Author Archives: Paul Older

The role of the microcirculation and integrative cardiovascular physiology in the pathogenesis of ICU-acquired weakness.

Mendelson AA; Erickson D; Villar R;

Frontiers in physiology [Front Physiol] 2023 May 10; Vol. 14, pp. 1170429.
Date of Electronic Publication: 2023 May 10 (Print Publication: 2023).

Skeletal muscle dysfunction after critical illness, defined as ICU-acquired weakness (ICU-AW), is a complex and multifactorial syndrome that contributes significantly to long-term morbidity and reduced quality of life for ICU survivors and caregivers. Historically, research in this field has focused on pathological changes within the muscle itself, without much consideration for their in vivo physiological environment. Skeletal muscle has the widest range of oxygen metabolism of any organ, and regulation of oxygen supply with tissue demand is a fundamental requirement for locomotion and muscle function. During exercise, this process is exquisitely controlled and coordinated by the cardiovascular, respiratory, and autonomic systems, and also within the skeletal muscle microcirculation and mitochondria as the terminal site of oxygen exchange and utilization. This review highlights the potential contribution of the microcirculation and integrative cardiovascular physiology to the pathogenesis of ICU-AW. An overview of skeletal muscle microvascular structure and function is provided, as well as our understanding of microvascular dysfunction during the acute phase of critical illness; whether microvascular dysfunction persists after ICU discharge is currently not known. Molecular mechanisms that regulate crosstalk between endothelial cells and myocytes are discussed, including the role of the microcirculation in skeletal muscle atrophy, oxidative stress, and satellite cell biology. The concept of integrated control of oxygen delivery and utilization during exercise is introduced, with evidence of physiological dysfunction throughout the oxygen delivery pathway – from mouth to mitochondria – causing reduced exercise capacity in patients with chronic disease (e.g., heart failure, COPD). We suggest that objective and perceived weakness after critical illness represents a physiological failure of oxygen supply-demand matching – both globally throughout the body and locally within skeletal muscle. Lastly, we highlight the value of standardized cardiopulmonary exercise testing protocols for evaluating fitness in ICU survivors, and the application of near-infrared spectroscopy for directly measuring skeletal muscle oxygenation, representing potential advancements in ICU-AW research and rehabilitation.

The ventilatory component of the muscle metaboreflex is overstimulated in transthyretin cardiac amyloidosis patients with poor aerobic capacity.

Monfort A; Thevenet E; Enette L; Fagour C; Inamo J; Neviere R;

Frontiers in physiology [Front Physiol] 2023 May 15; Vol. 14, pp. 1174645.
Date of Electronic Publication: 2023 May 15 (Print Publication: 2023).

Background: The exercise pressor reflex, i.e., metabo- and mechano-reflex, partially regulates the control of ventilation and cardiovascular function during exercise. Abnormal exercise pressor reflex response has been associated with exaggerated ventilatory drive, sympathovagal imbalance and exercise limitation in chronic heart failure patients. Whether metaboreflex is over-activated and participate to poor aerobic capacity in patients with hereditary transthyretin cardiac amyloidosis (CA-TTR) is unknown.
Methods: Twenty-two CA-TTR patients (aged 76 ± 7, 68% male) with the V122I (p.Val142Ile) transthyretin underwent a thorough evaluation including heart rate variability metrics, electrochemical skin conductance (ESC), physical function cardiopulmonary exercise testing, and muscle metaboreflex assessment. Eleven control subjects were chosen for muscle metaboreflex assessment.
Results: Age-matched controls ( n = 11) and CA-TTR patients ( n = 22) had similar metaboreflex sensitivity for heart rate, stroke volume, cardiac index and mean systemic arterial pressure. Compared with age-matched controls, metaboreflex sensitivity for systemic vascular resistance (-18.64% ± 6.91% vs 3.14% ± 23.35%) and minute-ventilation responses (-9.65% ± 14.83% vs 11.84% ± 23.1%) was markedly increased in CA-TTR patients. Values of ESC displayed positive correlations with stroke volume ( r = 0.53, p = 0.011) and cardiac index ( r = 0.51, p = 0.015) components of metaboreflex sensitivity, an inverse correlation with systemic vascular resistance ( r = -0.55, p = 0.008) and a trend with mean arterial ( r = -0.42, p = 0.052) components of metaboreflex sensitivity. Peak aerobic capacity (peak VO 2 %) displayed an inverse correlation with the ventilation component of metaboreflex sensitivity ( r = -0.62, p = 0.015).
Conclusion: Consistent with the “muscle hypothesis” in heart failure, it is proposed that deterioration of skeletal muscle function in hereditary CA-TTR patients may activate muscle metaboreflex, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and overall sympathetic activation.

Longitudinal Changes in Ventricular Mechanics in Adolescents after the Fontan Operation.

Aly S; Mertens L; Friedberg MK; Dragulescu A;

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography [J Am Soc Echocardiogr] 2023 May 24.
Date of Electronic Publication: 2023 May 24.

Background: Ventricular dysfunction is a significant clinical challenge in the long-term follow-up of patients with single ventricle (SV) physiology. Ventricular function and myocardial mechanics can be studied using speckle-tracking echocardiography (STE) which provides information on myocardial deformation. Limited information is available on serial changes in SV myocardial mechanics after the Fontan operation.
Aims: In this study, we wanted to describe serial changes in myocardial mechanics in children after the Fontan operation and the relationship of these changes with myocardial fibrosis markers as obtained by cardiac magnetic resonance (CMR) and exercise performance parameters.
Hypothesis: We hypothesized that ventricular mechanics declines in SV patients over time and is associated with increased myocardial fibrosis and reduced exercise performance.
Methods: Single-center retrospective cohort study including adolescents after the Fontan operation. Ventricular strain and torsion were assessed using STE. CMR and cardiopulmonary exercise testing data closest to the latest echocardiograms were obtained. The most recent follow-up echocardiographic and CMR data were compared to sex and age-matched controls as well as to individual patients’ early post-Fontan data.
Results: 50 SV patients (31 LV, 13 RV, and 6 co-dominant) were included. Median time at follow-up echocardiogram from the time of Fontan was 12.8 (10.6-16.6) years. Compared to early post-Fontan echocardiograms, follow-up assessment showed reduced global longitudinal strain [-17.5% (-14.5 to -19.5) vs -19.8% (-16.0 to -21.7), p=0.01], circumferential strain [-15.7% (-11.4 to -18.7) vs -18.9% (-15.2 to -25.0), p=0.009], reduced torsion [1.28˚/cm (0.51 to 1.74) vs 1.72˚/cm (0.92 to 2.34), p= 0.02] with decreased apical rotation but no significant change in basal rotation. Single RVs had lower torsion compared to single LVs [1.04 ˚/cm (0.12 to 2.20) vs 1.25 ˚/cm (0.25 to 2.51), p=0.01]. T1 values were higher in SV compared to controls [1009±36ms vs 958±40ms, p=0.004], and in single RV compared to LV (1023±19ms vs 1006±17ms, p=0.02). T1 correlated circumferential strain (r=0.59, p=0.04) and inversely correlated with O 2 saturation (r=-0.67, p<0.001), and torsion (r=-0.71, p=0.02). Peak oxygen consumption correlated with torsion (r=0.52, p=0.001) and untwist rates (r=0.23, p=0.03) CONCLUSION: Post Fontan, there is a progressive decrease in myocardial deformation parameters. The progressive decrease in SV torsion is related to a decrease in apical rotation, which is more pronounced in single RVs. Decreased torsion is associated with increased markers of myocardial fibrosis and lower maximal exercise capacity. Torsional mechanics may be an important parameter to monitor after Fontan palliation but further prognostic information is required.

Effect of voxelotor on cardiopulmonary testing in youths with sickle cell anemia in a pilot study.

Phan V; Hershenson J; Caldarera L; Larkin SK; Wheeler K; Cortez AL; Dulman R; Briere N; Lewis A; Kuypers FA;
Yang E;

Pediatric blood & cancer [Pediatr Blood Cancer] 2023 May 29, pp. e30423.
Date of Electronic Publication: 2023 May 29.

Background: Individuals with sickle cell anemia (SCA) exhibit decreased exercise capacity. Anemia limits oxygen-carrying capacity and affects cardiopulmonary fitness. The drug voxelotor raises hemoglobin in SCA. We hypothesized that voxelotor improves exercise capacity in youths with SCA.
Methods: In a single-center, open-label, single-arm, longitudinal interventional pilot study (NCT04581356), SCA patients aged 12 and older, stably maintained on hydroxyurea, were treated with 1500 mg voxelotor daily, and performed cardiopulmonary exercise testing before (CPET#1) and after voxelotor (CPET#2). A modified Bruce Protocol was performed on a motorized treadmill, and breath-by-breath gas exchange data were collected. Peak oxygen consumption (peak VO 2 ), anaerobic threshold, O 2 pulse, VE/VCO 2 slope, and time exercised were compared for each participant. The primary endpoint was change in peak VO 2 . Hematologic parameters were measured before each CPET. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected.
Results: Ten hemoglobin SS patients aged 12-24 completed the study. All demonstrated expected hemoglobin rise, with average +1.6 g/dL (p = .003) and P 50 left shift of average -11 mmHg (p < .0001) with decreased oxygen off-loading at low pO 2 . The change in % predicted peak VO 2 from CPET#1 to CPET#2 ranged from -12.8% to +11.3%, with significant improvement of more than 5% in one subject, more than 5% decrease in five subjects, and insignificant change of less than 5% in four subjects. All 10 CGIC and seven of 10 PGIC responses were positive.
Conclusion: In a pilot study of 10 youths with SCA, voxelotor treatment did not improve peak VO 2 in 9 out of 10 patients.

Exercise Capacity and Ventilatory Efficiency in Patients With Pulmonary Arterial Hypertension.

Tobita K; Goda A; Teruya K; Nishida Y; Takeuchi K; Kikuchi H; Inami T; Kohno T; Tashiro S;Yamada S; .Satoh T; Soejima K;

Journal of the American Heart Association [J Am Heart Assoc] 2023 Jun 01, pp. e026890.
Date of Electronic Publication: 2023 Jun 01.

Background The symptom for identification of pulmonary arterial hypertension (PAH) is dyspnea on exertion, with a concomitant decrease in exercise capacity. Even patients with hemodynamically improved PAH may have impaired exercise tolerance; however, the effect of central and peripheral factors on exercise tolerance remains unclear. We explored the factors contributing to exercise capacity and ventilatory efficiency in patients with hemodynamically normalized PAH after medical treatment.
Methods and Results In total, 82 patients with PAH (age: median 46 [interquartile range, 39-51] years; male:female, 23:59) and mean pulmonary arterial pressure ≤30 mm Hg at rest were enrolled. The exercise capacity, indicated by the 6-minute walk distance and peak oxygen consumption, and the ventilatory efficiency, indicated by the minute ventilation versus carbon dioxide output slope, were assessed using cardiopulmonary exercise testing with a right heart catheter. The mean pulmonary arterial pressure was 21 (17-25) mm Hg, and the 6-minute walk distance was 530 (458-565) m, whereas the peak oxygen consumption was 18.8 (14.8-21.6) mLꞏmin -1 ꞏkg -1 . The multivariate model that best predicted 6-minute walk distance included peak arterial mixed venous oxygen content difference (β=0.46, P <0.001), whereas the best peak oxygen consumption predictors included peak cardiac output (β=0.72, P <0.001), peak arterial mixed venous oxygen content difference (β=0.56, P <0.001), and resting mean pulmonary arterial pressure (β=-0.25, P =0.026). The parameter that best predicted minute ventilation versus carbon dioxide output slope was the resting mean pulmonary arterial pressure (β=0.35, P =0.041). Quadriceps muscle strength was moderately correlated with exercise capacity (6-minute walk distance; ρ=0.57, P <0.001; peak oxygen consumption: ρ=0.56, P <0.001) and weakly correlated with ventilatory efficiency (ρ = -0.32, P =0.007).
Conclusions Central and peripheral factors are closely related to impaired exercise tolerance in patients with hemodynamically normalized PAH.

Impact of the Remission of Type 2 Diabetes on Cardiovascular Structure and Function, Exercise Capacity and Risk Profile: A Propensity Matched Analysis.

Bilak JM; Yeo JL; Gulsin GS; Marsh AM; Sian M; Dattani A; Ayton SL; Parke KS; Bain M; Pang W; Boulos S; Pierre TGS; Davies MJ; Yates T; McCann GP; Brady EM;

Journal of cardiovascular development and disease [J Cardiovasc Dev Dis] 2023 Apr 24; Vol. 10 (5).
Date of Electronic Publication: 2023 Apr 24.

Type 2 diabetes (T2D) confers a high risk of heart failure frequently with evidence of cardiovascular structural and functional abnormalities before symptom onset. The effects of remission of T2D on cardiovascular structure and function are unknown. The impact of the remission of T2D, beyond weight loss and glycaemia, on cardiovascular structure and function and exercise capacity is described. Adults with T2D without cardiovascular disease underwent multimodality cardiovascular imaging, cardiopulmonary exercise testing and cardiometabolic profiling. T2D remission cases (Glycated hemoglobin (HbA1c) < 6.5% without glucose-lowering therapy, ≥3 months) were propensity score matched 1:4 based on age, sex, ethnicity and time of exposure to those with active T2D ( n = 100) with the nearest-neighbour method and 1:1 with non-T2D controls ( n = 25). T2D remission was associated with a lower leptin-adiponectin ratio, hepatic steatosis and triglycerides, a trend towards greater exercise capacity and significantly lower minute ventilation/carbon dioxide production (VE/VCO2 slope) vs. active T2D (27.74 ± 3.95 vs. 30.52 ± 5.46, p < 0.0025). Evidence of concentric remodeling remained in T2D remission vs. controls (left ventricular mass/volume ratio 0.88 ± 0.10 vs. 0.80 ± 0.10, p < 0.025). T2D remission is associated with an improved metabolic risk profile and ventilatory response to exercise without concomitant improvements in cardiovascular structure or function. There is a requirement for continued attention to risk factor control for this important patient population.

A new method for estimating the first ventilatory threshold in patients with chronic respiratory diseases: A feasibility study.

Pernot J; Ribon A; Degano B;

Respiratory medicine and research [Respir Med Res] 2023 Apr 29; Vol. 83, pp. 101022.
Date of Electronic Publication: 2023 Apr 29.

Background: The identification of the first ventilatory threshold (VT1) on an incremental cardiopulmonary exercise test (CPET) is useful to guide exercise reconditioning. However, determination of the VT1 is sometimes difficult in patients with chronic respiratory disease. Our hypothesis was that it would be possible to identify a “clinical threshold” based on patients’ perceptions at which they subjectively consider that they can perform endurance training during a rehabilitation programme.
Methods: Workloads at which patients identified a “clinical threshold” during a submaximal exercise were compared with workloads recorded at VT1 determined during a maximal CPET. Patients with a VT1 and/or a “clinical threshold” obtained at a workload <25 W were excluded from the analysis.
Results: A “clinical threshold” could be determined in the 86 patients included. Data from 63 patients were retained for the analysis, of which only 52 had a VT1 that could be identified. The agreement between the workloads determined at VT1 and at the “clinical threshold” was almost perfect, with a Lin’s concordance coefficient (cc) of 0.82.
Conclusions: In the context of chronic respiratory diseases, it is possible to use patients’ sensations (which are by nature subjective) to identify a workload on a cycle ergometer, which corresponds to the workload at the first ventilatory threshold determined objectively during CPET.
Competing Interests: Declaration of Competing Interest Prof. Degano reports personal fees and non-financial support from GSK, Chiesi, AstraZeneca, Nuvaira, Menarini and Boehringer Ingelheim, outside the submitted work. The other authors declare that they have no conflict of interest for the submitted work. The results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

Relationship between Blood Volume, Blood Lactate Quantity, and Lactate Concentrations during Exercise.

Schierbauer J; Wolf A; Wachsmuth NB; Maassen N; Schmidt WFJ;

Metabolites [Metabolites] 2023 May 06; Vol. 13 (5).
Date of Electronic Publication: 2023 May 06.

We wanted to determine the influence of total blood volume (BV) and blood lactate quantity on lactate concentrations during incremental exercise. Twenty-six healthy, nonsmoking, heterogeneously trained females (27.5 ± 5.9 ys) performed an incremental cardiopulmonary exercise test on a cycle ergometer during which maximum oxygen uptake (V·O 2max ), lactate concentrations ([La ]) and hemoglobin concentrations ([Hb]) were determined. Hemoglobin mass and blood volume (BV) were determined using an optimised carbon monoxide-rebreathing method. V·O 2max and maximum power (P max ) ranged between 32 and 62 mL·min -1 ·kg -1 and 2.3 and 5.5 W·kg -1 , respectively. BV ranged between 81 and 121 mL·kg -1 of lean body mass and decreased by 280 ± 115 mL (5.7%, p = 0.001) until P max . At P max , the [La ] was significantly correlated to the systemic lactate quantity (La , r = 0.84, p < 0.0001) but also significantly negatively correlated to the BV (r = -0.44, p < 0.05). We calculated that the exercise-induced BV shifts significantly reduced the lactate transport capacity by 10.8% ( p < 0.0001). Our results demonstrate that both the total BV and La have a major influence on the resulting [La ] during dynamic exercise. Moreover, the blood La transport capacity might be significantly reduced by the shift in plasma volume. We conclude, that the total BV might be another relevant factor in the interpretation of [La ] during a cardio-pulmonary exercise test.

Clinical Utility of the Cardiorespiratory Optimal Point in Patients with Heart Failure.

Kroesen SH; Bakker EA;Snoek JA; van Kimmenade RRJ; Molinger J; Araújo CG; Hopman MTE; Eijsvogels TMH;

Medicine and science in sports and exercise [Med Sci Sports Exerc] 2023 May 15.
Date of Electronic Publication: 2023 May 15.

Introduction: We assessed the cardiorespiratory optimal point (COP) – the minimal VE/VO2 in a given minute of an incremental cardiopulmonary exercise test – in patients with heart failure (HF) and aimed to determine 1) its association with patient and disease characteristics, 2) changes following an exercise-based cardiac rehabilitation program (CR), and 3) the association with clinical outcomes.
Methods: We studied 277 HF patients (67 [58-74] years, 30% female, 72% HFrEF) between 2009 and 2018. Patients participated in a 12- to 24-week CR program, and COP was assessed pre- and post-CR. Patient and disease characteristics and clinical outcomes (mortality and cardiovascular-related hospitalization) were extracted from patient files. The incidence of clinical outcomes was compared across COP tertiles (low: <26.0; moderate: 26.0-30.7; high: >30.7).
Results: Median COP was 28.2 [24.9-32.1] and was reached at 51 ± 15% of VO2peak. Lower age, female sex, higher body mass index, the absence of a pacemaker or the absence of chronic obstructive pulmonary disease and lower NT-proBNP concentrations were associated with a lower COP. Participation in CR reduced COP (-0.8, 95% confidence interval (CI): -1.3; -0.3). Low COP had a reduced risk (adjusted hazard ratio 0.53, 95%CI 0.33; 0.84) for adverse clinical outcomes as compared to high COP.
Conclusions: Classic cardiovascular risk factors are associated with a higher, more unfavorable, COP. CR-based exercise training reduces COP, while a lower COP is associated with a better clinical prognosis. As COP can be established during a submaximal exercise test, this may offer novel risk stratification possibilities for HF care programs.
Competing Interests: Conflict of Interest and Funding Source: This project is supported by a Eurostars Grant (E!114585). All the authors have no conflicts of interest or financial ties to disclose. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine.

Exercise recommendations for patients with hypertrophic cardiomyopathy.

Bryde R; Martinez MW; Emery MS;

Progress in cardiovascular diseases [Prog Cardiovasc Dis] 2023 May 16.
Date of Electronic Publication: 2023 May 16.

Individuals with hypertrophic cardiomyopathy (HCM) have historically been advised to limit exercise and sports participation to mild-intensity activities due to concerns for sudden cardiac arrest (SCA). However, more contemporary data have shown SCA is rare in patients with HCM and emerging data is shifting towards support for the safety of exercise in this patient population. Recent guidelines endorse exercise in patients with HCM after a comprehensive evaluation and shared-decision making with an expert provider.

Competing Interests: Declaration of Competing Interest Dr. Emery reports personal fees (Advisory Board, Speakers Bureau) from Bristol Meyers Squibb. Dr. Martinez reports compensation for his role with Major League Soccer and from the Bristol Meyers Squibb advisory board. Dr. Bryde has no conflicts to report.