Category Archives: Publications

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

Vignati C; Morosin M; Fusini L; Pezzuto B; Spadafora EDe Martino F; Salvioni E; Rovai S; Filardi PP; Sinagra G; Agostoni P;

European Journal Of Preventive Cardiology [Eur J Prev Cardiol] 2019 Apr 25, pp. 2047487319845967. Date of Electronic Publication: 2019 Apr 25.

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.

Prediction of heart failure and death in an adult population of Fontan patients.

Sieweke JT; Haghikia A; Riehle C; Klages C; Akin M; König T; Zwadlo C; Treptau J; Schäfer A; Bauersachs J;
Westhoff-Bleck M;

Cardiology In The Young [Cardiol Young] 2019 Apr 30, pp. 1-8. Date of Electronic Publication: 2019 Apr 30.

Background: Late Fontan survivors are at high risk to experience heart failure and death. Therefore, the current study sought to investigate the role of non-invasive diagnostics as prognostic markers for failure of the systemic ventricle following Fontan procedure.
Methods: This monocentric, longitudinal observational study included 60 patients with a median age of 24.5 (19-29) years, who were subjected to cardiac magnetic resonance imaging, echocardiography, cardiopulmonary exercise testing, and blood analysis. The primary endpoint of this study was decompensated heart failure with symptoms at rest, peripheral and/or pulmonary edema, and/or death.
Results: During a follow-up of 24 months, 5 patients died and 5 patients suffered from decompensated heart failure. Clinical (NYHA class, initial surgery), functional (VO2 peak, ejection fraction, cardiac index), circulating biomarkers (N-terminal pro brain natriuretic peptide), and imaging parameters (end diastolic volume index, end systolic volume index, mass-index, contractility, afterload) were significantly related to the primary endpoint. Multi-variate regression analysis identified afterload as assessed by cardiac magnetic resonance imaging as an independent predictor of the primary endpoint (hazard ratio 1.98, 95% confidence interval 1.19-3.29, p = 0.009).
Conclusion: We identified distinct parameters of cardiopulmonary exercise testing, cardiac magnetic resonance imaging, and blood testing as markers for future decompensated heart failure and death in patients with Fontan circulation. Importantly, our data also identify increased afterload as an independent predictor for increased morbidity and mortality. This parameter is easy to assess by non-invasive cardiac magnetic resonance imaging. Its modulation may represent a potential therapeutic approach target in these high-risk patients.

Can strenuous exercise harm the heart? Insights from a study of cardiovascular neural regulation in amateur triathletes.

Dalla Vecchia LA; Barbic F; De Maria B; Cozzolino D; Gatti R; Dipaola F; Brunetta E; Zamuner AR; Porta A; Furlan R;

Plos One [PLoS One] 2019 May 07; Vol. 14 (5), pp. e0216567.

Regular exercise is recommended to improve the cardiovascular risk profile. However, there is growing evidence that extreme volumes and intensity of long-term exertion may increase the risk of acute cardiac events. The aim of this study is to investigate the after-effects of regular, strenuous physical training on the cardiovascular neural regulation in a group of amateur triathletes compared to age-matched sedentary controls. We enrolled 11 non-elite triathletes (4 women, age 24±4 years), who had refrained from exercise for 72 hours, and 11 age-matched healthy non-athletes (3 women, age 25±2 years). Comprehensive echocardiographic and cardiopulmonary exercise tests were performed at baseline. Electrocardiogram, non-invasive blood pressure, respiratory activity, and muscle sympathetic nerve activity (MSNA) were continuously recorded in a supine position (REST) and during an incremental 15° step-wise head-up tilt test up to 75° (TILT). Blood samples were collected for determination of stress mediators. Autoregressive spectral analysis provided the indices of the cardiac sympathetic (LFRR) and vagal (HFRR) activity, the vascular sympathetic control (LFSAP), and the cardiac sympatho-vagal modulation (LF/HF). Compared to controls, triathletes were characterized by greater LFRR, LF/HF ratio, LFSAP, MSNA, and lower HFRR at REST and during TILT, i.e. greater overall cardiovascular sympathetic modulation together with lower cardiac vagal activity. Cortisol and adrenocorticotropic hormone concentrations were also higher in triathletes. In conclusion, triathletes were characterized by signs of sustained cardiovascular sympathetic overactivity. This might represent a risk factor for future cardiovascular events, given the known association between chronic excessive sympathetic activity and increased cardiovascular risk

A Meta-analysis of Diagnostic Test Agreement Between Eucapnic Voluntary Hyperventilation and Cardiopulmonary Exercise Tests for Exercise-Induced Bronchoconstriction.

Iftikhar IH; Greer M; Jaiteh A;

Lung [Lung] 2019 May 10. Date of Electronic Publication: 2019 May 10.

Introduction: Exercise-induced bronchoconstriction (EIB) is very common in athletes. Cardiopulmonary exercise tests (CPET) have traditionally been used for the diagnosis of EIB. However, alternative indirect bronchoprovocation tests have recently been used as surrogate tests. One of these is the eucapnic voluntary hyperventilation (EVH). This meta-analysis studied the agreement between the two tests.
Methods: An extensive search in PubMed and Medline was conducted for studies where participants underwent both CPET and EVH with measurement of forced expiratory volume in 1-second (FEV1). After extracting data using two-by-two contingency tables, pooled positive and negative agreements were first calculated between the two tests, with EVH benchmarked against CPET, and then, pooled positive and negative agreements were calculated with CPET benchmarked against EVH.
Results: The pooled positive and negative agreements between EVH and CPET (with CPET as the reference) were 0.62 [(95% confidence interval 0.54-0.70), I2 77%] and 0.61 [(0.56-0.65)), I2 81%]. The pooled positive and negative agreements between CPET and EVH (with EVH as the reference) were 0.36 [(0.30-0.42), I2 93%] and 0.82 [(0.77-0.86), I2 78%]. The average of positive test results with EVH across all studies was greater than that of CPETs (58.84% vs. 39.51%).
Conclusions: Results of this meta-analysis show poor positive agreement between the two tests but high negative agreement (specifically using EVH as reference), suggesting that either test can be used for correctly identifying those without EIB. Results also suggest that the chances of a test resulting positive are higher with EVH than with CPET.

Exercise performance and symptoms in lowlanders with COPD ascending to moderate altitude: randomized trial.

Furian M; Flueck D; Latshang TD; Scheiwiller PM; Segitz SD; Mueller-Mottet
S; Murer C; Steiner A; Ulrich S; Rothe T; Kohler M; Bloch KE.

International Journal of Copd. 13:3529-3538, 2018.

Objective: To evaluate the effects of altitude travel on exercise
performance and symptoms in lowlanders with COPD.
Design: Randomized crossover trial.
Setting: University Hospital Zurich (490 m), research facility in
mountain villages, Davos Clavadel (1,650 m) and Davos Jakobshorn (2,590m).
Participants: Forty COPD patients, Global Initiative for Obstructive Lung
Disease (GOLD) grade 2-3, living below 800 m, median (quartiles) age 67 y
(60; 69), forced expiratory volume in 1 second 57% predicted (49; 70)
Intervention: Two-day sojourns at 490 m, 1,650 m, and 2,590 m in
randomized order.
Outcome measures: Six-minute walk distance (6MWD), cardiopulmonary
exercise tests, symptoms, and other health effects.
Results: At 490 m, days 1 and 2, median (quartiles) 6MWD were 558 m (477;
587) and 577 m (531; 629). At 2,590 m, days 1 and 2, mean changes in 6MWD
from corresponding day at 490 m were -41 m (95% CI -51 to -31) and -40 m
(-53 to -27), n=40, P<0.05, both changes. At 1,650 m, day 1, 6MWD had
changed by -22 m (-32 to -13), maximal oxygen uptake during bicycle
exercise by -7% (-13 to 0) vs 490 m, P<0.05, both changes. At 490 m, 1,650
m, and 2,590 m, day 1, resting PaO2 were 9.0 (8.4; 9.4), 8.1 (7.5; 8.6),
and 6.8 (6.3; 7.4) kPa, respectively, P<0.05 higher altitudes vs 490 m.
While staying at higher altitudes, nine patients (24%) experienced
symptoms or adverse health effects requiring oxygen therapy or relocation
to lower altitude.

Conclusion: During sojourns at 1,650 m and 2,590 m, lowlanders with
moderate to severe COPD experienced a mild reduction in exercise
performance and nearly one quarter required oxygen therapy or descent to
lower altitude because of adverse health effects. The findings may help to
counsel COPD patients planning altitude travel.

Pulmonary Function Testing and Cardiopulmonary Exercise Testing: An Overview. [Review]

Krol K; Morgan MA; Khurana S.

Medical Clinics of North America. 103(3):565-576, 2019 May.

Respiratory symptoms are common reasons for patients to seek care and
contribute significantly to use of health care resources. Identifying the
underlying etiology of a respiratory symptom is key to management; yet,
pinpointing the cause can be a challenge. Familiarity with the tools
available to help discern between the various contributing etiologies is
crucial in guiding management. Assessment and quantification of pulmonary
function can provide an objective measure to guide diagnosis and therapy.
We review key points of pulmonary function evaluation, highlighting
indications and contraindications, fundamentals of interpretation, and the
limitations of each individual component.

Cardiopulmonary Exercise Testing for Surgical Risk Stratification in Adults with Congenital Heart Disease.

Birkey T; Dixon J; Jacobsen R; Ginde S; Nugent M; Yan K; Simpson P; Kovach J

Pediatric Cardiology. 39(7):1468-1475, 2018 Oct.

Adult congenital heart disease (ACHD) patients often require repeat
cardiothoracic surgery, which may result in significant morbidity and
mortality. Currently, there are few pre-operative risk assessment tools
available. In the general adult population, pre-operative cardiopulmonary
exercise testing (CPET) has a predictive value for post-operative
morbidity and mortality following major non-cardiac surgery. The utility
of CPET for risk assessment in ACHD patients requiring cardiothoracic
surgery has not been evaluated. Retrospective chart review was conducted
on 75 ACHD patients who underwent CPET less than 12 months prior to major
cardiothoracic surgery at Children’s Hospital of Wisconsin. Minimally
invasive procedures, cardiomyopathy, acquired heart disease, single
ventricle physiology, and heart transplant patients were excluded.
Demographic information, CPET results, and peri-operative surgical data
were collected. The study population was 56% male with a median age of 25
years (17-58). Prolonged post-operative length of stay correlated with
increased ventilatory efficiency slope (VE/[Formula: see text] slope) (P =
0.007). Prolonged intubation time correlated with decreased peak HR (P =
0.008), decreased exercise time (P = 0.002), decreased heart rate response
(P = 0.008) and decreased relative peak oxygen consumption (P = 0.034).
Post-operative complications were documented in 59% of patients. While
trends were noted between post-operative complications and some
measurements of exercise capacity, none met statistical significance.
Future studies may further define the relationship between exercise
capacity and post-operative morbidity in ACHD patients.


High intensity interval training protects the heart during increased metabolic demand in patients with type 2 diabetes: a randomised controlled trial.

Suryanegara J; Cassidy S; Ninkovic V; Popovic D; Grbovic M; Okwose N;
Trenell MI; MacGowan GG; Jakovljevic DG.

Acta Diabetologica. 56(3):321-329, 2019 Mar.

AIM: The present study assessed the effect of high intensity interval
training on cardiac function during prolonged submaximal exercise in
patients with type 2 diabetes.
METHODS: Twenty-six patients with type 2 diabetes were randomized to a 12
week of high intensity interval training (3 sessions/week) or standard
care control group. All patients underwent prolonged (i.e. 60 min)
submaximal cardiopulmonary exercise testing (at 50% of previously assess
maximal functional capacity) with non-invasive gas-exchange and
haemodynamic measurements including cardiac output and stroke volume
before and after the intervention.
RESULTS: At baseline (prior to intervention) there was no significant
difference between the intervention and control group in peak exercise
oxygen consumption (20.3 +/- 6.1 vs. 21.7 +/- 5.5 ml/kg/min, p = 0.21),
and peak exercise heart rate (156.3 +/- 15.0 vs. 153.8 +/- 12.5 beats/min,
p = 0.28). During follow-up assessment both groups utilized similar amount
of oxygen during prolonged submaximal exercise (15.0 +/- 2.4 vs. 15.2 +/-
2.2 ml/min/kg, p = 0.71). However, cardiac function i.e. cardiac output
during submaximal exercise decreased significantly by 21% in exercise
group (16.2 +/- 2.7-12.8 +/- 3.6 L/min, p = 0.03), but not in the control
group (15.7 +/- 4.9-16.3 +/- 4.1 L/min, p = 0.12). Reduction in exercise
cardiac output observed in the exercise group was due to a significant
decrease in stroke volume by 13% (p = 0.03) and heart rate by 9% (p =
CONCLUSION: Following high intensity interval training patients with type
2 diabetes demonstrate reduced cardiac output during prolonged submaximal
cardiopulmonary exercise testing. Ability of patients to maintain
prolonged increased metabolic demand but with reduced cardiac output
suggests cardiac protective role of high intensity interval training in
type 2 diabetes.

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk.

Imboden MT; Harber MP; Whaley MH; Finch WH; Bishop DL; Fleenor BS;
Kaminsky LA.

Progress in Cardiovascular Diseases. 62(2):157-162, 2019 Mar – Apr.

BACKGROUND: The relationship between cardiorespiratory fitness (CRF) and
mortality risk has typically been assessed using a single measurement,
though some evidence suggests the change in CRF over time influences risk.
This evidence is predominantly based on studies using estimated CRF
(CRFe). The strength of this relationship using change in directly
measured CRF over time in apparently healthy men and women is not well
PURPOSE: To examine the association of change in CRF over time, measured
using cardiopulmonary exercise testing (CPX), with all-cause and
disease-specific mortality and to compare baseline and subsequent CRF
measurements as predictors of all-cause mortality.
METHODS: Participants included 833 apparently healthy men and women
(42.9+/-10.8years) who underwent two maximal CPXs, the second CPX being
>=1year following the baseline assessment (mean 8.6years, range 1.0 to
40.3years). Participants were followed for up to 17.7 (SD 11.8)years for
all-cause-, cardiovascular disease- (CVD), and cancer mortality.
Cox-proportional hazard models were performed to determine the association
between the change in CRF, computed as visit 1 (CPX1) peak oxygen
consumption (VO2peak []) – visit 2 (CPX2) VO2peak, and
mortality outcomes. A Wald-Chi square test of equality was used to compare
the strength of CPX1 to CPX2 VO2peak in predicting mortality.
RESULTS: During follow-up, 172 participants died. Overall, the change in
CPX-CRF was inversely related to all-cause, CVD, and cancer mortality
(p<0.05). Each increase was associated with a ~11, 15, and
16% (all p<0.001) reduction in all-cause, CVD, and cancer mortality,
respectively. The inverse relationship between CRF and all-cause mortality
was significant (p<0.05) when men and women were examined independently,
after adjusting for years since first CPX, baseline VO2peak, and age.
Further, the Wald Chi-square test of equality found CPX2 VO2peak to be a
significantly stronger predictor of all-cause mortality than CPX1 VO2peak
CONCLUSION: The change in CRF over time was inversely related to
mortality outcomes, and mortality was better predicted by CRF measured at
subsequent test than CPX1 CRF. These findings emphasize the importance of
adopting lifestyle behaviors that promote CRF, as well as support the need
for routine assessment of CRF in clinical practice to better assess risk.

Cardiorespiratory fitness and cardiovascular disease – The past, present, and future. [Review]

Kaminsky LA; Arena R; Ellingsen O; Harber MP; Myers J; Ozemek C; Ross R

Progress in Cardiovascular Diseases. 62(2):86-93, 2019 Mar – Apr.

The importance of cardiorespiratory fitness (CRF) is now well established
and it is increasingly being recognized as an essential variable which
should be assessed in health screenings. The key findings that have
established the clinical significance of CRF are reviewed in this report,
along with an overview of the current relevance of exercise as a form of
medicine that can provide a number of positive health outcomes, including
increasing CRF. Current assessment options for assessing CRF are also
reviewed, including the direct measurement via cardiopulmonary exercise
testing which now can be interpreted with age and sex-specific reference
values. Future directions for the use of CRF and related measures are