Ramos PS, Araújo CG

Rev Port Cardiol. 2017 Apr;36(4):261-269. doi: 10.1016/j.repc.2016.09.017. Epub
2017 Mar 17

INTRODUCTION AND AIM: The cardiorespiratory optimal point (COP) is a novel index,
calculated as the minimum oxygen ventilatory equivalent (VE/VO2) obtained during
cardiopulmonary exercise testing (CPET). In this study we demonstrate the
prognostic value of COP both independently and in combination with maximum oxygen
consumption (VO2max) in community-dwelling adults.
METHODS: Maximal cycle ergometer CPET was performed in 3331 adults (66% men) aged
40-85 years, healthy (18%) or with chronic disease (81%). COP cut-off values of
<22, 22-30, and >30 were selected based on the log-rank test. Risk discrimination
was assessed using COP as an independent predictor and combined with VO2max.
RESULTS: Median follow-up was 6.4 years (7.1% mortality). Subjects with COP >30
demonstrated increased mortality compared to those with COP <22 (hazard ratio
[HR] 6.86, 95% confidence interval [CI] 3.69-12.75, p<0.001). Multivariate
analysis including gender, age, body mass index, and the forced expiratory volume
in 1 s/vital capacity ratio showed adjusted HR for COP >30 of 3.72 (95% CI
1.98-6.98; p<0.001) and for COP 22-30 of 2.15 (95% CI 1.15-4.03, p<0.001).
Combining COP and VO2max data further enhanced risk discrimination.
CONCLUSIONS: COP >30, either independently or in combination with low VO2max, is
a good predictor of all-cause mortality in community-dwelling adults (healthy or
with chronic disease). COP is a submaximal prognostic index that is simple to
obtain and adds to CPET assessment, especially for adults unable or unwilling to
achieve maximal exercise.

Edelmann F, Bobenko A, Gelbrich G, Hasenfuss G,
Herrmann-Lingen C, Duvinage A, Schwarz S, Mende M, Prettin C,
Trippel T, Lindhorst R, Morris D, Pieske-Kraigher E, Nolte
K, Düngen HD, Wachter R, Halle M, Pieske B.

Eur J Heart Fail. 2017 Aug;19(8):1067-1074. doi: 10.1002/ejhf.862. Epub 2017 May
17.

Heart failure with preserved ejection fraction (HFpEF) is a common disease with
high incidence and increasing prevalence. Patients suffer from functional
limitation, poor health-related quality of life, and reduced prognosis. A pilot
study in a smaller group of HFpEF patients showed that structured, supervised
exercise training (ET) improves maximal exercise capacity, diastolic function,
and physical quality of life. However, the long-term effects of ET on
patient-related outcomes remain unclear in HFpEF. The primary objective of the
Exercise training in Diastolic Heart Failure (Ex-DHF) trial is to investigate
whether a 12 month supervised ET can improve a clinically meaningful composite
outcome score in HFpEF patients. Components of the outcome score are all-cause
mortality, hospitalizations, NYHA functional class, global self-rated health,
maximal exercise capacity, and diastolic function. After undergoing baseline
assessments to determine whether ET can be performed safely, 320 patients at 11
trial sites with stable HFpEF are randomized 1:1 to supervised ET in addition to
usual care or to usual care alone. Patients randomized to ET perform supervised
endurance/resistance ET (3 times/week at a certified training centre) for 12
months. At baseline and during follow-up, anthropometry, echocardiography,
cardiopulmonary exercise testing, and health-related quality of life evaluation
are performed. Blood samples are collected to examine various biomarkers. Overall
physical activity, training sessions, and adherence are monitored and documented
throughout the study using patient diaries, heart rate monitors, and
accelerometers. The Ex-DHF trial is the first multicentre trial to assess the
long-term effects of a supervised ET programme on different outcome measures in
patients with HFpEF.

Popovic D, Damjanovic S, Djordjevic T, Martic D, Ignjatovic S,
Milinkovic N, Banovic M, Lasica R, Petrovic M, Guazzi M, Arena
R.

Stress. 2017 Sep;20(5):523-531.

OBJECTIVES: Despite considerable knowledge regarding the importance of stress in
coronary artery disease (CAD) pathogenesis, its underestimation persists in
routine clinical practice, in part attributable to lack of a standardized,
objective assessment. The current study examined the ability of stress hormones
to predict CAD severity and prognosis at basal conditions as well as during and
following an exertional stimulus.
MATERIALS AND METHODS: Forty Caucasian subjects with significant coronary artery
lesions (≥50%) were included. Within 2 months of coronary angiography,
cardiopulmonary exercise testing (CPET) on a recumbent ergometer was performed in
conjunction with stress echocardiography (SE). At rest, peak and after 3 min of
recovery following CPET, plasma levels of cortisol, adrenocorticotropic hormone
(ACTH) and NT-pro-brain natriuretic peptide (NT-pro-BNP) were measured by
immunoassay sandwich technique, radioimmunoassay, and radioimmunometric
technique, respectively. Subjects were subsequently followed a mean of
32 ± 10 months.
RESULTS AND DISCUSSION: Mean ejection fraction was 56.7 ± 9.6%. Subjects with 1-2
stenotic coronary arteries (SCA) demonstrated a significantly lower plasma
cortisol levels during CPET compared to those with 3-SCA (p < .05), whereas ACTH
and NT-pro-BNP were not significantly different (p > .05). Among CPET, SE, and
hormonal parameters, cortisol at rest and during CPET recovery demonstrated the
best predictive value in distinguishing between 1-, 2-, and 3-SCA [area under ROC
curve 0.75 and 0.77 (SE = 0.11, 0.10; p = .043, .04) for rest and recovery,
respectively]. ΔCortisol peak/rest predicted cumulative cardiac events (area
under ROC curve 0.75, SE = 0.10, p = .049).
CONCLUSIONS: Cortisol at rest and following an exercise test holds predictive
value for CAD severity and prognosis, further demonstrating a link between stress
and unwanted cardiac events.

Whittaker JD, Meecham L, Summerour V, Khalil S, Layton G, Yousif
M, Jennings A, Wall M, Newman J

Eur J Vasc Endovasc Surg. 2017 Nov;54(5):579-586. doi:
10.1016/j.ejvs.2017.07.023.

OBJECTIVES: The aim was to assess the survival of patients who had been turned
down for repair of an abdominal aortic aneurysm (AAA) and to examine the factors
influencing this.
METHODS: This was a retrospective observational study of a prospectively
maintained database of all patients turned down for AAA intervention by the Black
Country Vascular Network multidisciplinary team (MDT) from January 2013 to
December 2015. Data on AAA size, cardiopulmonary exercise testing (CPET) and
cause of death were recorded.
RESULTS: There were 112 patients. The median age at turndown was 83.9 years (IQR
10.2 years). The median AAA size at turndown was 63 mm (IQR 16.7 mm). The median
follow-up time after turndown was 324 days (IQR 537.5 days). Sixty-four patients
(57.1%) were deceased after 2 years, with a median survival time of 462 days (IQR
579 days). Patients who died had a significantly larger AAA dimension (median
65 mm, IQR 18.5 mm) than those surviving to date (median 59 mm, IQR 10 mm,
p = .004). Using Cox regression analysis, the probability of 1 year survival in
the whole population was 0.614. The probability of 2 year survival was 0.388.
When accounting for age, gender, AAA dimension, and British Aneurysm Repair risk
score, no factors had significant influence over survival. Of the 64 deceased
patients, 30 had an accessible cause of death: 36.7% of these were due to
ruptured AAAs. There was no significant difference in AAA size between those
dying of ruptures and those dying of other causes (p = .225, mean 74 mm and 67 mm
respectively).
CONCLUSIONS: Being turned down for AAA repair carries a significant short-term
risk of mortality. Those turned down for repair carried significant levels of
comorbid disease but no factors considered were found to be independently
predictive of the length of survival.

Comment in
Eur J Vasc Endovasc Surg. 2017 Nov;54(5):587

“There will inevitably be heterogeneity between institutions in terms of fitness threshold levels for offering abdominal aortic aneurysm (AAA) repair. If the threshold is set too high, there is a risk of denying a proportion of patients who would have otherwise potentially benefited from repair and had their AAA rupture prevented. If the threshold is set too low, this may result in high peri-operative mortality, and in the longer term, lower overall life expectancy among those repaired which will negate any long-term benefit from AAA repair………”

Sandberg C, Hedström M, Wadell K, Dellborg M, Ahnfelt A,
Zetterström AK, Öhrn A, Johansson B.

Congenit Heart Dis. 2018 Mar;13(2):254-262.

OBJECTIVE: The beneficial effects of exercise training in acquired heart failure
and coronary artery disease are well known and have been implemented in current
treatment guidelines. Knowledge on appropriate exercise training regimes for
adults with congenital heart disease is limited, thus further studies are needed.
The aim of this study was to examine the effect of home-based interval exercise
training on maximal endurance capacity and peak exercise capacity.
DESIGN: Randomized controlled trial.
METHODS: Twenty-six adults with complex congenital heart disease were recruited
from specialized units for adult congenital heart disease. Patients were
randomized to either an intervention group-12 weeks of home-based interval
exercise training on a cycle ergometer (n = 16), or a control group (n = 10). The
latter was instructed to maintain their habitual physical activities. An
incremental cardiopulmonary exercise test and a constant work rate
cardiopulmonary exercise test at 75% of peak workload were performed
preintervention and postintervention.
RESULTS: Twenty-three patients completed the protocol and were followed
(intervention n = 13, control n = 10). Postintervention exercise time at constant
work rate cardiopulmonary exercise test increased in the intervention group
compared to controls (median[range] 12[-4 to 52]min vs 0[-4 to 5]min, P = .001).
At incremental cardiopulmonary exercise test, peak VO2 increased 15% within the
intervention group (P = .019) compared to 2% within the control group (P = .8).
However, in comparison between the groups no difference was found (285[-200 to
535] ml/min vs 17[-380 to 306] ml/min, P = .10). In addition, peak workload at
incremental cardiopulmonary exercise test increased in the intervention group
compared to controls (20[-10 to 70]W vs 0[-20 to 15]W, P = .003).
CONCLUSION: Home-based interval exercise training increased endurance capacity
and peak exercise capacity in adults with complex congenital heart disease.
Aerobic endurance might be more relevant than peak oxygen uptake with regard to
daily activities, and therefore a more clinically relevant measure to evaluate.

Mezzani A; Pistono M; Agostoni P; Giordano A; Gnemmi M; Imparato A; Temporelli P; Corrà U;

Plos One [PLoS One] 2018 Jun 01; Vol. 13 (6), pp. e0187112. Date of Electronic Publication: 20180601 (Print Publication: 2018)

Exercise ventilation/perfusion matching in continuous-flow left ventricular assist device recipients (LVAD) has not been studied systematically. Twenty-five LVAD and two groups of 15 reduced ejection fraction chronic heart failure (HFrEF) patients with peak VO2 matched to that of LVAD (HFrEF-matched) and ≥14 ml/kg/min (HFrEF≥14), respectively, underwent cardiopulmonary exercise testing with arterial blood gas analysis, echocardiogram and venous blood sampling for renal function evaluation. Arterial-end-tidal PCO2 difference (P(a-ET)CO2) and physiological dead space-tidal volume ratio (VD/VT) were used as descriptors of alveolar and total wasted ventilation, respectively. Tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio (TAPSE/PASP) and blood urea nitrogen/creatinine ratio were calculated in all patients and used as surrogates of right ventriculo-arterial coupling and circulating effective volume, respectively. LVAD and HFrEF-matched showed no rest-to-peak change of P(a-ET)CO2 (4.5±2.4 vs. 4.3±2.2 mm Hg and 4.1±1.4 vs. 3.8±2.5 mm Hg, respectively, both p >0.40), whereas a decrease was observed in HFrEF≥14 (6.5±3.6 vs. 2.8±2.0 mm Hg, p <0.0001). Rest-to-peak changes of P(a-ET)CO2 correlated to those of VD/VT (r = 0.70, p <0.0001). Multiple regression indicated TAPSE/PASP and blood urea nitrogen/creatinine ratio as independent predictors of peak P(a-ET)CO2. LVAD exercise gas exchange is characterized by alveolar wasted ventilation, i.e. hypoperfusion of ventilated alveoli, similar to that of advanced HFrEF patients and related to surrogates of right ventriculo-arterial coupling and circulating effective volume.

Yuan P, Ni HJ, Chen TX, Pudasaini B, Jiang R, Liu H, Zhao
QH, Wang L, Gong SG, Liu JM

Hypertens Res. 2017 Oct 5;40(10):868-875. doi: 10.1038/hr.2017.52. Epub 2017 Jun
1.

Cardiopulmonary exercise testing (CPET) has been used for prognosis in idiopathic
pulmonary arterial hypertension (IPAH). We explored whether sex differences had
an impact on prognostic assessments of CPET in IPAH. Data were retrieved from 21
male and 36 female incident IPAH patients who underwent both right heart
catheterization and CPET from 2010 to 2016 at Shanghai Pulmonary Hospital. Cox
proportional hazards analysis was used to assess the prognostic value of CPET.
The mean duration of follow-up was 22±15 months. Nine men and 15 women had an
event. The differences in clinical parameters in the whole population were not
the same as the inter-subgroup differences. Event-free women had significantly
higher cardiac output, lower pulmonary vascular resistance and percentage of
predicted FVC compared with event men (all P<0.05). Event-free men had
significantly higher end-tidal partial pressure of CO2 (PETCO2) at anaerobic
threshold (AT), peak workload, PETCO2, maximum oxygen consumption (VO2)/minute
ventilation (VE), and oxygen uptake efficiency slope and lower end-tidal partial
pressure of O2 (PETO2) at AT, peak PETO2, and lowest VE/VCO2 compared with event
men. Event-free women had dramatically higher peak VO2, VCO2, VE and O2 pulse
than event women (all P<0.05). Peak PETCO2 was the independent predictor of
event-free survival in all patients and males, whereas peak O2 pulse was the
independent predictor of event-free survival in females. Men with peak
PETCO2⩾20.50 mm Hg, women with peak O2 pulse ⩾6.25 ml per beat and all patients
with peak PETCO2⩾27.03 mm Hg had significantly better event-free survival.
Sex-specific CPET parameters are predictors of poor outcomes. Decreased peak
PETCO2 in men and peak O2 pulse in women were associated with lower event-free
survival in IPAH.

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.

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
10.

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.

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)