Category Archives: Publications

Oxygen consumption and carbon-dioxide recovery kinetics in the prediction of coronary artery disease severity and outcome.

Popovic D, Martic D, Djordjevic T, Pesic V, Guazzi M, Myers J,
Mohebi R, Arena R

Int J Cardiol. 2017 Dec 1;248:39-45. doi: 10.1016/j.ijcard.2017.06.107. Epub 2017
Jun 28.

BACKGROUND: Revascularization appears to be beneficial only in patients with high
levels of ischemia. This study examined the utility of gas analysis during the
recovery phase of cardiopulmonary exercise testing (CPET) in predicting coronary
artery disease (CAD) severity and prognosis.
METHODS: 40 Caucasian patients (21.2% females), mean age 63.5±7.6 with
significant coronary artery lesions (≥50%) were studied. Within two months of
coronary angiography, CPET on a treadmill (TM) and recumbent ergometer (RE) were
performed on two visits 2-4days apart; subjects were subsequently followed
32±10months. Myocardial wall motion was recorded by echocardiography at rest and
peak exercise. Ischemia was quantified by the wall motion score index (WMSI).
RESULTS: Mean ejection fraction was 56.7±9.6%. Patients with 1-2 stenotic
coronary arteries (SCA) showed a poorer CPET response during the recovery phase
than patients with 3-SCA. ROC analysis revealed the change of carbon-dioxide
output (∆VCO2) recovery/peak (area under ROC curve 0.77, p=0.02, Sn=87.5%,
Sp=70.4%) and oxygen uptake (∆VO2) recovery/peak during TM CPET (area under ROC
curve 0.76, p=0.03, Sn 75.0%, Sp 77.8%) were significant in distinguishing
between 1-2-SCA and 3-SCA. The same variables predicted ΔWMSI peak/rest on
univariate analysis (p<0.05). Multivariate Cox analysis revealed a high
predictive value of ∆VO2 recovery/peak obtained during TM CPET for composite
endpoint of cumulative cardiac events (HR=1.27, CI=1.07-1.51, p=0.008).
CONCLUSIONS: The current study suggests CPET parameters in recovery hold
predictive value for CAD severity and prognosis. TM testing seems to be a better
approach in the assessment of CAD severity and prognosis.

Frailty and maximal exercise capacity in adult lung transplant candidates

Layton AM, Armstrong HF, Baldwin MR, Podolanczuk AJ, Pieszchata
NM, Singer JP, Arcasoy SM, Meza KS, D’Ovidio F, Lederer DJ

Respir Med. 2017 Oct;131:70-76. doi: 10.1016/j.rmed.2017.08.010. Epub 2017 Aug

BACKGROUND: Frail lung transplant candidates are more likely to be delisted or
die without receiving a transplant. Further knowledge of what frailty represents
in this population will assist in developing interventions to prevent frailty
from developing. We set out to determine whether frail lung transplant candidates
have reduced exercise capacity independent of disease severity and diagnosis.
METHODS: Sixty-eight adult lung transplant candidates underwent cardiopulmonary
exercise testing (CPET) and a frailty assessment (Fried’s Frailty Phenotype
(FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O2). We
used linear regression to adjust for age, gender, diagnosis, and lung allocation
score (LAS).
RESULTS: The mean ± SD age was 57 ± 11 years, 51% were women, 57% had
interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had
cystic fibrosis, and the mean LAS was 40.2 (range 19.2-94.5). In adjusted models,
peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O2 decreased by
1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After
adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O2
was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to
non-frail participants. Frailty accounted for 16% of the variance (R2) of watts
and 19% of the variance of V˙O2 in adjusted models.
CONCLUSION: Frailty contributes to reduced exercise capacity among lung
transplant candidates independent of disease severity.

Utility of Growth Differentiation Factor-15, A Marker of Oxidative Stress and Inflammation, in Chronic Heart Failure: Insights From the HF-ACTION Study.

Sharma A, Stevens SR, Lucas J, Fiuzat M, Adams KF, Whellan DJ,
Donahue MP, Kitzman DW, Piña IL, Zannad F, Kraus WE, O’Connor
CM, Felker GM

JACC Heart Fail. 2017 Oct;5(10):724-734

OBJECTIVES: This study sought to determine the relationship between growth
differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with
heart failure and reduced ejection fraction (HFrEF).
BACKGROUND: The prognostic utility of GDF-15, a member of the transforming growth
factor-β cytokine family, among patients with HF is unclear.
METHODS: We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION
(Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training)
trial, a randomized clinical trial of exercise training in patients with HFrEF.
Median follow-up was 30 months. Cox proportional hazard models assessed the
relationships between GDF-15 and clinical outcomes.
RESULTS: The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest
tertile of GDF-15 were older and had measurements of more severe HF (higher
N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentrations and lower
peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was
a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03
when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment
for demographic and clinical and biomarkers including high sensitivity troponin T
(hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did
not improve discrimination (as measured by changes in c-statistics and
the integrated discrimination improvement) in addition to baseline variables,
including hs-TnT and NT-proBNP or variables found in CPX testing.
CONCLUSIONS: In demographically diverse, well-managed patients with HFrEF, GDF-15
therapy provided independent prognostic information in addition to established
predictors of outcomes. These data support a possible role for GDF-15 in the risk
stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial
Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)

Lung clearance index (LCI) as a predictor of exercise limitation among CF patients.

Avramidou V, Hatziagorou E, Kampouras A, Hebestreit H, Kourouki E,
Kirvassilis F, Tsanakas J

Pediatr Pulmonol. 2018 Jan;53(1):81-87. doi: 10.1002/ppul.23833. Epub 2017 Sep

INTRODUCTION: FEV1 is often considered the gold standard to monitor lung disease
in cystic fibrosis (CF). Recently, there has been increasing interest in multiple
breath washout (MBW) and cardiopulmonary exercise testing (CPET) as alternative
or even more sensitive techniques. However, limited data exist on associations
among the above methods.
AIM: To evaluate the correlations between outcome measures of MBW and CPET and to
examine if ventilation inhomogeneity can predict exercise intolerance.
SUBJECTS AND METHODS: Ninety-seven children and adults with CF (47 males, mean
[range] age 14.9 (6.6; 26.7) years, mean FEV1 : 90.8% predicted, mean lung
clearance index [LCI]: 11.4, and mean peak oxygen uptake [VO2 peak]: 82.4%
predicted) performed spirometry, MBW, and CPET on the same day during their
admission or outpatient visit.
RESULTS: LCI, m1 /m0 , and m2 /m0 (P < 0.001) as well as VO2 peak%, breathing
reserve (BR), minute ventilation (VE)/VO2 (P < 0.001), and VE/carbon dioxide
release (VCO2 ) (P = 0.006) correlated significantly with FEV1 %. LCI, m1 /m0 ,
and m2 /m0 correlated with VO2 peak (P ≤ 0.001), VE (L/min) (P < 0.05), BR
(P < 0.01), VE/VO2 (P < 0.001), and VE/VCO2 (P < 0.01). Multiple regression
analysis showed that LCI could predict BR% (P < 0.001, r2 :0.272) and VE/VO2
(P < 0.001, r2 : 0.207) while LCI and FRC could predict VO2 peak% P < 0.001, r2 :
0.216) and VE/VCO2 (P < 0.001, r2 : 0.226).
CONCLUSION: Ventilation inhomogeneity as indicated by increased LCI is associated
with less efficient ventilation during strenuous exercise and negatively impacts
exercise capacity in CF.

The oxygen uptake efficiency slope is not a valid surrogate of aerobic fitness in cystic fibrosis.

Williams CA, Tomlinson OW, Chubbock LV, Stevens D, Saynor
ZL, Oades PJ, Barker AR

Pediatr Pulmonol. 2018 Jan;53(1):36-42. doi: 10.1002/ppul.23896. Epub 2017 Oct

BACKGROUND: Maximal cardiopulmonary exercise testing is recommended on an annual
basis for children with cystic fibrosis (CF), due to clinically useful prognostic
information provided by maximal oxygen uptake (V̇ O2max ). However, not all
patients are able, or willing, to reach V̇O2max , and therefore submaximal
alternatives are required. This study explored the validity of the oxygen uptake
efficiency slope (OUES) as a submaximal measure of V̇O2max in children and
adolescents with CF.
METHODS: Data were collated from 72 cardiopulmonary exercise tests (36 CF, 36
controls), with OUES determined relative to maximal and submaximal parameters of
exercise intensity, time, and individual metabolic thresholds. Pearson’s
correlation coefficients, independent t-tests, and factorial ANOVAs were used to
determine validity.
RESULTS: Significant (P < 0.05) correlations with V̇O2max were observed for most
expressions of OUES, but were consistently weaker in CF (r = 0.30-0.47) when
compared to CON (r = 0.58-0.89). Mean differences for all OUES parameters between
groups were not significant (P > 0.05). When split by V̇O2max tertiles, minimal
significant differences were found between, and within, groups for OUES,
indicating poor discrimination of V̇O2max .
CONCLUSIONS: The OUES is not a valid (sub) maximal measure of V̇O2max in children
and adolescents with mild-to-moderate CF. Clinicians should continue to use
maximal markers (ie, V̇O2max ) of exercise capacity.

Congenital heart disease in adults: Assessmentof functional capacity using cardiopulmonary exercise testing.

Aguiar Rosa S; Agapito A; Soares RM; Sousa L; Oliveira JA; Abreu A; Silva AS; Alves S; Aidos H; Pinto FF; Ferreira RC;

Revista Portuguesa De Cardiologia: Orgao Oficial Da Sociedade Portuguesa De Cardiologia = Portuguese Journal Of Cardiology: An Official Journal Of The Portuguese Society Of Cardiology [Rev Port Cardiol] 2018 May 15. Date of Electronic Publication: 2018 May 15.

Aim: The aim of the study was to compare functional capacity in different types of congenital heart disease (CHD), as assessed by cardiopulmonary exercise testing (CPET).
Methods: A retrospective analysis was performed of adult patients with CHD who had undergone CPET in a single tertiary center. Diagnoses were divided into repaired tetralogy of Fallot, transposition of the great arteries (TGA) after Senning or Mustard procedures or congenitally corrected TGA, complex defects, shunts, left heart valve disease and right ventricular outflow tract obstruction.
Results: We analyzed 154 CPET cases. There were significant differences between groups, with the lowest peak oxygen consumption (VO2) values seen in patients with cardiac shunts (39% with Eisenmenger physiology) (17.2±7.1ml/kg/min, compared to 26.2±7.0ml/kg/min in tetralogy of Fallot patients; p<0.001), the lowest percentage of predicted peak VO2 in complex heart defects (50.1±13.0%) and the highest minute ventilation/carbon dioxide production slope in cardiac shunts (38.4±13.4). Chronotropism was impaired in patients with complex defects. Eisenmenger syndrome (n=17) was associated with the lowest peak VO2 (16.9±4.8 vs. 23.6±7.8ml/kg/min; p=0.001) and the highest minute ventilation/carbon dioxide production slope (44.8±14.7 vs. 31.0± 8.5; p=0.002). Age, cyanosis, CPET duration, peak systolic blood pressure, time to anaerobic threshold and heart rate at anaerobic threshold were predictors of the combined outcome of all-cause mortality and hospitalization for cardiac cause.
Conclusion: Across the spectrum of CHD, cardiac shunts (particularly in those with Eisenmenger syndrome) and complex defects were associated with lower functional capacity and attenuated chronotropic response to exercise.

Left atrial myocardial dysfunction after chronic abuse of anabolic androgenic steroids: a speckle tracking echocardiography analysis.

D’Andrea A; Radmilovic J; Caselli S; Carbone A; Scarafile R; Sperlongano S; Tocci G; Formisano T; Martone F; Liccardo B; D’Alto M; Bossone E; Galderisi M; Golino P;

The International Journal Of Cardiovascular Imaging [Int J Cardiovasc Imaging] 2018 May 22. Date of Electronic Publication: 2018 May 22.

Anabolic-androgenic steroids (AAS) are used by power athletes to improve performance. However, the real effects of the chronic consumption of AAS on cardiovascular structures are subjects of intense debate. To detect by speckle tracking echocardiography (STE) underlying left atrial (LA) dysfunction in athletes abusing AAS and assess possible correlation between LA myocardial function and exercise capacity during cardiopulmonary stress test. 65 top-level competitive bodybuilders were selected (45 males), including 35 athletes misusing AAS for at least 5 years (users), 30 anabolic-free bodybuilders (non-users), compared to 40 age- and sex-matched healthy sedentary controls. Standard Doppler echocardiography, STE analysis and bicycle ergometric test were performed to assess LA myocardial function and exercise capacity. Athletes showed increased left ventricular (LV) mass index, wall thickness and stroke volume compared with controls, whereas LV ejection fraction, LV end-diastolic diameter and transmitral Doppler indexes were comparable between the three groups. Conversely, LA volume index, LV and LA strain and LV E/Em were significantly increased in AAS users. By multivariate analyses, LV E/Em (beta = - 0.30, p < 0.01), LA volume index (- 0.42, p < 0.001) and number of weeks of AAS use per year (- 0.54, p < 0.001) emerged as the only independent determinants of LA lateral wall peak STE. In addition, a close association between LA myocardial function and VO2 peak during cardiopulmonary exercise testing was evidenced (p < 0.001), showing a powerful incremental value with respect to clinical and standard echocardiographic data. STE represents a promising technique to assess LA myocardial function in athletes abusing steroids. AAS users showed a more impaired LA deformation, associated with reduced functional capacity during physical effort.

Associations of Exercise Tolerance With Hemodynamic Parameters for Pulmonary Arterial Hypertension and for Chronic Thromboembolic Pulmonary Hypertension.

Tsuboi Y, Tanaka H, Nishio R, Sawa T, Terashita D, Nakayama K,
Satomi-Kobayashi S, Sakai Y, Emoto N, Hirata KI.

J Cardiopulm Rehabil Prev. 2017 Sep;37(5):341-346

PURPOSE: Pulmonary arterial hypertension (PAH) and chronic thromboembolic
pulmonary hypertension (CTEPH) are the main subgroups of pulmonary hypertension
(PH). Despite differences in their etiologies, both diseases are characterized by
vascular remodeling, resulting in progressive right heart failure. Noninvasive
periodic evaluation of exercise tolerance has become increasingly important.
Cardiopulmonary exercise testing (CPET) and a 6-minute walk test (6MWT) are now
both recommended for evaluating exercise tolerance, but there is insufficient
knowledge about possible differences in the associations of exercise tolerance
with right heart catheterization (RHC) data for patients with PAH and CTEPH.
METHODS: A retrospective study was performed with 57 patients with PH (24 with
PAH and 33 with CTEPH) all of whom underwent echocardiography, CPET, 6MWT, and
RESULTS: For both patients with PAH and CTEPH, peak heart rate during CPET was
significantly higher than that from 6MWT, whereas minimum peripheral oxygen
saturation during CPET and 6MWT was similar. For patients with PAH, significant
correlations were observed between peak (Equation is included in full-text
article.)O2 and cardiac index (CI) (r = 0.59; P = .002) and between (Equation is
included in full-text article.)E/(Equation is included in full-text article.)CO2
slopes and CI (r =-0.46, P = .02), as well as a nonsignificant correlation
tendency for peak (Equation is included in full-text article.)O2 and pulmonary
vascular resistance (PVR) and for (Equation is included in full-text
article.)E/(Equation is included in full-text article.)CO2 and PVR (r =-0.39; P =
.05; and r = 0.39; P = .06, respectively). For patients with CTEPH, however, a
significant correlation was observed only between (Equation is included in
full-text article.)E/(Equation is included in full-text article.)CO2 slopes and
CI (r =-0.38; P = .02).
CONCLUSION: PH etiology should be considered when assessing exercise tolerance,
whereas CPET can be effective in addition to hemodynamic assessment by means of
RHC for periodic evaluation during followup.

Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing

Moneghetti KJ, Kobayashi Y, Christle JW, Ariyama M, Vrtovec
B, Kouznetsova T, Wilson A, Ashley E, Wheeler MT,
Myers J, Haddad F

Echocardiography. 2017 Aug;34(8):1179-1186. doi: 10.1111/echo.13623. Epub 2017
Jul 6

BACKGROUND: Left ventricular (LV) contractile reserve assessed using imaging and
cardiopulmonary exercise testing (CPX) has been shown to predict outcome in
patients with dilated cardiomyopathy (DCM). Few clinical studies have, however,
analyzed the relationship between them.
METHODS: A cohort of 75 ambulatory patients with DCM underwent stress treadmill
echocardiography with CPX. LV contractile reserve was calculated as absolute
change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest
)/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS).
Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory
efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope).
Values of contractile reserve were compared to matched controls. We also explored
which metric of ventricular response (absolute or percent change) was less
dependent on baseline LV function.
RESULTS: Patients with DCM had a mean age, rest and peak LVEF of 44±10 years,
42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak
cardiac output was the strongest parameter associated with peak VO2 (r=.63,
P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance
in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 .
With regard to ventilatory efficiency, the strongest parameter that emerged was
right atrial volume index (r=.36, P<.001). Percent change in LVEF was more
independent of baseline function than absolute change.
CONCLUSION: Echocardiographic contractile reserve and CPX provide complementary
information. Percent change in contractile reserve was most independent of
baseline function, therefore may be preferred when analyzing the ventricular
response to exercise.