Category Archives: Publications

Declining Risk of Sudden Death in Heart Failure

Shen L, Jhund PS, Petrie MC, et al.

N Engl J Med. 2017;377(1):41-51.

BACKGROUND: The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail.
METHODS: We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization.
RESULTS: Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis.
CONCLUSIONS: Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.).

Impaired myocardial relaxation with exercise determines peak aerobic exercise capacity in heart failure with preserved ejection fraction.

ESC Heart Fail. 2017 Aug;4(3):351-355. doi: 10.1002/ehf2.12147. Epub 2017 May 6.

Trankle C, Canada JM, Buckley L, Carbone S, Dixon D, Arena
R, Van Tassell B, Abbate A

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a clinical
syndrome characterized by impaired exercise capacity due to shortness of breath
and/or fatigue. Assessment of diastolic dysfunction at rest and with exercise may
provide insight into the pathophysiology of exercise intolerance in HFpEF.
AIMS: To measure echocardio-Doppler-derived parameters of diastolic function as
they relate to various indices of aerobic exercise capacity in HFpEF.
METHODS: We selected 16 subjects with clinically stable HFpEF, no evidence of
volume overload, but impaired functional capacity by cardiopulmonary exercise
testing [peak oxygen consumption (VO2 )]. We measured the transmitral E and A
flow velocities, E/A ratio, and E deceleration time (DT) and tissue Doppler E’
velocity. We also indexed the E’ to the DT, as additional measure of impaired
relaxation (E’DT ), and calculated the diastolic functional reserve index (DFRI),
as the product of E’ at rest and change in E’ with exercise.
RESULTS: E’ velocity, at rest and peak exercise, as well as the DFRI positively
correlated with peak VO2 , whereas DT, E’DT , and E/E’ with exercise inversely
correlated with peak VO2 . Of note, the E’DT at rest also significantly predicted
E’ velocity at peak exercise (R = +0.81, P < 0.001). Exercise E’ was the only
independent predictor of peak VO2 at multivariable analysis (R = +0.67,
P = 0.005).
CONCLUSIONS: The E’ velocity at peak exercise is a strong and independent
predictor of aerobic exercise capacity as measured by peak VO2 in patients with
HFpEF, providing the link between abnormal myocardial relaxation with exercise
and impaired aerobic exercise capacity in HFpEF..

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

Pediatr Cardiol. 2017 Aug 3. doi: 10.1007/s00246-017-1697-3. [Epub ahead of

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

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.

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

Pediatr Cardiol. 2017 Jul 24. doi: 10.1007/s00246-017-1695-5. [Epub ahead of

Li J, Luo S, Liu F, An Q

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..

Exercise Prescriptions for Training and Rehabilitation in Patients with Heart and Lung Disease.

Ann Am Thorac Soc. 2017 Jul 18. doi: 10.1513/AnnalsATS.201702-160FR. [Epub ahead
of print]

Palermo P, Corrà U.

Rehabilitation in patients with advanced cardiac and pulmonary disease has been
shown to increase survival and improve quality of life among many other benefits.
Exercise training is the fundamental ingredient in these rehabilitation programs.
However, determining the amount of exercise is not straightforward or uniform.
Most rehabilitation and training program fix the time of exercise and set the
exercise intensity to the goals of the rehabilitation program and the
exercise-related hurdles of the individual. The exercise training intensity
prescription must balance the desired gain in conditioning with safety.
Symptom-limited cardiopulmonary exercise testing is the fundamental tool to
identify the exercise intensity and define the appropriate training. In addition,
cardiopulmonary exercise testing provides an understanding of the systems
involved in oxygen transport and utilization making it possible to identify the
factors limiting exercise capacity in individual patients.

Exercise Training Improves Ventilatory Efficiency in Patients With a Small Abdominal Aortic Aneurysm: A RANDOMIZED CONTROLLED STUDY.

J Cardiopulm Rehabil Prev. 2017 Jul 19. doi: 10.1097/HCR.0000000000000270. [Epub
ahead of print]

Lima RM, Vainshelboim B, Ganatra R, Dalman R, Chan K, Myers J.

PURPOSE: To investigate the effects of exercise training on ventilatory
efficiency and physiological responses to submaximal exercise in subjects with
small abdominal aortic aneurysm (AAA).
METHODS: Sixty-five male patients (72.3 ± 7.0 years) were randomized to exercise
training (n = 33) or usual care group (n = 32). Exercise subjects participated in
a training groups for 3 mo. Cardiopulmonary exercise testing was performed before
and after the study period and peak VO2, the ventilatory threshold (VT), the
oxygen uptake efficiency slope (OUES), and the VE2/VCO2 slope were identified.
Baseline work rates at VT were matched to examine cardiopulmonary responses after
RESULTS: Significant interactions indicating improvements before and after
training in the exercise group were noted for time (P < .01), VO2 (P < .01), and
work rate (P < .01) at the VT. At peak effort, significant interactions were
noted for time (P < .01) and work rate (P < .01), while borderline significance
was noted for absolute (P = .07) and relative (P = .04) VO2. Significant
interactions were observed for the OUES both when using all exercise data (P =
.04) and when calculated up to the VT (P < .01). For the VE2/VCO2 slope,
significance was noted only when calculated up to the VT (P = .04). After
training, heart rate, VE, VO2 and respiratory exchange ratio were significantly
attenuated for the same baseline work rate only in the exercise group (all P <
CONCLUSIONS: Exercise training improves ventilatory efficiency in patients with
small AAA. In addition, patients who exercised exhibited less demanding
cardiorespiratory responses to submaximal effort.

Cardiopulmonary Exercise Testing and Surgery.

Older PO, Levett DZ

Ann Am Thorac Soc. 2017. May 16

The surgical patient population is increasingly elderly and comorbid and poses challenges to perioperative physicians. Accurate pre-operative risk stratification is important to direct perioperative care. Reduced aerobic fitness is associated with increased post-operative morbidity and mortality. Cardiopulmonary exercise testing is an integrated and dynamic test that gives an objective measure of aerobic fitness or functional capacity and identifies the cause of exercise intolerance. Cardiopulmonary exercise testing provides an individualized estimate of patient risk that can be used to predict post-operative morbidity and mortality. This technology can therefore be used to inform collaborative decision making and patient consent; to triage the patient to an appropriate peri-operative care environment; to diagnose unexpected comorbidity; to optimize medical co-morbidities pre-operatively and to direct individualized pre-operative exercise programmes. Functional capacity, evaluated as the anaerobic threshold and peak oxygen uptake (VO2peak) predicts post-operative morbidity and mortality in the majority of surgical cohort studies. The ventilatory equivalents for carbon dioxide (an index of gas exchange efficiency), is predictive of surgical outcome in some cohorts. Prospective cohort studies are needed to improve the precision of risk estimates for different patient groups and to clarify the best combination of variables to predict outcome. Early data suggests that preoperative exercise training improves fitness, reduces the debilitating effects of neoadjuvant chemotherapy and may improve clinical outcomes. Further research is required to identify the most effective type of training and the minimum duration required for a positive effect.

Total haemoglobin mass, but not haemoglobin concentration, is associated with preoperative cardiopulmonary exercise testing-derived oxygen-consumption variables.

Otto JM, Plumb JOM, Wakeham D, et al.

Br J Anaesth. 2017;118(5):747-754

Background: Cardiopulmonary exercise testing (CPET) measures peak exertional oxygen consumption ( V O2peak ) and that at the anaerobic threshold ( V O2 at AT, i.e. the point at which anaerobic metabolism contributes substantially to overall metabolism). Lower values are associated with excess postoperative morbidity and mortality. A reduced haemoglobin concentration ([Hb]) results from a reduction in total haemoglobin mass (tHb-mass) or an increase in plasma volume. Thus, tHb-mass might be a more useful measure of oxygen-carrying capacity and might correlate better with CPET-derived fitness measures in preoperative patients than does circulating [Hb]. Methods: Before major elective surgery, CPET was performed, and both tHb-mass (optimized carbon monoxide rebreathing method) and circulating [Hb] were determined. Results: In 42 patients (83% male), [Hb] was unrelated to V O2 at AT and V O2peak ( r =0.02, P =0.89 and r =0.04, P =0.80, respectively) and explained none of the variance in either measure. In contrast, tHb-mass was related to both ( r =0.661, P <0.0001 and r =0.483, P =0.001 for V O2 at AT and V O2peak , respectively). The tHb-mass explained 44% of variance in V O2 at AT ( P <0.0001) and 23% in V O2peak ( P =0.001).
Conclusions: In contrast to [Hb], tHb-mass is an important determinant of physical fitness before major elective surgery. Further studies should determine whether low tHb-mass is predictive of poor outcome and whether targeted increases in tHb-mass might thus improve outcome.

Cardiopulmonary reserve as determined by cardiopulmonary exercise testing correlates with length of stay and predicts complications after radical cystectomy.

Tolchard S, Angell J, Pyke M, et al.

BJU Int. 2015;115(4):554-561

OBJECTIVE: To investigate whether poor preoperative cardiopulmonary reserve and comorbid state dictate high-risk status and can predict complications in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: In all, 105 consecutive patients with transitional cell carcinoma (TCC; stage T1-T3) undergoing robot-assisted (38 patients) or open (67) RC in a single UK centre underwent preoperative cardiopulmonary exercise testing (CPET). Prospective primary outcome variables were all-cause complications and postoperative length of stay (LOS). Binary logistic regression analysis identified potential predictive factor(s) and the predictive accuracy of CPET for all-cause complications was examined using receiver operator characteristic (ROC) curve analysis. Correlations analysis employed Spearman’s rank correlation and group comparison, the Mann-Whitney U-test and Fisher’s exact test. Any relationships were confirmed using the Mantel-Haenszel common odds ratio estimate, Kaplan-Meier analysis and the chi-squared test.

RESULTS: The anaerobic threshold (AT) was negatively (r = -206, P = 0.035), and the ventilatory equivalent for carbon dioxide (VE/VCO(2)) positively (r = 0.324, P = 0.001) correlated with complications and LOS. Logistic regression analysis identified low AT (<11 mL/kg/min), high VE/VC0(2) (>/=33) and hypertension as significant factors, such that, in their presence patients were 5.55-times more likely to have complications at 90 days postoperatively [P = 0.001, 95% confidence interval (CI) 2.2-13.9]. ROC analysis showed a high significance (area under the curve 0.78, 95% CI 0.69-0.87; P < 0.001). In addition, based on CPET criteria >50% of patients presenting for RC had significant heart failure, whereas preoperatively only very few (2%) had this diagnosis. Analysis using the Mann-Whitney test showed that a VE/VCO(2) >/=33 was the most significant determinant of LOS (P = 0.004). Kaplan-Meier analysis showed that patients in this group had an additional median LOS of 4 days (P = 0.008). Finally, patients with an American Society of Anesthesiologists grade of 3 (ASA 3) and those on long-term beta-blocker therapy were found to be at particular risk of myocardial infarction (MI) and death after RC with odds ratios of 4.0 (95% CI 1.05-15.2; P = 0.042) and 6.3 (95% CI 1.60-24.8; P = 0.008).

CONCLUSION: Patients with poor cardiopulmonary reserve and hypertension are at higher risk of postoperative complications and have increased LOS after RC. Heart failure is known to be a significant determinant of perioperative death and is significantly under diagnosed in this patient group.

Effects of persistent Fontan fenestration patency on cardiopulmonary exercise testing variables.

Heal ME, Jackson LB, Atz AM, Butts RJ

Congenit Heart Dis. 2017 Jun 15. doi: 10.1111/chd.12451. [Epub ahead of print]

Cardiopulmonary exercise testing (CPET) aids in clinical assessment of patients
with Fontan circulation. Effects of persistent fenestration on CPET variables
have not been clearly defined. Associations between fenestration and CPET
variables at anaerobic threshold (AT) and peak exercise were explored in the
Pediatric Heart Network Fontan Cross-Sectional Study cohort. Fenestration patency
was associated with a greater decrease in oxygen saturation from rest to peak
exercise (fenestration -4.9 ± 3.8 v. nonfenestration -3 ± 3.5; P < .001).
Physiological dead space at peak exercise was higher in fenestrated v.
nonfenestrated (25.2 ± 16.1 v. 21.4 ± 15.2; P = .03). There was a weak
association between fenestration patency and maximal work and heart rate.
Fenestration patency was also weakly correlated with oxygen pulse, work and
VE/VCO2 at AT. The effect of persistent fenestration on CPET measurements was
minimal in this study, likely due to the cross-sectional design.