Kovacs E; Fabian A; Tokodi M; Sydo N; Csulak E; Juhasz V; Lakatos BK; Vago H; Kovacs A; Merkely B; Kiss O;

Scientific reports [Sci Rep] 2022 Dec 15; Vol. 12 (1), pp. 21686.
Date of Electronic Publication: 2022 Dec 15.

After SARS-CoV-2 infection, strict recommendations for return-to-sport were published. However, data are insufficient about the long-term effects on athletic performance. After suffering SARS-CoV-2 infection, and returning to maximal-intensity trainings, control examinations were performed with vita-maxima cardiopulmonary exercise testing (CPET). From various sports, 165 asymptomatic elite athletes (male: 122, age: 20y (IQR: 17-24y), training:16 h/w (IQR: 12-20 h/w), follow-up:93.5 days (IQR: 66.8-130.0 days) were examined. During CPET examinations, athletes achieved 94.7 ± 4.3% of maximal heart rate, 50.9 ± 6.0 mL/kg/min maximal oxygen uptake (V̇O _2max ), and 143.7 ± 30.4L/min maximal ventilation. Exercise induced arrhythmias (n = 7), significant horizontal/descending ST-depression (n = 3), ischemic heart disease (n = 1), hypertension (n = 7), slightly elevated pulmonary pressure (n = 2), and training-related hs-Troponin-T increase (n = 1) were revealed. Self-controlled CPET comparisons were performed in 62 athletes: due to intensive re-building training, exercise time, V̇O _2max and ventilation increased compared to pre-COVID-19 results. However, exercise capacity decreased in 6 athletes. Further 18 athletes with ongoing minor long post-COVID symptoms, pathological ECG (ischemic ST-T changes, and arrhythmias) or laboratory findings (hsTroponin-T elevation) were controlled. Previous SARS-CoV-2-related myocarditis (n = 1), ischaemic heart disease (n = 1), anomalous coronary artery origin (n = 1), significant ventricular (n = 2) or atrial (n = 1) arrhythmias were diagnosed. Three months after SARS-CoV-2 infection, most of the athletes had satisfactory fitness levels. Some cases with SARS-CoV-2 related or not related pathologies requiring further examinations, treatment, or follow-up were revealed.

Babity M, Zamodics M, Konig A, Kiss AR, Horvath , Gregor Z, Rakoczi R, Kovacs E, Fabian A, Tokodi M, Sydo N,
Csulak E, Juhasz V, Lakatos BK, Vago H, Kovacs A, Merkely B, Kiss O;

Sci Rep. 2022 Dec 15;12(1):21686

After SARS-CoV-2 infection, strict recommendations for return-to-sport were published. However, data are insufficient about the long-term effects on athletic performance. After suffering SARS-CoV-2 infection, and returning to maximal-intensity trainings, control examinations were performed with vita-maxima cardiopulmonary exercise testing (CPET). From various sports, 165 asymptomatic elite athletes (male: 122, age: 20y (IQR: 17-24y), training:16 h/w (IQR: 12-20 h/w), follow-up:93.5 days (IQR: 66.8-130.0 days) were examined. During CPET examinations, athletes achieved 94.7 ± 4.3% of maximal heart rate, 50.9 ± 6.0 mL/kg/min maximal oxygen uptake (V̇O2max), and 143.7 ± 30.4L/min maximal ventilation. Exercise induced arrhythmias (n = 7), significant horizontal/descending ST-depression (n = 3), ischemic heart disease (n = 1), hypertension (n = 7), slightly elevated pulmonary pressure (n = 2), and training-related hs-Troponin-T increase (n = 1) were revealed. Self-controlled CPET comparisons were performed in 62 athletes: due to intensive re-building training, exercise time, V̇O2max and ventilation increased compared to pre-COVID-19 results. However, exercise capacity decreased in 6 athletes. Further 18 athletes with ongoing minor long post-COVID symptoms, pathological ECG (ischemic ST-T changes, and arrhythmias) or laboratory findings (hsTroponin-T elevation) were controlled. Previous SARS-CoV-2-related myocarditis (n = 1), ischaemic heart disease (n = 1), anomalous coronary artery origin (n = 1), significant ventricular (n = 2) or atrial (n = 1) arrhythmias were diagnosed. Three months after SARS-CoV-2 infection, most of the athletes had satisfactory fitness levels. Some cases with SARS-CoV-2 related or not related pathologies requiring further examinations, treatment, or follow-up were revealed.

Xia B; Cao P; Zhang L; Huang H; Li R; Yin X;

International journal of hypertension [Int J Hypertens] 2022 Nov 28; Vol. 2022, pp. 8910453.
Date of Electronic Publication: 2022 Nov 28 (Print Publication: 2022).

Objective: Cardiopulmonary exercise testing (CPET) has been used to explore the blood pressure response and potential cardiovascular system structure and dysfunction in male patients with essential hypertension during exercise, to provide a scientific basis for safe and effective exercise rehabilitation and improvement of prognosis.
Methods: A total of 100 male patients with essential hypertension (aged 18-60) who were admitted to the outpatient department of the Center for Diagnosis and Treatment of Cardiovascular Diseases of Jilin University from September 2018 to January 2021 were enrolled in this study. The patients had normal cardiac structure in resting state without clinical manifestations of heart failure or systematic regularization of treatment at the time of admission. Symptom-restricted CPET was performed and blood pressure was measured during and after exercise. According to Framingham criteria, male systolic blood pressure (SBP) ≥210 mmHg during exercise was defined as exercise hypertension (EH), and the subjects were divided into EH group ( n  = 47) and non-EH group ( n  = 53). Based on whether the oxygen pulse (VO ₂ /HR) plateau appeared immediately after anaerobic threshold (AT), the EH group was further divided into the VO ₂ /HR plateau immediately after AT (EH-ATP) group ( n  = 19) and EH-non-ATP group ( n  = 28). The basic clinical data and related parameters, key CPET indicators, were compared between groups.
Result: Body mass index (BMI) visceral fat, resting SBP, and SBP variability in EH group were significantly higher than those in non-EH group. Moreover, VO ₂ /HR at AT and the ratio of VO ₂ /HR plateau appearing immediately after AT in EH group were significantly higher than those in the non-EH group. The resting SBP, 15-minute SBP variability, and the presence of VO ₂ /HR plateau were independent risk factors for EH. In addition, work rate (WR) at AT but also WR, oxygen consumption per minute (VO ₂ ), VO ₂ /kg, and VO ₂ /HR at peak were significantly lower in the EH-ATP group compared to the EH-non-ATP group. Peak diastolic blood pressure (DBP) increment and decreased △VO ₂ /△WR for AT to peak were independent risk factors for VO ₂ /HR plateau appearing immediately after AT in EH patients.
Conclusion: EH patients have impaired autonomic nervous function and are prone to exercise-induced cardiac dysfunction. EH patients with exercise-induced cardiac dysfunction have reduced peak cardiac output and exercise tolerance and impaired vascular diastolic function. CPET examination should be performed on EH patients and EH patients with exercise-induced cardiac dysfunction to develop precise drug therapy and effective individual exercise prescription, to avoid arteriosclerosis and exercise-induced cardiac damage.

Chen SM; Wu PJ; Wang LY; Wei CL; Cheng CI; Fang HY; Fang YN; Chen YL; SHuang DK; Lee FY; Chen MC;

ESC heart failure [ESC Heart Fail] 2022 Dec 02.
Date of Electronic Publication: 2022 Dec 02.

Aims: The timely selection of severe heart failure (HF) patients for cardiac transplantation and advanced HF therapy is challenging. Peak oxygen consumption (VO ₂ ) values obtained by the cardiopulmonary exercise testing are used to determine the transplant recipient list. This study reassessed the prognostic predictability of peak VO ₂ and compared it with the Heart Failure Survival Score (HFSS) in the modern optimized guideline-directed medical therapy (GDMT) era.
Methods and Results: We retrospectively selected 377 acute HF patients discharged from the hospital. The primary outcome was a composite of all-cause mortality, or urgent cardiac transplantation. We divided these patients into the more GDMT (two or more types of GDMT) and less GDMT groups (fewer than two types of GDMT) and compared the performance of their peak VO ₂ and HFSS in predicting primary outcomes. The median follow-up period was 3.3 years. The primary outcome occurred in 57 participants. Peak VO ₂ outperformed HFSS when predicting 1 year (0.81 vs. 0.61; P = 0.017) and 2 year (0.78 vs. 0.58; P < 0.001) major outcomes. The cutoff peak VO ₂ for predicting a 20% risk of a major outcome within 2 years was 10.2 (11.8-7.0) for the total cohort. Multivariate Cox regression analyses showed that peak VO ₂ , sodium, previous implantable cardioverter defibrillator (ICD) implantation, and estimated glomerular filtration rate were significant predictors of major outcomes.
Conclusions: Optimizing the cutoff value of peak VO ₂ is required in the current GDMT era for advanced HF therapy. Other clinical factors such as ICD use, hyponatraemia, and chronic kidney disease could also be used to predict poor prognosis. The improvement of resource allocation and patient outcomes could be achieved by careful selection of appropriate patients for advanced HF therapies, such as cardiac transplantation.

Lynch DR; Mathews KD; Perlman S; Zesiewicz T; Subramony S; Omidvar O; Vogel AP; Krtolica A; Litterman N;
van der Ploeg L; Heerinckx F; Milner P; Midei M;

Journal of neurology [J Neurol] 2022 Dec 03.
Date of Electronic Publication: 2022 Dec 03.

Objectives: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial.
Methods: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2.
Results: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study.
Interpretations: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Thomas GK; Del Buono MG; Damonte JI; Moroni F; Mihalick V; Billingsley HE; Vecchiè A; Trankle CR; Talasaz A; Carbone S; Markley R; Turlington J; Duncan P; Lu J; Arena R; VAN Tassell B; Abbate A; Canada JM;

Minerva cardiology and angiology [Minerva Cardiol Angiol] 2022 Dec 05.
Date of Electronic Publication: 2022 Dec 05.

Background: Previous studies have shown that patients with heart failure with reduced ejection fraction (HFrEF) and anemia have reduced peak oxygen consumption (VO<inf>2</inf>). Black or African American (B-AA) patients have a higher prevalence of anemia and are underrepresented in clinical studies of HFrEF. The aim of this study was to determine the contribution of hemoglobin to peak VO<inf>2</inf> in B-AA patients recently hospitalized for acute decompensated HFrEF.
Methods: We analyzed cardiopulmonary exercise testing (CPX) data measured within two weeks of discharge for acute decompensated HF in B-AA patients with HFrEF (left ventricular ejection fraction [LVEF] ≤40%) without severe anemia (Hb<8 g/dL). Blood samples were collected prior to CPX. Data are reported as median [interquartile range] and compared between groups with the Mann-Whitney, Chi-Square, and Spearman’s rank tests.
Results: We included 81 patients; 27 (33%) women, 57 [27-79] years of age, Body Mass Index of 33 [15-55] kg/m ² and LVEF of 30 [23-36] %. Hemoglobin ranged between 9.1 to 18.1 g/dL (median= 13.3 [11.9-14.5] g/dL); 26 (32%) were considered to have anemia based on a Hb concentration of males <13 g/dL and females <12 g/dL. Peak VO<inf>2</inf> was lower in patients with anemia (11.8 [10.0-14.2] vs. 14.1 [10.6-17.0] mL·kg ^-1 ·min ^-1 ; P=0.010) with a significant correlation between peak VO<inf>2</inf> and hemoglobin concentration (R=+0.455; P<0.001).
Conclusions: Anemia is prevalent among B-AA patients with recently decompensated HFrEF and appears to be a significant contributor to reductions in peak VO<inf>2</inf>.

McCarthy OM; Birch Kristensen K; Christensen MB; Schmidt S; Ranjan AG; Nicholas C; Bain SC; Nørgaard K;
Bracken R;

Diabetes, obesity & metabolism [Diabetes Obes Metab] 2022 Dec 08.
Date of Electronic Publication: 2022 Dec 08.

Aims: 1) To profile acute glycaemic dynamics during graded exercise testing (GXT) and 2) explore the influence of glycaemic indicators on the physiological responses to GXT in adults with T1D using insulin pump therapy.
Methods: This was a retrospective analysis of pooled data from four clinical trials with identical GXT protocols. Data was obtained from 45 adults with type 1 diabetes using insulin pumps ([30 females], HbA _1c : 59.5±0.5 mmol.mol ^-1 [7.6±1.0 %], age: 49.7±13.0 years, diabetes duration: 31.2±13.5 years, V̇O _2peak : 29.5±8.0 mL.min ^-1 .kg ^-1 ). Integrated cardiopulmonary variables were collected continuously via spiroergometry. Plasma glucose (PG) was obtained every three minutes during GXT as well as the point of volitional exhaustion. Data were assessed via general linear modelling techniques with age and gender adjustment. Significance was accepted at P ≤0.05.
Results: Despite increasing duration and intensity, PG concentrations remained similar to rest values (8.8±2.3 mmol.L ^-1 ) throughout exercise (p=0.419) with an overall change of +0.3±1.1 mmol.L ^-1 . Starting glycaemia bore no influence on subsequent GXT responses. Per 1% increment in HbA _1c there was an associated decrease in V̇O _2peak of 3.8 mL.min ^-1 .kg ^-1 (p<0.001) and power _peak of 0.33 watts.kg ^-1 (p<0.001) concomitant with attenuations in indices of peripheral oxygen extraction ([O ₂ pulse] -1.2 mL.beat ^-1 , p=0.023).
Conclusion: In adults with long-standing type 1 diabetes using insulin pump therapy, circulating glucose remains stable during a graded incremental cycle test to volitional exhaustion. Glycaemic indicators are inversely associated with aerobic rate, oxygen economy and mechanical output across the exercise intensity spectrum. An appreciation of these nexuses may help guide appropriate decision making for optimal exercise management strategies.