Babu AS, Arena R, Morris NR

Adv Exp Med Biol. 2017;1000:153-172.

Pulmonary hypertension (PH) is a chronic, debilitating condition which gravely
affects exercise tolerance and quality of life. Though most therapies focus
purely on medical intervention, there is a growing body of evidence to suggest
the role and benefits of exercise training. This chapter discusses the various
physiological basis for exercise intolerance observed in PH and highlights the
rationale for exercise training. Recent evidence related to exercise training is
summarized and potential pathways to suggest adaptations to exercise training are
put forward. While keeping the paper applicable to clinicians, details on
evaluating exercise intolerance, prescribing exercise and setting up
rehabilitation centers for PH are discussed

Canada JM; Trankle CR; Buckley LF; Carbone S; Abouzaki NA; Kadariya D; Shah K; Cooke R;
Kontos MC; Patel J; Mankad P; Schatz A; Bhatnagar A; Arena R; Van Tassell BW; Abbate A

The American Journal Of Cardiology [Am J
Cardiol], ISSN: 1879-1913, 2017 Nov 15; Vol. 120 (10), pp. 1854-1857

Hospital admission for
decompensated heart failure marks a critical inflection point in a
patient’s health. Despite the improvement in signs or symptoms during
hospitalization, patients have a high likelihood of readmission,
reflecting a lack of resolution of the underlying condition.
Surprisingly, no studies have characterized the cardiorespiratory
fitness of such patients. Fifty-two patients (38 [73%] male, age 57 [52
to 65] years, left ventricular ejection fraction 31% [24 to 38])
underwent cardiopulmonary exercise testing 4 (1 to 10) days after
hospital discharge, when stable and without overt signs of volume
overload. Transthoracic Doppler echocardiography, measurement of
N-terminal pro-B-natriuretic peptide, and quality of life were also
assessed. Aerobic exercise capacity was severely reduced: peak oxygen
consumption (pVO2) was 14.1 (11.2 to 16.3) ml/kg/min. Ventilatory
inefficiency as indicated by the minute ventilation carbon dioxide
production relation (VE/VCO2 slope) >30 and oxygen uptake efficiency
slope <2.0 was noted in 41 (77%) and 39 (75%) patients, respectively.
Forty-five (87%) patients had 1 of 2 high-risk features
(pVO2 < 14 ml/kg/min or VE/VCO2 >30). Perceived functional capacity,
measured by the Duke Activity Status Index, was also severely reduced
and correlated with pVO2. N-terminal pro-B-natriuretic peptide levels
and early transmitral velocity/early mitral annulus velocity (E/e’)
ratio at echocardiography showed a modest correlation with lower pVO2.
In conclusion, patients with recently decompensated systolic heart
failure demonstrate severe impairment in cardiorespiratory fitness,
severely limiting quality of life.

JACC Heart Fail. 2017 Oct;5(10):724-734. doi: 10.1016/j.jchf.2017.07.013

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.

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]

American College of Cardiology Foundation

Van Iterson EH, Johnson BD, Borlaug BA, Olson TP

Eur J Heart Fail. 2017 Oct 8. doi: 10.1002/ejhf.913. [Epub ahead of print]

AIMS: Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF)
ejection fraction demonstrate an increased ventilatory equivalent for carbon
dioxide (V̇E /V̇CO2 ) slope. The physiological correlates of the V̇E /V̇CO2 slope
remain unclear in the two HF phenotypes. We hypothesized that changes in the
physiological dead space to tidal volume ratio (VD /VT ) and arterial CO2 tension
(PaCO2 ) differentially contribute to the V̇E /V̇CO2 slope in HFrEF vs. HFpEF.

METHODS AND RESULTS: Adults with HFrEF (n = 32) and HFpEF (n = 27)
[mean ± standard deviation (SD) left ventricular ejection fraction: 22 ± 7% and
61 ± 9%, respectively; mean ± SD body mass index: 28 ± 4 kg/m(2) and
33 ± 6 kg/m(2) , respectively; P < 0.01] performed cardiopulmonary exercise
testing with breath-by-breath ventilation and gas exchange measurements. PaCO2
was measured via radial arterial catheterization. We calculated the V̇E /V̇CO2
slope via linear regression, and VD /VT  = 1 - [(863 × V̇CO2 )/(V̇E  × PaCO2 )].
Resting VD /VT (0.48 ± 0.08 vs. 0.41 ± 0.11; P = 0.04), but not PaCO2
(38 ± 5 mmHg vs. 40 ± 3 mmHg; P = 0.21) differed between HFrEF and HFpEF. Peak
exercise VD /VT (0.39 ± 0.08 vs. 0.32 ± 0.12; P = 0.02) and PaCO2 (33 ± 6 mmHg
vs. 38 ± 4 mmHg; P < 0.01) differed between HFrEF and HFpEF. The V̇E /V̇CO2 slope
was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P < 0.01). Variance
associated with the V̇E /V̇CO2 slope in HFrEF and HFpEF was explained by peak
exercise VD /VT (R(2)  = 0.30 and R(2)  = 0.50, respectively) and PaCO2 (R(2)
= 0.64 and R(2)  = 0.28, respectively), but the relative contributions of each
differed (all P < 0.01).

CONCLUSIONS: Relationships between the V̇E /V̇CO2 slope and both VD /VT and PaCO2
are robust, but differ between HFpEF and HFrEF. Increasing V̇E /V̇CO2 slope
appears to be strongly explained by mechanisms influential in regulating PaCO2 in
HFrEF, which contrasts with the strong role of increased VD /VT in HFpEF.

Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS,
Wagner PD, Lewis GD

Circulation. 2017 Oct 9. pii:

Background -Heart failure with preserved ejection fraction (HFpEF) is a common
syndrome with a pressing shortage of therapies. Exercise intolerance is a
cardinal symptom of HFpEF, yet its pathophysiology remains uncertain.

Methods -We investigated the mechanism of exercise intolerance in each of 134 patients
referred for cardiopulmonary exercise testing (CPET): 79 with HFpEF and 55
controls. We performed CPET with invasive monitoring to measure hemodynamics,
blood gases, and gas exchange during exercise. We used these measurements to
quantify 6 steps of oxygen transport and utilization (the “O2 pathway”) in each
HFpEF patient, identifying the defective steps that impair each one’s exercise
capacity (peak VO2). We then quantified the functional significance of each O2
pathway defect by calculating the improvement in exercise capacity a patient
could expect from correcting the defect.

Results -Peak VO2 was reduced by 34%±2% (mean±SEM, P<0.001) in HFpEF
compared with controls of comparable age, gender,
and body mass index. The vast majority (97%) of HFpEF patients harbored defects
at multiple steps of the O2 pathway, the identity and magnitude of which varied
widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were
impaired relative to controls by an average of 27±3% and 36±2%, respectively
(P<0.001 for both). Due to interactions between a given patient’s defects, the
predicted benefit of correcting any single one was often minor; on average,
correcting a patient’s cardiac output led to a 7±0.5% predicted improvement in
exercise intolerance, while correcting a patient’s muscle diffusion capacity led
to a 27±1% improvement. At the individual level, the impact of any given O2
pathway defect on a patient’s exercise capacity was strongly influenced by
comorbid defects.

Conclusions -Systematic analysis of the O2 pathway in HFpEF
showed that exercise capacity was undermined by multiple defects, including
reductions in cardiac output and skeletal muscle diffusion capacity. An important
source of disease heterogeneity stemmed from variation in each patient’s personal
profile of defects. Personalized O2 pathway analysis could identify patients most
likely to benefit from treating a specific defect; however, the system properties
of O2 transport favor treating multiple defects at once, as with exercise
training.

Rogan A; McCarthy K; McGregor G; Hamborg T; Evans G; Hewins S; Aldridge N;
Fletcher S; Krishnan N; Higgins R; Zehnder D; Ting SM,

Plos One [PLoS One], ISSN: 1932-6203, 2017 Sep 14; Vol. 12 (9), pp. e0183926

Background:
Patients with advanced chronic kidney disease (CKD) experience complex
functional and structural changes of the cardiopulmonary and
musculoskeletal system. This results in reduced exercise tolerance,
quality of life and ultimately premature death. We investigated the
relationship between subjective measures of health related quality of
life and objective, standardised functional measures for cardiovascular
and pulmonary health.

Methods: Between April 2010 and January 2013, 143
CKD stage-5 or CKD5d patients (age 46.0±1.1y, 62.2% male), were
recruited prospectively. A control group of 83 healthy individuals
treated for essential hypertension (HTN; age 53.2±0.9y, 48.22% male)
were recruited at random. All patients completed the SF-36 health
survey questionnaire, echocardiography, vascular tonometry and
cardiopulmonary exercise testing.

Results: Patients with CKD had significantly lower SF-36 scores than the HTN group; for physical
component score (PCS; 45.0 vs 53.9, p<0.001) and mental component score
(MCS; 46.9 vs. 54.9, p<0.001). CKD subjects had significantly poorer
exercise tolerance and cardiorespiratory performance compared with HTN
(maximal oxygen uptake; VO2peak 19.9 vs 25.0ml/kg/min, p<0.001).
VO2peak was a significant independent predictor of PCS in both groups
(CKD: b = 0.35, p = 0.02 vs HTN: b = 0.27, p = 0.001). No associations
were noted between PCS scores and echocardiographic characteristics,
vascular elasticity and cardiac biomarkers in either group. No
associations were noted between MCS and any variable. The interaction
effect of study group with VO2peak on PCS was not significant (ΔB =
0.08; 95%CI -0.28-0.45, p = 0.7). However, overall for a given VO2peak,
the measured PCS was much lower for patients with CKD than for HTN
cohort, a likely consequence of systemic uremia effects.

Conclusion: In CKD and HTN, objective physical performance has a significant effect on
quality of life; particularly self-reported physical health and
functioning. Therefore, these quality of life measures are indeed a
good reflection of physical health correlating highly with objective
physical performance measures.

Pimentel M, Zimerman A, Chemello D, Giaretta V, Andrades
M, Silvello D, Zimerman L, Rohde LE

J Interv Card Electrophysiol. 2017 Mar;48(2):131-139.

PURPOSE: Risk stratification of serious arrhythmic events in patients with
nonischemic heart failure (HF), beyond estimates of left ventricular ejection
fraction (LVEF), remains an important clinical challenge. This study aims to
determine the clinical value of different noninvasive and invasive tests as
predictors of serious arrhythmic events in patients with nonischemic HF.

METHODS: A prospective observational study was conducted including 106
nonischemic HF patients who underwent a comprehensive clinical and laboratory
evaluation including two-dimensional echocardiography, 24-h Holter monitoring,
cardiopulmonary exercise testing (CPX), and an invasive electrophysiological
study. The study’s primary end-point was either syncope, appropriate therapy by
implantable cardioverter-defibrillators, or sudden cardiac death.

RESULTS: During a mean follow-up of 704 ± 320 days, the primary end-point
occurred in 15 patients (14.2%). In multivariable analysis, LV end-diastolic
diameter >73 mm (hazard ratio [HR] 3.7; p = 0.016), exercise periodic breathing
(EPB) on CPX (HR 2.88; p = 0.045), and non-sustained ventricular tachycardia
(NSVT) ≥10 beats (HR 8.2; p < 0.01) remained independently associated with
serious arrhythmic events. The positive predictive value of the presence of two
of these predictors ranged from 44 to 100%. The absence of all three factors
(n = 65, 61% of the sample) identified a subset of patients with low risk of
future arrhythmic events, with a negative predictive value of 96.9%.

CONCLUSIONS: In this cohort study of nonischemic HF patients, LV dimension, EPB,
and NSVT ≥10 beats were independent predictors of serious arrhythmic events. The
presence or absence of these characteristics identified sub-groups of high and
low risk of serious arrhythmic events, respectively.

Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS,
Wagner PD, Lewis GD
Mass. General, Boston

Circulation. 2017 Oct 9. pii

Background -Heart failure with preserved ejection fraction (HFpEF) is a common
syndrome with a pressing shortage of therapies. Exercise intolerance is a
cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. Methods -We
investigated the mechanism of exercise intolerance in each of 134 patients
referred for cardiopulmonary exercise testing (CPET): 79 with HFpEF and 55
controls. We performed CPET with invasive monitoring to measure hemodynamics,
blood gases, and gas exchange during exercise. We used these measurements to
quantify 6 steps of oxygen transport and utilization (the “O2 pathway”) in each
HFpEF patient, identifying the defective steps that impair each one’s exercise
capacity (peak VO2). We then quantified the functional significance of each O2
pathway defect by calculating the improvement in exercise capacity a patient
could expect from correcting the defect.

Results -Peak VO2 was reduced by 34%±2% (mean±SEM, P<0.001) in HFpEF
compared with controls of comparable age, gender,
and body mass index. The vast majority (97%) of HFpEF patients harbored defects
at multiple steps of the O2 pathway, the identity and magnitude of which varied
widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were
impaired relative to controls by an average of 27±3% and 36±2%, respectively
(P<0.001 for both). Due to interactions between a given patient’s defects, the
predicted benefit of correcting any single one was often minor; on average,
correcting a patient’s cardiac output led to a 7±0.5% predicted improvement in
exercise intolerance, while correcting a patient’s muscle diffusion capacity led
to a 27±1% improvement. At the individual level, the impact of any given O2
pathway defect on a patient’s exercise capacity was strongly influenced by
comorbid defects.

Conclusions -Systematic analysis of the O2 pathway in HFpEF
showed that exercise capacity was undermined by multiple defects, including
reductions in cardiac output and skeletal muscle diffusion capacity. An important
source of disease heterogeneity stemmed from variation in each patient’s personal
profile of defects. Personalized O2 pathway analysis could identify patients most
likely to benefit from treating a specific defect; however, the system properties
of O2 transport favor treating multiple defects at once, as with exercise
training.

Guazzi M; Bandera F; Ozemek C; Systrom D; Arena R

Journal Of The American College Of Cardiology [J Am Coll Cardiol], ISSN: 1558-3597, 2017 Sep 26; Vol. 70 (13), pp. 1618-1636;

Compared with traditional exercise tests, cardiopulmonary exercise testing (CPET) provides a thorough assessment of exercise integrative physiology involving the pulmonary, cardiovascular, muscular, and cellular oxidative systems. Due to the prognostic ability of key variables, CPET applications in cardiology have grown impressively to include all forms of exercise intolerance, with a predominant focus on heart failure with reduced or with preserved ejection fraction. As impaired cardiac output and peripheral oxygen diffusion are the main determinants of the abnormal functional response in cardiac patients, invasive CPET has gained new popularity, especially for diagnosing early heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension. The most impactful advance has recently come from the introduction of CPET combined with echocardiography or CPET imaging, which provides basic information regarding cardiac and valve morphology and function. This review highlights modern CPET use as a single or combined test that allows the pathophysiological bases of exercise limitation to be translated, quite easily, into clinical practice.

Dallaire F; Wald RM; Marelli A,

Pediatric Cardiology [Pediatr Cardiol], ISSN:
1432-1971, 2017 Aug; Vol. 38 (6), pp. 1097-1105;

Tetralogy of Fallot is the most common form of
cyanotic congenital heart disease. As a result of the surgical
strategies employed at the time of initial repair, chronic pulmonary
regurgitation (PR) is prevalent in this population. Despite sustained
research efforts, patient selection and timing of pulmonary valve
replacement (PVR) to address PR in young asymptomatic patients with
repaired tetralogy of Fallot (rToF) remain a fundamental but as yet
unanswered question in the field of congenital heart disease. The
ability of the heart to compensate for the chronic volume overload
imposed by PR is critical in the evaluation of the risks and benefits
of PVR. The difficulty in clarifying the functional impact of PR on the
cardiovascular capacity may be in part responsible for the uncertainty
surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET)
may be used to assess abnormal cardiovascular response to increased
physiologic demands. However, its use as a tool for risk stratification
in asymptomatic adolescents and young adults with rToF is still
ill-defined. In this paper, we review the role of CPET as a potentially
valuable adjunct to current risk stratification strategies with a focus
on asymptomatic rToF adolescents and young adults being considered for
PVR. The role of maximal and submaximal exercise measurements to
identify young patients with a decreased or borderline low peak VO2
resulting from impaired ventricular function is explored. Current
knowledge gaps and research perspectives are highlighted.