Yasui Y; Nakamura K; Omote K; Ishizaka S; Takenaka S; Mizuguchi Y; Shimono Y; Kazui S; Takahashi Y; Saiin K; Naito S; Tada A; Kobayashi Y; Sato T; Kamiya K; Nagai T; Anzai T;

The American journal of cardiology [Am J Cardiol] 2023 Mar 01; Vol. 193, pp. 37-43.
Date of Electronic Publication: 2023 Mar 01.

The prognostic impact of peak workload-to-weight ratio (PWR) during cardiopulmonary exercise testing (CPET) and its determinants in patients with chronic heart failure (CHF) are not well understood. Consecutive 514 patients with CHF referred for CPET at the Hokkaido University Hospital between 2013 and 2018 were identified. The primary outcome was a composite of hospitalization because of worsening heart failure and death. PWR was calculated as peak workload normalized to body weight (W/kg) by CPET. Patients with low PWR (cut-off median 1.38 [W/kg], n = 257) were older and more anemic than those with high PWR (n = 257). In CPET, patients with low PWR displayed reduced peak oxygen consumption and impaired ventilatory efficiency compared with those with high PWR, whereas the peak respiratory exchange ratio was not significantly different between the 2 groups. There were 89 patients with events over a median follow-up period of 3.3 (interquartile range 0.8 to 5.5) years. The incidence of composite events was significantly higher in patients with low PWR than in those with high PWR (log-rank p <0.0001). In the multivariable Cox regression, lower PWR was associated with adverse events (hazard ratio 0.31, 95% confidence interval 0.13 to 0.73, p = 0.008). Low hemoglobin concentration was strongly related to impaired PWR (β coefficient = 0.43, per 1 g/100 ml increased, p <0.0001). In conclusion, PWR was associated with worse clinical outcomes, where blood hemoglobin was strongly related to PWR. Further study is required to identify therapies targeting peak workload achievements in exercise stress tests to improve the outcome in patients with CHF.

Edward JA; Parker H; Stöhr EJ; McDonnell BJ; O’Gean K; Schulte M; Lawley JS; Cornwell WK 3rd;

Journal of cardiac failure [J Card Fail] 2023 Mar 03.
Date of Electronic Publication: 2023 Mar 03.

Background: Exertional dyspnea is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but quantitative data regarding exertional hemodynamics are lacking.
Objectives: Characterize exertional cardiopulmonary hemodynamics in patients with HFrEF.
Methods: Thirty-five HFrEF patients (59±12 years, 30 males) completed invasive cardiopulmonary exercise testing (CPET). Data were collected at rest, submaximal exercise and peak effort on upright cycle ergometry. Cardiovascular and pulmonary vascular hemodynamics were recorded. Fick cardiac output (Qc) was determined. Hemodynamic predictors of peak oxygen uptake (VO ₂ ) were identified.
Results: Left ventricular ejection fraction and cardiac index were 23±8% and 2.9±1.1 L/min/m ² , respectively. PeakVO ₂ was 11.8±3.3 ml/kg/min and ventilatory efficiency slope was 53±13. Right atrial pressure increased from rest to peak exercise (4±5 v. 7±6mmHg,). Mean pulmonary arterial pressure increased from rest to peak exercise (27±13 v. 38±14mmHg). Pulmonary artery pulsatility index increased from rest to peak exercise, while pulmonary arterial capacitance and pulmonary vascular resistance declined.
Conclusions: HFrEF patients suffer from marked increases in filling pressures during exercise. These findings provide new insight into cardiopulmonary abnormalities contributing to impairments in exercise capacity in this population.

Dixon DD; Deo R; Shah SJ;

The American journal of cardiology [Am J Cardiol] 2023 Mar 06; Vol. 193, pp. 102-110.
Date of Electronic Publication: 2023 Mar 06.

Unsupervised machine learning (phenomapping) has been used successfully to identify novel subgroups (phenogroups) of heart failure with preserved ejection fraction (HFpEF). However, further investigation of pathophysiological differences between HFpEF phenogroups is necessary to help determine potential treatment options. We performed speckle-tracking echocardiography and cardiopulmonary exercise testing (CPET) in 301 and 150 patients with HFpEF, respectively, as part of a prospective phenomapping study (median age 65 [25th to 75th percentile 56 to 73] years, 39% Black individuals, 65% female). Linear regression was used to compare strain and CPET parameters by phenogroup. All indicies of cardiac mechanics except for left ventricular global circumferential strain worsened in a stepwise fashion from phenogroups 1 to 3 after adjustment for demographic and clinical factors. After further adjustment for conventional echocardiographic parameters, phenogroup 3 had the worst left ventricular global longitudinal, right ventricular free wall, and left atrial booster and reservoir strain. On CPET, phenogroup 2 had the lowest exercise time and absolute peak oxygen consumption (VO ₂ ), driven primarily by obesity, whereas phenogroup 3 achieved the lowest workload, relative peak oxygen consumption (VO ₂ ), and heart rate reserve on multivariable-adjusted analyses. In conclusion, HFpEF phenogroups identified by unsupervised machine learning analysis differ in the indicies of cardiac mechanics and exercise physiology.
Competing Interests: Disclosures Dr. Dixon was supported by a Sarnoff Cardiovascular Fellowship and has received a grant from Bristol Myers Squibb. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. The remaining authors have no conflicts of interest to declare.

Nemati S;Yavari T;Tafti F;Hooshanginezhad Z;Mohammadi T;

The Journal of cardiovascular nursing [J Cardiovasc Nurs] 2023 Mar 08.
Date of Electronic Publication: 2023 Mar 08.

Objective: We investigated relationships among predictors of improvement in exercise capacity after cardiac rehabilitation programs in patients after acute myocardial infarction.
Methods: We carried out a secondary analysis of data from 41 patients with a left ventricular ejection fraction ≥ 40% who underwent cardiac rehabilitation after the first myocardial infarction. Participants were assessed using a cardiopulmonary exercise test and stress echocardiography. A cluster analysis was performed, and the principal components were analyzed.
Results: Two distinct clusters with significantly different (P = .005) proportions of response to treatment (peak VO2 ≥ 1 mL/kg/min) were identified among patients. The first principal component explained 28.6% of the variance. We proposed an index composed of the top 5 variables from the first component to represent the improvement in exercise capacity. The index was the average of scaled O2 uptake and CO2 output at peak exercise, minute ventilation at peak, load achieved at peak exercise, and exercise time. The optimal cutoff for the improvement index was 0.12, which outperformed the peak VO2 ≥ 1 mL/kg/min criterion in recognizing the clusters, with a C-statistic of 91.7% and 72.3%, respectively.
Conclusion: The assessment of change in exercise capacity after cardiac rehabilitation could be improved using the composite index.

Sun P; Cen H; 00, China.Chen S; Chen X; Jiang W; Zhu H; Liu Y; Liu H; Lu W;

BMC cardiovascular disorders [BMC Cardiovasc Disord] 2023 Mar 09; Vol. 23 (1), pp. 128.
Date of Electronic Publication: 2023 Mar 09.

Background: Beta-blockers are first-line clinical drugs for the treatment of chronic heart failure (CHF). In the guidelines for cardiac rehabilitation, patients with heart failure who do or do not receive beta-blocker therapy have different reference thresholds for maximal oxygen uptake (VO _2max ). It has been reported that left atrial (LA) strain can be used to predict VO _2max in patients with heart failure, which can be used to assess exercise capacity. However, most existing studies included patients who did not receive beta-blocker therapy, which could have a heterogeneous influence on the conclusions. For the vast majority of CHF patients receiving beta-blockers, the exact relationship between LA strain parameters and exercise capacity is unclear.
Methods: This cross-sectional study enrolled 73 patients with CHF who received beta-blockers. All patients underwent a thorough resting echocardiogram and a cardiopulmonary exercise test to obtain VO _2max , which was used to reflect exercise capacity.
Results: LA reservoir strain, LA maximum volume index (LAVI _max ), LA minimum volume index (LAVI _min ) (P < 0.0001) and LA booster strain (P < 0.01) were all significantly correlated with VO _2max , and LA conduit strain was significantly correlated with VO _2max (P < 0.05) after adjusting for sex, age, and body mass index. LA reservoir strain, LAVI _max , LAVI _min (P < 0.001), and LA booster strain (P < 0.05) were significantly correlated with VO _2max after adjusting for left ventricular ejection fraction, the ratio of transmitral E velocity to tissue Doppler mitral annulus e’ velocity (E/e’), and tricuspid annular plane systolic excursion. LA reservoir strain with a cutoff value of 24.9% had a sensitivity of 74% and specificity of 63% for the identification of patients with VO _2max  < 16 mL/kg/min.
Conclusion: Among CHF patients receiving beta-blocker therapy, resting LA strain is linearly correlated with exercise capacity. LA reservoir strain is a robust independent predictor of reduced exercise capacity among all resting echocardiography parameters.

Akazawa Y; Fujioka T; Yazaki K; Strbad M; Hörer J; Kühn A; Hui W;Slorach C; Roehlig C; Mertens L; Bijnens BH; Vogt M; Friedberg MK;

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography [J Am Soc Echocardiogr] 2023 Feb 23.
Date of Electronic Publication: 2023 Feb 23.

Background: Abnormal atrioventricular and intraventricular electrical conduction and dysfunction of the functional right ventricle (fRV) are common in Ebstein anomaly (EA). However, fRV mechanical dyssynchrony and its relation to fRV function are poorly characterized. We evaluated fRV mechanical dyssynchrony in EA patients in relation to fRV remodeling, dysfunction and exercise intolerance.
Methods: We retrospectively analyzed data from non-operated EA patients and age-matched controls who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR) and cardiopulmonary exercise testing to quantify RV remodeling, dysfunction and exercise capacity. The relation of these to fRV dyssynchrony was retrospectively investigated. RV mechanical dyssynchrony was defined by early fRV septal activation (right-sided septal flash), RV lateral wall pre-stretch/late contraction, post-systolic shortening, and intra-RV delay using 2-dimensional strain echocardiography. The standard deviation of time to peak shortening among the fRV segments was calculated as a parameter of mechanical dispersion.
Results: Thirty-five EA patients (10 of whom were <18 years of age) and 35 age-matched controls were studied. EA patients had worse RV function and increased intra-RV dyssynchrony versus controls. 19/35 (54%) of EA patients had early septal activation with simultaneous stretch and consequent late activation and post-systolic shortening of RV lateral segments. Intra-fRV mechanical delay correlated with fRV end diastolic volume index (fRVEDVI) (r=0.43, P <0.05) and fRV end systolic volume index (fRVESVI) (r=0.63, P <0.001). fRV ejection fraction (fRVEF) was lower in EA with versus without right-sided septal flash (44.9±11.0 vs 54.2±8.2, P=0.012). fRV mechanical dispersion correlated with percent of predicted peak VO ₂ (r=-0.35, P <0.05).
Conclusions: In EA, fRV mechanical dyssynchrony is associated with fRV remodeling, dysfunction and impaired exercise capacity. Mechanical dyssynchrony as a therapeutic target in selected EA patients warrants further study.

Smyth RM; Neder JA; James MD; Vincent SG; Milne KM; Marillier M; de-Torres JP; Moran-Mendoza O; O’Donnell DE; Phillips DB

Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2023 Feb 27, pp. 104041.
Date of Electronic Publication: 2023 Feb 27.

The functional disturbances driving “out-of-proportion” dyspnoea in patients with fibrosing interstitial lung disease (f-ILD) showing only mild restrictive abnormalities remain poorly understood. Eighteen patients (10 with idiopathic pulmonary fibrosis) showing preserved spirometry and mildly reduced total lung capacity (≥70% predicted) and 18 controls underwent an incremental cardiopulmonary exercise test with measurements of operating lung volumes and Borg dyspnoea scores. Patients’ lower exercise tolerance was associated with higher ventilation (V̇ _E )/carbon dioxide (V̇CO ₂ ) compared with controls (V̇ _E /V̇CO ₂ nadir=35±3 versus 29±2; p<0.001). Patients showed higher tidal volume/inspiratory capacity and lower inspiratory reserve volume at a given exercise intensity, reporting higher dyspnoea scores as a function of both work rate and V̇ _E . Steeper dyspnoea-work rate slopes were associated with lower lung diffusing capacity, higher V̇ _E /V̇CO ₂ , and lower peak O ₂ uptake (p<0.05). Heightened ventilatory demands in the setting of progressively lower capacity for tidal volume expansion on exertion largely explain higher-than-expected dyspnoea in f-ILD patients with largely preserved dynamic and “static” lung volumes at rest.

Neidenbach R; Freilinger S; Stöcker F; Ewert P; Nagdyman N; Oberhoffer-Fritz R; Pieper L; Kaemmerer H; Hager A;

Cardiovascular diagnosis and therapy [Cardiovasc Diagn Ther] 2023 Feb 28; Vol. 13 (1), pp. 11-24.
Date of Electronic Publication: 2023 Jan 15.

Background: Since 1968, thousands of patients with a morphologically or functionally univentricular heart have been treated with a total cavopulmonary connection/Fontan operation. Because of the resulting passive pulmonary perfusion, blood flow is assisted by the pressure shift during respiration. Respiratory training is known to improve exercise capacity and cardiopulmonary function. However, there are limited data on whether respiratory training can also improve physical performance after Fontan surgery. The aim of the present study was to clarify the effects of six months of daily home-based inspiratory muscle training (IMT) aimed at increasing physical performance by strengthening respiratory muscles, improving lung function and peripheral oxygenation.
Methods: In this non-blinded randomized controlled trial, the effects of IMT on lung capacity and exercise capacity were measured in a large cohort of 40 Fontan patients (25% female; 12.3±2.2 years) who were under regular follow-up by the outpatient clinic of the Department of Congenital Heart Defects and Pediatric Cardiology of the German Heart Center Munich. After a lung function test and a cardiopulmonary exercise test, patients were randomly assigned in a parallel arm design to either an intervention group (IG) or a control group (CG) via stratified and computer-generated letter randomization from May 2014 to May 2015. The IG completed a daily, telephone-monitored IMT of three sets of 30 repetitions for six months with an inspiratory resistive training device (POWERbreathe medic ^® ), the CG continued their usual daily activities without an IMT until the second examination within the timeframe of November 2014 until November 2015.
Results: After six months of IMT, lung capacity values in the IG (n=18) did not increase significantly compared to the CG [n=19; ΔFVC: IG: 0.21±0.16 l vs. CG 0.22±0.31 l; P=0.946 (CI: -0.16, 0.17); ΔFEV1: CG: 0.14±0.30 vs. IG: 0.17±0.20 P=0.707 (CI: -0.20, 0.14)]. Exercise capacity did not improve significantly, yet the maximum workload achieved trended to improve with an increase of 14% in the IG vs. 6.5% in the CG [P=0.113 (CI: -15.8, 1.76)]. There was a significant increase of oxygen saturation at rest in the IG compared to the CG [IG: 3.31%±4.09% vs. CG: 0.17%±2.92%, P=0.014 (CI: -5.60, -0.68)]. Compared to the CG, the mean oxygen saturation at peak exercise no longer dropped below 90% in the IG. This observation is thus not statistically significant, yet of clinical relevance.
Conclusions: The results of this study show benefits of an IMT in young Fontan patients. Even if some data are not statistically significant, they may still be clinically relevant and may contribute to a multidisciplinary approach in patient care. IMT should therefore be an additional target and integrated into the training program to improve the prognosis of Fontan patients.

Boulmpou A; Boutou AK; Pella E; Sarafidis P; Papadopoulos CE; Vassilikos V;

Cardiology in review [Cardiol Rev] 2022 Dec 13.
Date of Electronic Publication: 2022 Dec 13.

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial clinical syndrome involving a rather complex pathophysiologic substrate and quite a challenging diagnosis. Exercise intolerance is a major feature of HFpEF, and in many cases, diagnosis is suspected in subjects presenting with exertional dyspnea. Cardiopulmonary exercise testing (CPET) is a noninvasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, hematopoietic, neuropsychological, and metabolic functions during maximal or submaximal exercise. The assessment is based on the principle that system failure typically occurs when the system is under stress, and thus, CPET is currently considered to be the gold standard for identifying exercise intolerance, allowing the differential diagnosis of underlying causes. CPET is used in observational studies and clinical trials in HFpEF; however, in most cases, only a few from a wide variety of CPET parameters are examined, while the technique is largely underused in everyday cardiology practice. This article discusses the basic principles and methodology of CPET and studies that utilized CPET in patients with HFpEF, in an effort to increase awareness of CPET capabilities among practicing cardiologists.

Onofrei CD; Gottschall EB; Zell-Baran L; Rose CS; Kraus R; Pang K; Krefft SD;

Physiological reports [Physiol Rep] 2023 Jan; Vol. 11 (2), pp. e15520.

We identified a case of probable mitochondrial myopathy (MM) in a soldier with dyspnea and reduced exercise tolerance through cardiopulmonary exercise testing (CPET) following Southwest Asia (SWA) deployment. Muscle biopsy showed myopathic features. We compared demographic, occupational exposure, and clinical characteristics in symptomatic military deployers with and without probable MM diagnosed by CPET criteria. We evaluated 235 symptomatic military personnel who deployed to SWA and/or Afghanistan between 2010 and 2021. Of these, 168 underwent cycle ergometer maximal CPET with an indwelling arterial line. We defined probable MM based on five CPET criteria: arterial peak exercise lactate >12 mEq/L, anaerobic threshold (AT) ≤50%, maximum oxygen consumption (VO2 _max ) <95% predicted, oxygen (O2) pulse percent predicted (pp) at least 10% lower than heart rate pp, and elevated ventilatory equivalent for O2 at end exercise (VE/VO2 ≥ 40). We characterized demographics, smoking status/pack-years, spirometry, and deployment exposures, and used descriptive statistics to compare findings in those with and without probable MM. We found 9/168 (5.4%) deployers with probable MM. Compared to symptomatic deployers without probable MM, they were younger (p = 0.0025) and had lower mean BMI (p = 0.02). They had a higher mean forced expiratory volume (FEV1) _pp (p = 0.02) and mean arterial oxygen partial pressure (PaO2) at maximum exercise (p = 0.0003). We found no significant differences in smoking status, deployment frequency/duration, or inhalational exposures. Our findings suggest that mitochondrial myopathy may be a cause of dyspnea and reduced exercise tolerance in a subset of previously deployed military personnel. CPET with arterial line may assist with MM diagnosis and management.