Category Archives: Publications

Systolic Function of Right Ventricular Outflow Tract is a Better Predictor to Exercise Performance After Pulmonary Valve Replacement in Tetralogy of Fallot.

Li J, Luo S, Liu F, An Q

Pediatr Cardiol. 2017 Dec;38(8):1556-1561

Debate on the proper timing of pulmonary valve replacement (PVR) after repair of
tetralogy of Fallot is still continuing. We aim to clarify how the different
components of right ventricle (RV) changed with relieved volume overload in the
remodeling process after pulmonary valve replacement and gain a clear idea of the
relationship between different right ventricle components function and exercise
capacity after PVR in these patients. The medical records and results of cardiac
magnetic resonance imaging and cardiopulmonary exercise testing of 25 consecutive
eligible patients were reviewed. End-diastolic, end-systolic, and ejection
fraction (EF) were determined for the total RV and its components before and
after PVR. There was a marked increase in EF for the outlet after PVR
(39.5 ± 11.4 vs. 45.6 ± 12.7, P = 0.04); however, EF and volume change for the
other components showed no significant difference. Peak oxygen consumption (VO2)
correlated better with the RV outflow tract EF than with the EF of other
components of the RV or the global EF (r = 0.382, P = 0.018), and the time
interval between initial repair and PVR showed a significant correlation with
peak VO2 (r = -0.339, P = 0.037). Multivariate analysis showed the RV outflow
tract EF to be the only independent predictor of exercise capacity (β = 0.479;
P = 0.046). The systolic function of the RV outflow tract could be a reliable
determinant of intrinsic RV performance in repaired TOF (rTOF) patients and a
promising parameter for deciding timing of pulmonary valve replacement so as to
achieve the best possible exercise capacity in repaired TOF patients.

Importance of Non-invasive Right and Left Ventricular Variables on Exercise Capacity in Patients with Tetralogy of Fallot Hemodynamics.

Meierhofer C, Tavakkoli T, Kühn A, Ulm K, Hager A, Müller J,
Martinoff S, Ewert P, Stern H

Pediatr Cardiol. 2017 Dec;38(8):1569-1574.

Good quality of life correlates with a good exercise capacity in daily life in
patients with tetralogy of Fallot (ToF). Patients after correction of ToF usually
develop residual defects such as pulmonary regurgitation or stenosis of variable
severity. However, the importance of different hemodynamic parameters and their
impact on exercise capacity is unclear. We investigated several hemodynamic
parameters measured by cardiovascular magnetic resonance (CMR) and
echocardiography and evaluated which parameter has the most pronounced effect on
maximal exercise capacity determined by cardiopulmonary exercise testing (CPET).
132 patients with ToF-like hemodynamics were tested during routine follow-up with
CMR, echocardiography and CPET. Right and left ventricular volume data,
ventricular ejection fraction and pulmonary regurgitation were evaluated by CMR.
Echocardiographic pressure gradients in the right ventricular outflow tract and
through the tricuspid valve were measured. All data were classified and
correlated with the results of CPET evaluations of these patients. The analysis
was performed using the Random Forest model. In this way, we calculated the
importance of the different hemodynamic variables related to the maximal oxygen
uptake in CPET (VO2%predicted). Right ventricular pressure showed the most
important influence on maximal oxygen uptake, whereas pulmonary regurgitation and
right ventricular enddiastolic volume were not important hemodynamic variables to
predict maximal oxygen uptake in CPET. Maximal exercise capacity was only very
weakly influenced by right ventricular enddiastolic volume and not at all by
pulmonary regurgitation in patients with ToF. The variable with the most
pronounced influence was the right ventricular pressure.

Reference values for maximum work rate in apparently healthy Dutch/Flemish adults: data from the LowLands fitness registry

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Acta Cardiologica Published online: 22 Jun 2018

Background: The peak oxygen uptake (VO2peak) test is the gold standard for cardiorespiratory fitness. However, the test is demanding, requiring sophisticated apparatus for measuring the oxygen uptake. Peak work rate (WRpeak) testing is a promising substitute for peak VO2peak testing. However, there is a paucity of research conducted to determine reference values (RVs) for WRpeak.

Methods: The database from the LowLands fitness registry was used, containing data from health checks from apparently healthy subjects among various professions. Exercise tests were performed using a cycle ergometer and a calibrated metabolic cart. Analysis was executed on 3463 subjects, 2868 male and 595 female. Reference values with corresponding centiles were developed using the LMS method.

Results: VO2peak and WRpeak where highly associated with Pearson’s correlation of 0.9 (p = .001). Weight, height, maximum heart rate, and the respiratory exchange ratio had a positive significant effect (p < .001) on WRpeak, and age a negative significant effect, in both males and females. The following formulas were computed for RVs:

Conclusions: WRpeak can be used as a substitute for VO2peak when a respiratory gas-analysis system is not available. This study provides RVs for WRpeak and WRpeak/kg in a healthy Dutch/Flemish adult population using cycle ergometry. Further research is needed to obtain RVs for elderly subjects, specific diseases, ethnicities and ergometers.

Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study

Duminda N Wijeysundera, PhD; Prof Rupert M Pearse, MD; Mark A Shulman, MPH; Tom E F Abbott, PhD; Elizabeth Torres, BMSc; Althea Ambosta, MA; Bernard L Croal, MD; Prof John T Granton, MD; Kevin E Thorpe, MMath; Prof Michael P W Grocott, MD; Catherine Farrington, BAppSc; Prof Paul S Myles, DSc; Prof Brian H Cuthbertson, MD

,on behalf of the

The Lancet Volume 391, No. 10140, p2631–2640, 30 June 2018



Functional capacity is an important component of risk assessment for major surgery. Doctors’ clinical subjective assessment of patients’ functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery.


We did a multicentre, international, prospective cohort study at 25 hospitals: five in Canada, seven in the UK, ten in Australia, and three in New Zealand. We recruited adults aged at least 40 years who were scheduled for major non-cardiac surgery and deemed to have one or more risk factors for cardiac complications (eg, a history of heart failure, stroke, or diabetes) or coronary artery disease. Functional capacity was subjectively assessed in units of metabolic equivalents of tasks by the responsible anaesthesiologists in the preoperative assessment clinic, graded as poor (<4), moderate (4–10), or good (>10). All participants also completed the DASI questionnaire, underwent CPET to measure peak oxygen consumption, and had blood tests for measurement of NT pro-BNP concentrations. After surgery, patients had daily electrocardiograms and blood tests to measure troponin and creatinine concentrations until the third postoperative day or hospital discharge. The primary outcome was death or myocardial infarction within 30 days after surgery, assessed in all participants who underwent both CPET and surgery. Prognostic accuracy was assessed using logistic regression, receiver-operating-characteristic curves, and net risk reclassification.


Between March 1, 2013, and March 25, 2016, we included 1401 patients in the study. 28 (2%) of 1401 patients died or had a myocardial infarction within 30 days of surgery. Subjective assessment had 19·2% sensitivity (95% CI 14·2–25) and 94·7% specificity (93·2–95·9) for identifying the inability to attain four metabolic equivalents during CPET. Only DASI scores were associated with predicting the primary outcome (adjusted odds ratio 0·96, 95% CI 0·83–0·99; p=0·03).


Subjectively assessed functional capacity should not be used for preoperative risk evaluation. Clinicians could instead consider a measure such as DASI for cardiac risk assessment.


Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.


Cardiopulmonary Exercise Testing in Aortic Stenosis.


Dan Med J. 2017 May;64(5). pii: B5352.

Patients with moderate to severe aortic stenosis (AVA <1.3 cm2) who were judged,
by a referring cardiologist, as asymptomatic or equivocal symptomatic from the
aortic stenosis were included in the study. Patients with left ventricular
ejection fraction <50% were not included. Twenty-nine percent of the referred
patients were judged asymptomatic and 71% equivocal symptomatic from their valve
disease. The mean age was 72 years and 90% of the patients had an AVA-index <0.6
cm2/m2. By clinical evaluation in the outpatient clinic, 48% were judged as
having functional limitation corresponding to NYHA≥II. The study participants had
cardiopulmonary exercise testing (CPX) at inclusion, and, if relevant, pre- and
nine months post-aortic valve replacement (AVR). CPX was feasible in 130 of 131
study participants recruited across 19 months. The coefficient of variability by
test-retest was 5.4% and 4.6% for peak oxygen consumption (pVO2) and peak oxygen
pulse (pO2pulse= pVO2/peak heart rate), respectively. The stroke volume generally
increased with exercise, also in those with peak flow velocity across the aortic
valve (Vmax) >5 m/s, >4 m/s, and <4 m/s but with high valvuloarterial impedance
(Zva >5.5 mm Hg/(mL·m2 )). This was found both when assessed by inert gas
rebreathing and by the pO2pulse/hemoglobin index. Both resting and exercise
stroke volume were lower for the latter group, with Vmax <4 m/s but high
valvuloarterial impedance. A pVO2 <83% of the predicted, which corresponds to the
lower 95% percentile found in the healthy sedentary population, was predicted
independently by lower stroke volume during exercise, lower heart rate during
exercise, lower FEV1, and by higher ventilation/carbon dioxide exhaustion rate
(VE/VCO2), but not by the severity of the aortic stenosis as determined by
echocardiography. According to the CPX results, the patients were prospectively
grouped into 3 groups, as follows: 1) normal pVO2 (>83% of predicted) and
pO2pulse (>95% of predicted); 2) subnormal pVO2 or pO2pulse that according to CPX
could be explained by causes other than hemodynamic compromise; 3) subnormal pVO2
and pO2pulse. Groups 1 and 2 followed an initial conservative strategy, whereas
Group 3 was referred for angiogram and Heart Team evaluation for AVR. The
patients were followed for an average of 24 months and, in Groups 1 and 2, one
patient (0.9%) suffered cardiac death and seven were hospitalized with heart
failure (6.7%). The patient who died and another patient with heart failure had
both previously, during the study, declined AVR. For Groups 1 and 2, the rate of
the combined endpoint progression to cardiac death, hospitalization with heart
failure, or AVR was 37.5%, which seems lower than what was reported in the
literature by conventional assessment and strategy for younger asymptomatic
patients with comparable echocardiographic severity of aortic stenosis. The
endpoint progression to cardiac death, hospitalization with heart failure, or AVR
with improvement in pVO2 or in the Physical Component Score of the SF-36
health-related quality of life score was reached in 25.6% in Groups 1+2 and in
62.5% in Group 3 (p=0.003). A decreased pO2pulse, which expresses stroke volume
at peak exercise, predicted this endpoint. In 73 operated patients without left
ventricular dysfunction and no coronary stenosis, including 37 patients from the
above-mentioned study, a CPX 9 months post-AVR showed that the pVO2, on average,
was less than that predicted (mean 89% of the predicted ) and 35% of the patients
had a subnormal pVO2 (<83% of that predicted). A preoperative mean gradient <40
mm Hg across the aortic valve, the presence of atrial fibrillation, and a
permanent pacemaker post-AVR all predicted a post-AVR pVO2 <83% of that
predicted. For the 37 patients with a pre-AVR CPX, a postoperative decrease >10%
in the absolute pVO2 was noted in 30% and an increase >10% in 24% of patients. A
decrease >10% in pVO2 was predicted by preoperative mean gradient <40 mm Hg and
an increase in pVO2 was predicted by preoperative AVAI <0.4 cm2/m2 and
preoperative pO2pulse <the median in the study population (<98% of that
predicted).CONCLUSIONS: In this group of patients, where clinical assessment is
difficult and conventional exercise testing is regarded as less useful, CPX
showed high feasibility and reproducibility. CPX therefore has potential as a
useful tool for serial monitoring. In general, the stroke volume increased during
exercise, including in patients with severe aortic stenosis or decreased resting
stroke volume. CPX gives information on hemodynamics and the physiologic
components that determine decreased pVO2. CPX seems useful to identify 1)
patients with a low risk of cardiac death and low risk of progression to symptoms
from the aortic stenosis, and 2) patients with hemodynamic compromise who improve
in functional capacity after AVR. Patients with a preoperative mean gradient <40
mm Hg across the aortic valve, with the presence of atrial fibrillation or who
have a permanent pacemaker, postoperatively seem to benefit less from AVR,
whereas the benefit seems larger in those with more severe aortic stenosis and a
decreased pO2pulse. These findings may be of importance for decisions and
information of patients before AVR.

The Association Between Endurance Training and Heart Rate Variability: The Confounding Role of Heart Rate.

Herzig D; Asatryan B; Brugger N;Eser P; Wilhelm M;

Frontiers In Physiology [Front Physiol] 2018 Jun 19; Vol. 9, pp. 756. Date of Electronic Publication: 2018 06 19

Heart rate variability (HRV) is a widely used marker of cardiac autonomic nervous activity (CANA). Changes in HRV with exercise training have often been interpreted as increases in vagal activity. HRV is strongly associated with heart rate, which in turn, is associated with heart size. There is strong evidence from basic studies that lower heart rate in response to exercise training is caused by morphological and electrical remodeling of the heart. In a cross-sectional study in participants of a 10 mile race, we investigated the influence of endurance exercise on HRV parameters independently of heart size and heart rate. One-hundred-and-seventy-two runners (52 females and 120 males) ranging from novice runners with a first participation to an endurance event to highly trained runners, with up to 15 h of training per week, were included in the analysis. R-R intervals were recorded by electrocardiography over 24 h. Left ventricular end diastolic volume indexed to body surface area (LVEDVI) was assessed by transthoracic echocardiography and peak oxygen consumption (VO2peak) by cardiopulmonary exercise testing. Exercise was quantified by VO2peak, training volume, and race performance. HRV was determined during deep sleep. HRV markers of vagal activity were moderately associated with exercise variables (standardized β = 0.28-0.40, all p < 0.01). These associations disappeared when controlling for heart rate and LVEDVI. Due to the intrinsic association between heart rate and HRV, conclusions based on HRV parameters do not necessarily reflect differences in CANA. Based on current evidence, we discourage the use of HRV as a marker of CANA when measuring the effect of chronic exercise.

Functional outcome in contemporary children and young adults with tetralogy of Fallot after repair.

Hock J; Häcker AL; Reiner B; Oberhoffer R;Hager A; Ewert P; Müller J;

Archives Of Disease In Childhood [Arch Dis Child] 2018 Jul 03. Date of Electronic Publication: 2018 Jul 03.

Objective: Functional outcome measures are of growing importance in the aftercare of patients with congenital heart disease. This study addresses the functional status with regard to exercise capacity, health-related physical fitness (HRPF) and arterial stiffness in a recent cohort of children, adolescents and young adults with tetralogy of Fallot (ToF) after repair.
Design: Single-centre, uncontrolled and prospective cohort study.
Setting: Outpatient department of the German Heart Centre Munich; July 2014-January 2018.
Patients: One hundred and six patients with ToF after repair (13.5±3.7 years, 40 females) were included. Data were compared with a recent cohort of healthy controls (HCs) (n=1700, 12.8±2.6 years, 833 females).
Main Outcome Measures: Patients underwent a symptom-limited cardiopulmonary exercise test, performed an HRPF test (FitnessGram) and had an assessment of their arterial stiffness (Mobil-O-Graph).
Results: Compared with HC, patients with ToF showed lower predicted [Formula: see text]O2 peak (ToF: 80.4% ± 16.8% vs HC: 102.6% ± 18.1%, p<0.001), impaired ventilatory efficiency (ToF: 29.6 ± 3.6 vs HC: 27.4 ± 2.9, p<0.001), chronotropic incompetence (ToF: 167 ± 17 bpm vs HC: 190 ± 17 bpm, p<0.001) and reduced HRPF (ToF z-score: -0.65 ± 0.87 vs HC z-score: 0.03 ± 0.65, p<0.001). Surrogates of arterial stiffness, central and peripheral systolic blood pressure, did not differ between the two groups.
Conclusions: Contemporary children, adolescents and young adults with ToF still have functional limitations. How impaired HRPF and limited exercise capacity interact and how they can be modified needs to be evaluated in further intervention studies.

Seasonal changes influence the improvement in asthma symptoms by exercise training in subjects with asthma.

Mendes FAR; França-Pinto A; Martins MA; Cukier A; Stelmach R; Giavina-Bianchi P; Carvalho CRF;

The Journal Of Asthma: Official Journal Of The Association For The Care Of Asthma [J Asthma] 2018 Jul 04, pp. 1-19.

Objective: To investigate whether patients with moderate to severe asthma who commence an exercise training program in winter or summer show differences in exercise capacity, health-related quality of life (HRQoL) and asthma symptoms.
Methods: Forty-two consecutive subjects visiting the outpatient clinic were enrolled in the 17-week rehabilitation program. One group of patients received the intervention from summer to winter (SWG, n = 21), and the other group participated from winter to summer (WSG, n = 21). Before and after the exercise training program, all patients were evaluated by cardiopulmonary exercise test, pulmonary function test, quality of life questionnaire and a daily diary that evaluated clinical asthma symptoms.
Results: After the training period, both groups improved similarly in health-related quality of life (HRQoL) and aerobic capacity. The WSG patients had a greater increase that those in the SWG in asthma symptom-free days (p < 0.05, Table 2).
Conclusions: Our results indicate that seasonal variations affect the improvement in asthma symptoms after an exercise training program but have no effect on health-related quality of life, exercise capacity or pulmonary function.

A method for determining exercise oscillatory ventilation in heart failure: Prognostic value and practical implications.

Vainshelboim B, Amin A, Christle JW, Hebbal S, Ashley EA, Myers J

Int J Cardiol. 2017 Dec 15;249:287-291. doi: 10.1016/j.ijcard.2017.09.028. Epub
2017 Sep 14.

BACKGROUND: Exercise oscillatory ventilation (EOV) has been shown to be a
powerful prognostic marker in chronic heart failure (CHF). However, EOV is poorly
defined, its measurement lacks standardization and it is underutilized in
clinical practice. The purpose of this pilot study was to investigate the
prognostic value of a modified definition of EOV in patients with CHF.
METHODS: Eighty-nine CHF patients (56.5±8.4years) (64% NYHA class III-IV)
underwent cardiopulmonary exercise testing. EOV was defined as meeting all the
following criteria: (1) ≥3 consecutive cyclic fluctuations of ventilation during
exercise; (2) average amplitude over 3 ventilatory oscillations ≥5L; and (3) an
average length of three oscillatory cycles 40s to 140s. Adverse cardiac events
were tracked during 28±19months follow up. Cox proportional hazard analysis was
used to determine the association between cardiac events and EOV.
RESULTS: Forty-eight patients (54%) met all three criteria and were determined to
have EOV. These patients exhibited significantly increased risk for adverse
cardiac events [hazard ratio=2.2, 95% CI (1.2 to 4.1), p=0.011] compared to
patients without EOV. After adjusting for age and established prognostic
covariates (peak VO2 and VE/VCO2 slope), the modified EOV definition was the only
significant variable in the multivariate model [hazard ratio=2.0, 95% CI (1.1 to
3.7), p=0.035].
CONCLUSIONS: The proposed method for determining EOV was independently associated
with increased risk for adverse cardiac events in CHF patients. While larger
prospective studies are needed, this definition provides a relatively simple and
more objective characterization of EOV, suggesting its potential application in
clinical practice.

The Role of Gas Exchange Variables in Cardiopulmonary Exercise Testing for Risk Stratification and Management of Heart Failure with Reduced Ejection Fraction.

Wagner J; Agostoni P; Arena R;Belardinelli R; Dumitrescu D; Hager A; Myers J; Riley M; Takken T; Schmidt-Trucksäss A;

American Heart Journal [Am Heart J] 2018 May 22; Vol. 202, pp. 116-126. Date of Electronic Publication: 2018 May 22.

Heart failure with reduced ejection fraction (HFrEF) is common in the developed world and results in significant morbidity and mortality. Accurate risk assessment methods and prognostic variables are therefore needed to guide clinical decision making for medical therapy and surgical interventions with the ultimate goal of decreasing risk and improving health outcomes. The purpose of this review is to examine the role of cardiopulmonary exercise testing (CPET) and its most commonly used ventilatory gas exchange variables for the purpose of risk stratification and management of HFrEF. We evaluated five widely studied gas exchange variables from CPET in HFrEF patients based on nine previously used systematic criteria for biomarkers. This paper provides clinicians with a comprehensive and critical overview, class recommendations and evidence levels. Although some CPET variables met more criteria than others, evidence supporting the clinical assessment of variables beyond peak V̇O2 is well-established. A multi-variable approach also including the V̇E-V̇CO2 slope and EOV is therefore recommended.