Author Archives: Paul Older

Beyond VO2: the complex cardiopulmonary exercise test

I. Mattavelli, C. Vignati, S. Farina, A. Apostolo, G. Cattadori, F. De Martino, et al.

Eur J Prev Cardiol 2023 Vol. 30 Issue Suppl 2 Pages ii34-ii39

Cardiopulmonary exercise test (CPET) is a valuable diagnostic tool with a specific application in heart failure (HF) thanks to the strong prognostic value of its parameters. The most important value provided by CPET is the peak oxygen uptake (peak VO2), the maximum rate of oxygen consumption attainable during physical exertion. According to the Fick principle, VO2 equals cardiac output (Qc) times the arteriovenous content difference [C(a-v)O2], where Ca is the arterial oxygen and Cv is the mixed venous oxygen content, respectively; therefore, VO2 can be reduced both by impaired O2 delivery (reduced Qc) or extraction (reduced arteriovenous O2 content). However, standard CPET is not capable of discriminating between these different impairments, leading to the need for ‘complex’ CPET technologies. Among non-invasive methods for Qc measurement during CPET, inert gas rebreathing and thoracic impedance cardiography are the most used techniques, both validated in healthy subjects and patients with HF, at rest and during exercise. On the other hand, the non-invasive assessment of peripheral muscle perfusion is possible with the application of near-infrared spectroscopy, capable of measuring tissue oxygenation. Measuring Qc allows, by having haemoglobin values available, to discriminate how much any VO2 deficit depends on the muscle, anaemia or he

The alveolar-capillary unit in the physiopathological conditions of heart failure: identification of a potential marker

C. Banfi, P. Gugliandolo, S. Paolillo, A. Mallia, E. Gianazza and P. Agostoni

Eur J Prev Cardiol 2023 Vol. 30 Issue Suppl 2 Pages ii2-ii8

In this review, we describe the structure and function of the alveolar-capillary membrane and the identification of a novel potential marker of its integrity in the context of heart failure (HF). The alveolar-capillary membrane is indeed a crucial structure for the maintenance of the lung parenchyma gas exchange capacity, and the occurrence of pathological conditions determining lung fluids accumulation, such as HF, might significantly impair lung diffusion capacity altering the alveolar-capillary membrane protective functions. In the years, we found that the presence of immature forms of the surfactant protein-type B (proSP-B) in the circulation reflects alterations in the alveolar-capillary membrane integrity. We discussed our main achievements showing that proSP-B, due to its chemical properties, specifically binds to high-density lipoprotein, impairing their antioxidant activity, and likely contributing to the progression of the disease. Further, we found that immature proSP-B, not the mature protein, is related to lung abnormalities, more precisely than the lung function parameters. Thus, to the list of the potential proposed markers of HF, we add proSP-B, which represents a precise marker of alveolar-capillary membrane dysfunction in HF, correlates with prognosis, and represents a precocious marker of drug therapy

Physiology of exercise and heart failure treatments: cardiopulmonary exercise testing as a tool for choosing the optimal therapeutic strategy

J. Campodonico, M. Contini, M. Alimento, M. Mapelli, E. Salvioni, I. Mattavelli, et al

Eur J Prev Cardiol 2023 Vol. 30 Issue Suppl 2 Pages ii54-ii62

In the last decades, the pharmacological treatment of heart failure (HF) become more complex due to the availability of new highly effective drugs. Although the cardiovascular effects of HF therapies have been extensively described, less known are their effects on cardiopulmonary function considered as a whole, both at rest and in response to exercise. This is a ‘holistic’ approach to disease treatment that can be accurately evaluated by a cardiopulmonary exercise test. The aim of this paper is to assess the main differences in the effects of different drugs [angiotensin-converting enzyme (ACE)-inhibitors, Angiotensin II receptor blockers, beta-blockers, Angiotensin receptor-neprilysin inhibitors, renal sodium-glucose co-transporter 2 inhibitors, iron supplementation] on cardiopulmonary function in patients with HF, both at rest and during exercise, and to understand how these differences can be taken into account when choosing the most appropriate treatment protocol for each individual patient leading to a precision medicine approach.

Activities of daily living in heart failure patients and healthy subjects: when the cardiopulmonary assessment goes beyond traditional exercise test protocols

M. Mapelli, E. Salvioni, I. Mattavelli, P. Gugliandolo, A. Bonomi, P. Palermo, et al.

Eur J Prev Cardiol 2023 Vol. 30 Issue Suppl 2 Pages ii47-ii53

Heart failure (HF) patients traditionally report dyspnoea as their main symptom. Although the cardiopulmonary exercise test (CPET) and 6 min walking test are the standardized tools in assessing functional capacity, neither cycle ergometers nor treadmill maximal efforts do fully represent the actual HF patients’ everyday activities [activities of daily living (ADLs)] (i.e. climbing the stairs). New-generation portable metabolimeters allow the clinician to measure task-related oxygen intake (VO2) in different scenarios and exercise protocols. In the last years, we have made considerable progress in understanding the ventilatory and metabolic behaviours of HF patients and healthy subjects during tasks aimed to reproduce ADLs. In this paper, we describe the most recent findings in the field, with special attention to the relationship between the metabolic variables obtained during ADLs and CPET parameters (i.e. peak VO2), demonstrating, for example, how exercises traditionally thought to be undemanding, such as a walk, instead represent supramaximal efforts, particularly for subjects with advanced HF and/or artificial heart (left ventricular assist devices) wearers.
This article summarizes the most recent evidence on the cardiometabolic behaviours of a full spectrum of heart failure (HF) patients of different severity during their daily life activities (i.e. walking, making a bed, and taking the stairs).Heart failure patients experience symptoms (mostly dyspnoea) during daily activities that sometimes represent maximal or supramaximal exercises for them, particularly for the most severe patients.Measuring metabolic parameters (O2 intake, ventilation, and CO2 production) through appropriate devices during these activities provides a better understanding of the pathophysiological mechanisms underlying HF patients’ symptoms and their adaptation. This can lead to the detection of new parameters that can become novel patient-centred prognostic markers or therapeutic targets for drugs and rehabilitation treatments.

Exercise oscillatory ventilation: the past, present, and future

G. Cunha, A. Apostolo, F. De Martino, E. Salvioni, I. Matavelli and P. Agostoni

Eur J Prev Cardiol 2023 Vol. 30 Issue Suppl 2 Pages ii22-ii27

Exercise oscillatory ventilation (EOV) is a fascinating event that can be appreciated in the cardiopulmonary exercise test and is characterized by a cyclic fluctuation of minute ventilation, tidal volume, oxygen uptake, carbon dioxide production, and end-tidal pressure for oxygen and carbon dioxide. Its mechanisms stem from a dysregulation of the normal control feedback of ventilation involving one or more of its components, namely, chemoreflex delay, chemoreflex gain, plant delay, and plant gain. In this review, we intend to breakdown therapeutic targets according to pathophysiology and revise the prognostic value of exercise oscillatory ventilation in the setting of heart failure and other diagnoses.

Two is better than one: the double diffusion technique in classifying heart failure

Zavorsky, G;  Agostoni, P;

ERJ Open Res 2024 Vol. 10 Issue 1

BACKGROUND: Heart failure (HF) is a chronic condition in which the heart does not pump enough blood to meet the body’s demands. Diffusing capacity of the lung for nitric oxide (D(LNO)) and carbon monoxide (D(LCO)) may be used to classify patients with HF, as D(LNO) and D(LCO) are lung function measurements that reflect pulmonary gas exchange. Our objectives were to determine 1) if D(LNO) added to D(LCO) testing predicts HF better than D(LCO) alone and 2) whether the binary classification of HF is better when D(LNO) z-scores are combined with D(LCO) z-scores than using D(LCO) z-scores alone.
METHODS: This was a retrospective secondary data analysis in 140 New York Heart Association Class II HF patients (ejection fraction <40%) and 50 patients without HF. z-scores for D(LNO), D(LCO) and D(LNO)+D(LCO) were created from reference equations from three articles. The model with the lowest Bayesian Information Criterion was the best predictive model. Binary HF classification was evaluated with the Matthews Correlation Coefficient (MCC). RESULTS: The top two of 12 models were combined z-score models. The highest MCC (0.51) was from combined z-score models. At most, only 32% of the variance in the odds of having HF was explained by combined z-scores.
CONCLUSIONS: Combined z-scores explained 32% of the variation in the likelihood of an individual having HF, which was higher than models using D(LNO) or D(LCO) z-scores alone. Combined z-score models had a moderate ability to classify patients with HF. We recommend using the NO-CO double diffusion technique to assess gas exchange impairment in those suspected of HF.

What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the Metabolic Exercise combined with Cardiac and Kidney Indexes score dataset

D. Magri, G. Gallo, M. Piepoli, E. Salvioni, M. Mapelli, C. Vignati, et al.

Eur J Prev Cardiol 2024 Vol. 31 Issue 2 Pages 263-271

AIMS: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters.
METHODS AND RESULTS: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from </=75% to </=60% and pHRR% </= 65% to </=50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% </= 75% and a pHRR% </= 50% represented the most accurate cut-off values in predicting the outcome.
CONCLUSION: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies.
Chronotropic incompetence is an easy-to-obtain additive parameter for cardiovascular death risk stratification in heart failure with mildly reduced ejection fraction (HFmrEF). Peak heart rate and peak heart rate reserve are associated with exercise capacity in HFmrEF. Peak heart rate and peak heart rate reserve are associated with cardiovascular death in HFmrEF.

Using Machine Learning-Based Algorithms to Identify and Quantify Exercise Limitations in Clinical Practice: Are We There Yet?

Med Sci Sports Exercise 2024 Feb 1;56(2):159-169

Introduction: Well-trained staff is needed to interpret cardiopulmonary exercise tests (CPET). We aimed to examine the accuracy of machine learning-based algorithms to classify exercise limitations and their severity in clinical practice compared with expert consensus using patients presenting at a pulmonary clinic.

Methods: This study included 200 historical CPET data sets (48.5% female) of patients older than 40 yr referred for CPET because of unexplained dyspnea, preoperative examination, and evaluation of therapy progress. Data sets were independently rated by experts according to the severity of pulmonary-vascular, mechanical-ventilatory, cardiocirculatory, and muscular limitations using a visual analog scale. Decision trees and random forests analyses were calculated.

Results: Mean deviations between experts in the respective limitation categories ranged from 1.0 to 1.1 points (SD, 1.2) before consensus. Random forests identified parameters of particular importance for detecting specific constraints. Central parameters were nadir ventilatory efficiency for CO 2 , ventilatory efficiency slope for CO 2 (pulmonary-vascular limitations); breathing reserve, forced expiratory volume in 1 s, and forced vital capacity (mechanical-ventilatory limitations); and peak oxygen uptake, O 2 uptake/work rate slope, and % change of the latter (cardiocirculatory limitations). Thresholds differentiating between different limitation severities were reported. The accuracy of the most accurate decision tree of each category was comparable to expert ratings. Finally, a combined decision tree was created quantifying combined system limitations within one patient.

Conclusions: Machine learning-based algorithms may be a viable option to facilitate the interpretation of CPET and identify exercise limitations. Our findings may further support clinical decision making and aid the development of standardized rating instruments.

Accelerometer Metrics: Healthy Adult Reference Values, Associations with Cardiorespiratory Fitness, and Clinical Implications

Med Sci Sports Exercise 2024 Feb 1;56(2):170-180.

Purpose: Accelerometer-assessed physical activity (PA) can be summarized using cut-point-free or population-specific cut-point-based outcomes. We aimed to 1) examine the interrelationship between cut-point-free (intensity gradient (IG) and average acceleration (AvAcc)) and cut-point-based accelerometer metrics, 2) compare the association between cardiorespiratory fitness (CRF) and cut-point-free metrics to that with cut-point-based metrics in healthy adults aged 20 to 89 yr and patients with heart failure, and 3) provide age-, sex-, and CRF-related reference values for healthy adults.

Methods: In the COmPLETE study, 463 healthy adults and 67 patients with heart failure wore GENEActiv accelerometers on their nondominant wrist and underwent cardiopulmonary exercise testing. Cut-point-free (IG: distribution of intensity of activity across the day; AvAcc: proxy of volume of activity) and traditional (moderate-to-vigorous and vigorous activity) metrics were generated. The “interpretablePA” R-package was developed to translate findings into clinical practice.

Results: IG and AvAcc yield complementary information on PA with both IG ( P = 0.009) and AvAcc ( P < 0.001) independently associated with CRF in healthy individuals (adjusted R2 = 73.9%). Only IG was independently associated with CRF in patients with heart failure ( P = 0.043, adjusted R2 = 38.4%). The best cut-point-free and cut-point-based model had similar predictive value for CRF in both cohorts. We produced age- and sex-specific reference values and percentile curves for IG, AvAcc, moderate-to-vigorous PA, and vigorous PA for healthy adults.

Conclusions: IG and AvAcc are strongly associated with CRF and thus indirectly with the risk of noncommunicable diseases and mortality, in healthy adults and patients with heart failure. However, unlike cut-point-based metrics, IG and AvAcc are comparable across populations. Our reference values provide a healthy age- and sex-specific comparison that may enhance the translation and utility of cut-point-free metrics in clinical practice.

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A verification phase adds little value to the determination of maximum oxygen uptake in well-trained adults

Eur J Appl Physiol 2024 Jan 18

Purpose: The objective was to investigate if performing a sub-peak or supra-peak verification phase following a ramp test provides additional value for determining ‘true’ maximum oxygen uptake ([Formula: see text]O2).

Methods: 17 and 14 well-trained males and females, respectively, performed two ramp tests each followed by a verification phase. While the ramp tests were identical, the verification phase differed in power output, wherein the power output was either 95% or 105% of the peak power output from the ramp test. The recovery phase before the verification phase lasted until capillary blood lactate concentration was ≤ 4 mmol·L-1. If a [Formula: see text]O2 plateau occurred during ramp test, the following verification phase was considered to provide no added value. If no [Formula: see text]O2 plateau occurred and the highest [Formula: see text]O2 ([Formula: see text]O2peak) during verification phase was < 97%, between 97 and 103%, or > 103% of [Formula: see text]O2peak achieved during the ramp test, no value, potential value, and certain value were attributed to the verification phase, respectively.

Results: Mean (standard deviation) [Formula: see text]O2peak during both ramp tests was 64.5 (6.0) mL·kg-1·min-1 for males and 54.8 (6.2) mL·kg-1·min-1 for females. For the 95% verification phase, 20 tests showed either a [Formula: see text]O2 plateau during ramp test or a verification [Formula: see text]O2peak < 97%, indicating no value, 11 showed potential value, and 0 certain value. For the 105% verification phase, the values were 26, 5, and 0 tests, respectively.

Conclusion: In well-trained adults, a sub-peak verification phase might add little value in determining ‘true’ maximum [Formula: see text]O2, while a supra-peak verification phase adds no value.