The left ventricular assist device 'skeleton man': case report-simple tools for skeletal muscle evaluation and very early aerobic/resistance/inspiratory training in cardiac cachexia.

Background: Skeletal muscle wasting (SMW) is highly prevalent in patients with heart failure (HF) at left ventricular assist device (LVAD) implantation and is associated with morbidity and mortality. At the same time, SMW is clinically under-recognized, while exercise training (ET) studies in weak LVAD patients are lacking. Case summary: A 60-year-old man with advanced HF, SMW, cardiac cachexia, and frailty was confined in bed for 6 months initially supported with intravenous inotropes and subsequently with an intra-aortic balloon pump. His frailty was recognized as an LVAD-responsive frailty, and patient was successfully implanted with a HeartWare (Medtronic). Post-surgery, patient was very weak, unable even to move in bed without assistance. We evaluated skeletal muscle using simple tools such as the Oxford scale, mid-thigh circumference, hand-held dynamometry, and maximum inspiratory pressure. Physical performance was assessed with the sit to stand test, gait speed test, pedal bike timing, and the 6 min walk test. On top of routine physiotherapy, patient underwent an 8-week modified aerobic/resistance/inspiratory (ARIS) ET programme at moderate intensity and showed significant improvements in skeletal muscle mass and strength and physical and functional capacity. Discussion: We want to emphasize the importance of skeletal muscle evaluation at LVAD implantation and the feasibility and effectiveness of early ARIS training in very weak patients.

Prognostic significance of blood pressure response to exercise in patients with systolic heart failure.

High systolic blood pressure (SBP) has been linked to worse cardiovascular outcomes. However, emerging data suggest that in patients with heart failure (HF), low SBP correlates with increased mortality. The purpose was to examine the impact of baseline and post-exercise systolic and diastolic blood pressure (DBP), as well as pulse pressure (PP), on cardiac mortality in patients with systolic HF. One hundred sixty patients with systolic HF (left ventricular ejection fraction 33 ± 8) were studied. Blood pressure (BP) levels were determined at rest and at peak exercise during a cardiopulmonary exercise test. Patients were followed up for a period of 2.5 ± 0.8 years. During this period 22 patients died and 5 subjects underwent heart transplantation. Patients with higher SBP and DBP at rest, and patients with SBP ≥160 mmHg and PP ≥75 mmHg at peak exercise had the most favorable prognosis. There was a fourfold increase in cardiac mortality risk for patients with SBP <160 mmHg at peak exercise (hazard ratio: 3.97, 95% confidence interval: 1.60-9.84) and a threefold increase for patients with PP <75 mmHg at peak exercise (hazard ratio: 2.96, 95% confidence interval: 1.29-6.82). There is an inverse relationship between SBP and cardiac mortality in patients with systolic HF. BP response to exercise could serve as a simple risk stratification model in HF patients.

Benefits of physical training on exercise capacity, inspiratory muscle function, and quality of life in patients with ventricular assist devices long-term postimplantation.

BACKGROUND: Capacity to exercise may not be fully restored in patients with heart failure even in the long term after ventricular assist device (VAD) implantation. The benefits of exercise training in patients with VAD are unknown. DESIGN AND METHODS: Fifteen patients, aged 38.3 ± 15.9 years, bridged to heart transplantation with left ventricular assist device or biventricular assist device were randomized at a ratio of 2 : 1 to a training group (TG, n = 10) or a control group (n = 5), 6.3 ± 4 months after implantation. Both the groups were advised to walk 30­45 min/day. TG also underwent moderate-intensity aerobic exercise using a bike or treadmill for 45 min, three to five times a week, combined with high-intensity inspiratory muscle training using a computer-designed software to respiratory exhaustion, two to three times a week for 10 weeks. The patients were tested using cardiopulmonary exercise testing, 6-min walk test, spirometry and electronic pressure manometer for inspiratory muscle strength (Pimax) and endurance (sustained Pimax) measurement. Quality of life was assessed with the Minnesota Living with Heart Failure questionnaire. RESULTS: TG improved peak oxygen consumption (19.3 ± 4.5 vs. 16.8 ± 3.7 ml/kg per min, P = 0.008) and VO2 at ventilatory threshold (15.1 ± 4.2 vs. 12 ± 5.6 ml/kg per min, P = 0.01), whereas the ventilation/carbon dioxide slope decreased (35.9 ± 5.6 vs. 40 ± 6.5, P = 0.009). The 6-min walk test distance increased (527 ± 76 vs. 462 ± 88 m, P = 0.005) and quality of life was improved (38.2 ± 11.6 vs. 48.9 ± 12.8, P = 0.005), as well as Pimax (131.8 ± 33 vs. 95.5 ± 28cmH2O, P = 0.005), sustained Pimax (484 ± 195 vs. 340 ± 193cmH2O/s/103, P = 0.005), and inspiratory lung capacity (2.4 ± 0.9 vs. 1.7 ± 0.7 L, P = 0.008) were improved. No significant changes were noted in the control group. CONCLUSION: Our findings indicate that exercise training may improve the functional status of VAD recipients even at a later period after implantation and thus, may have additional importance in cases of destination therapy.

Combined aerobic/resistance/inspiratory muscle training as the 'optimum' exercise programme for patients with chronic heart failure: ARISTOS-HF randomized clinical trial.

AIMS: An 'optimum' universally agreed exercise programme for heart failure (HF) patients has not been found. ARISTOS-HF randomized clinical trial evaluates whether combined aerobic training (AT)/resistance training (RT)/inspiratory muscle training (IMT) (ARIS) is superior to AT/RT, AT/IMT or AT in improving aerobic capacity, left ventricular dimensions, and secondary functional outcomes. METHODS AND RESULTS: Eighty-eight patients of New York Heart Association II-III, left ventricular ejection fraction ≤ 35% were randomized to an ARIS, AT/RT, AT/IMT, or AT group, exercising 3 times/week, 180 min/week for 12 weeks. Pre- and post-training, peakVO2 was evaluated with cardiopulmonary exercise testing, left ventricular dimensions using echocardiography, walking distance with the 6-min walk test (6MWT), quality of life by the Minnesota Living with HF Questionnaire (MLwHFQ), while a programme preference survey (PPS) was used. Seventy-four patients of [mean 95% (confidence interval, CI)] age 66.1 (64.3-67.9) years and peakVO2 17.3 (16.4-18.2) mL/kg/min were finally analysed. Between-group analysis showed a trend for increased peakVO2 (mL/kg/min) [mean contrasts (95% CI)] in the ARIS group [ARIS vs. AT/RT 1.71 (0.163-3.25)(.), vs. AT/IMT 1.50 (0.0152-2.99)(.), vs. AT 1.38 (-0.142 to 2.9)(.)], additional benefits in circulatory power (mL/kg/min⋅mmHg) [ARIS vs. AT/RT 376 (60.7-690)*, vs. AT/IMT 423 (121-725)*, vs. AT 345 (35.4-656)*], left ventricular end-systolic diameter (mm) [ARIS vs. AT/RT -2.11 (-3.65 to (-0.561))*, vs. AT -2.47 (-4.01 to (-0.929))**], 6MWT (m) [ARIS vs. AT/IMT 45.6 (18.3-72.9)**, vs. AT 55.2 (27.6-82.7)****], MLwHFQ [ARIS vs. AT/RT -7.79 (-11 to (-4.62))****, vs. AT -8.96 (-12.1 to (-5.84))****], and in PPS score [mean (95% CI)] [ARIS, 4.8 (4.7-5) vs. AT, 4.4 (4.2-4.7)*] [(.) P ≤ 0.1; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001]. CONCLUSION: ARISTOS-HF trial recommends exercise training for 180 min/week and supports the prescription of the ARIS training regime for HF patients (Clinical Trial Registration: http://www.clinicaltrials.gov. ARISTOS-HF Clinical Trial number, NCT03013270).

Restoring pulsatility and peakVO2 in the era of continuous flow, fixed pump speed, left ventricular assist devices: 'A hypothesis of pump's or patient's speed?'

Despite significant improvement in survival and functional capacity after continuous flow left ventricular assist device implantation, the patient's quality of life may remain limited by complications such as aortic valve insufficiency, thromboembolic episodes and gastrointestinal bleeding attributed to high shear stress continuous flow with attenuated or absence of pulsatile flow and by a reduced peak oxygen consumption (peakVO2) primarily associated with a fixed pump speed operation. Revision of current evidence suggests that high technology pump speed algorithms, a 'hypothesis of decreasing pump's speed' to promote pulsatile flow and a 'hypothesis of increasing pump's speed' to increase peakVO2, may only partially reverse these barriers. A 'hypothesis of increasing patient's speed' is introduced, suggesting that exercise training may further contribute to the patient's recovery, enhancing peakVO2 and pulsatile flow by improving skeletal muscle oxidative capacity and strength, peripheral vasodilatory and ventilatory responses, favour changes in preload/afterload and facilitate native flow, formulating the rationale for further studies in the field.

Exercise training in patients with ventricular assist devices: a review of the evidence and practical advice. A position paper from the Committee on Exercise Physiology and Training and the Committee of Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology.

Exercise training (ET) and secondary prevention measures in cardiovascular disease aim to stimulate early physical activity and to facilitate recovery and improve health behaviours. ET has also been proposed for heart failure patients with a ventricular assist device (VAD), to help recovery in the patient's functional capacity. However, the existing evidence in support of ET in these patients remains limited. After a review of current knowledge on the causes of the persistence of limitation in exercise capacity in VAD recipients, and concerning the benefit of ET in VAD patients, the Heart Failure Association of the European Society of Cardiology has developed the present document to provide practical advice on implementing ET. This includes appropriate screening to avoid complications and then starting with early mobilisation, ET prescription is individualised to meet the patient's needs. Finally, gaps in our knowledge are discussed.

The 'aerobic/resistance/inspiratory muscle training hypothesis in heart failure'.

Evidence from large multicentre exercise intervention trials in heart failure patients, investigating both moderate continuous aerobic training and high intensity interval training, indicates that the 'crème de la crème' exercise programme for this population remains to be found. The 'aerobic/resistance/inspiratory (ARIS) muscle training hypothesis in heart failure' is introduced, suggesting that combined ARIS muscle training may result in maximal exercise pathophysiological and functional benefits in heart failure patients. The hypothesis is based on the decoding of the 'skeletal muscle hypothesis in heart failure' and on revision of experimental evidence to date showing that exercise and functional intolerance in heart failure patients are associated not only with reduced muscle endurance, indication for aerobic training (AT), but also with reduced muscle strength and decreased inspiratory muscle function contributing to weakness, dyspnoea, fatigue and low aerobic capacity, forming the grounds for the addition of both resistance training (RT) and inspiratory muscle training (IMT) to AT. The hypothesis will be tested by comparing all potential exercise combinations, ARIS, AT/RT, AT/IMT, AT, evaluating both functional and cardiac indices in a large sample of heart failure patients of New York Heart Association class II-III and left ventricular ejection fraction ≤35% ad hoc by the multicentre randomized clinical trial, Aerobic Resistance, InSpiratory Training OutcomeS in Heart Failure (ARISTOS-HF trial).

Inspiratory work capacity is more severely depressed than inspiratory muscle strength in patients with heart failure: Novel applications for inspiratory muscle training.

BACKGROUND: We hypothesized that the ability to sustain maximal inspiratory pressure (SPImax) over time as a measure of work capacity may be more severely affected than inspiratory muscle strength (PImax) in patients with heart failure (HF). METHODS: We retrospectively investigated eighty patients with HF, NYHA II/III/ ambulatoryIV and a (mean±SD) LVEF 27±8%, and compared them to 25 healthy subjects (HS). During a maximal inspiratory manoeuvre from residual volume (RV) to total lung capacity, PImax was measured as the maximum mouth pressure at RV, inspiratory contraction time (ICT) as the time from RV to end of inspiration and SPImax as the area under a pressure-time curve using an electronic pressure manometer with designed-purpose software (Trainair(®), Project Electronics Ltd., London, UK). Exercise capacity was assessed with cardiopulmonary exercise testing and the 6-minute walk test (6MWT). RESULTS: Patients achieved a (mean±SD) peak VO2=15.7±3.4ml/kg/min and 6MWT=338±88m. PImax, ICT and SPImax were reduced in HF pts at 75%***, 61%*** and 52%*** of HS, and correlated with NYHA (r=-0.485***), (r=-0.507**), (r=-0.500***), peakVO2 (r=0.501***), (r=0.655***), (r=0.508***) and 6MWT (r=0.477***), (r=0.345**), (r=0.530***), respectively (*p<0.05, **p<0.01, ***p<0.001). CONCLUSION: PImax, ICT and SPImax were impaired in HF patients compared to HS and may be important determinants of exercise capacity. SPImax was severely depressed even in patients with relatively preserved PImax and should be considered as an additional target index for inspiratory muscle training. Equations are provided to predict SPImax in relation to age and exercise capacity in HF.

Combined aerobic/inspiratory muscle training vs. aerobic training in patients with chronic heart failure: The Vent-HeFT trial: a European prospective multicentre randomized trial.

AIMS: Vent-HeFT is a multicentre randomized trial designed to investigate the potential additive benefits of inspiratory muscle training (IMT) on aerobic training (AT) in patients with chronic heart failure (CHF). METHODS AND RESULTS: Forty-three CHF patients with a mean age of 58 ± 12 years, peak oxygen consumption (peak VO2 ) 17.9 ± 5 mL/kg/min, and LVEF 29.5 ± 5% were randomized to an AT/IMT group (n = 21) or to an AT/SHAM group (n = 22) in a 12-week exercise programme. AT involved 45 min of ergometer training at 70-80% of maximum heart rate, three times a week for both groups. In the AT/IMT group, IMT was performed at 60% of sustained maximal inspiratory pressure (SPImax ) while in the AT/SHAM group it was performed at 10% of SPImax , using a computer biofeedback trainer for 30 min, three times a week. At baseline and at 3 months, patients were evaluated for exercise capacity, lung function, inspiratory muscle strength (PImax ) and work capacity (SPImax ), quality of life (QoL), LVEF and LV diameter, dyspnoea, C-reactive protein (CRP), and NT-proBNP. IMT resulted in a significantly higher benefit in SPImax (P = 0.02), QoL (P = 0.002), dyspnoea (P = 0.004), CRP (P = 0.03), and NT-proBNP (P = 0.004). In both AT/IMT and AT/SHAM groups PImax (P < 0.001, P = 0.02), peak VO2 (P = 0.008, P = 0.04), and LVEF (P = 0.005, P = 0.002) improved significantly; however, without an additional benefit for either of the groups. CONCLUSION: This randomized multicentre study demonstrates that IMT combined with aerobic training provides additional benefits in functional and serum biomarkers in patients with moderate CHF. These findings advocate for application of IMT in cardiac rehabilitation programmes.

Thyroid hormone signalling is altered in response to physical training in patients with end-stage heart failure and mechanical assist devices: potential physiological consequences?

OBJECTIVES: The present study investigated the potential of the failing myocardium of patients with ventricular assist devices (VAD) to respond to physiological growth stimuli, such as exercise, by activating growth signalling pathways. This may be of therapeutic relevance in identifying novel pharmacological targets for therapies that could facilitate recovery after VAD implantation. METHODS: Twenty-two patients bridged to heart transplantation (HTx) with VAD were included in the study. A group of patients underwent moderate intensity aerobic exercise (GT), while another group of patients did not receive exercise training (CG). Thyroid hormone receptor alpha1 (TRα1) protein and total (t) and phosphorylated (p) protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) kinase signalling were measured in myocardial tissue by western blotting at pre-VAD and pre-HTx period. In addition, Thyroid hormone (TH) levels were measured in plasma. RESULTS: Peak oxygen consumption (VO2) at pre-HTx period was higher in patients subjected to training protocol [18.0 (0.8) for GT when compared with 13.7 (0.7) for CG group, P = 0.002]. N-terminal-prohormone of brain natriuretic peptide (NT-proBNP) levels were 1068 (148) for CG vs 626 (115) for GT group, P = 0.035. A switch towards up-regulation of physiological growth signalling was observed: the ratio of p-Akt/t-Akt was 2-fold higher in GT vs CG, P < 0.05 while p-JNK/t-JNK was 2.5-fold lower (P < 0.05) in GT vs CG, in pre-HTx samples. This response was accompanied by a 2.0-fold increase in TRα1 expression in pre-HTx samples with concomitant increase in circulating T3 in GT vs CG, P < 0.05. No differences in peak VO2, NT-proBNP, T3, TRα1, p/t-AKT and p/t-JNK were found between groups in the pre-VAD period. CONCLUSIONS: The unloaded failing myocardium responded to physical training by enhancing thyroid hormone signalling. This response was associated with an up-regulation of Akt and suppression of JNK activation.

Benefits of combined aerobic/resistance/inspiratory training in patients with chronic heart failure. A complete exercise model? A prospective randomised study.

BACKGROUND: We hypothesised that combined aerobic training (AT) with resistance training (RT) and inspiratory muscle training (IMT) could result in additional benefits over AT alone in patients with chronic heart failure (CHF). METHODS: Twenty-seven patients, age 58 ± 9 years, NYHA II/III and LVEF 29 ± 7% were randomly assigned to a 12-week AT (n=14) or a combined AT/RT/IMT (ARIS) (n=13) exercise program. AT consisted of bike exercise at 70-80% of max heart rate. ARIS training consisted of AT with RT of the quadriceps at 50% of 1 repetition maximum (1RM) and upper limb exercises using dumbbells of 1-2 kg as well as IMT at 60% of sustained maximal inspiratory pressure (SPI(max)). At baseline and after intervention patients underwent cardiopulmonary exercise testing, echocardiography, evaluation of dyspnea, muscle function and quality of life (QoL) scores. RESULTS: The ARIS program as compared to AT alone, resulted in additional improvement in quadriceps muscle strength (1RM, p=0.005) and endurance (50%1 RM × number of max repetitions, p=0.01), SPI(max) (p<0.001), exercise time (p=0.01), circulatory power (peak oxygen consumption × peak systolic blood pressure, p=0.05), dyspnea (p=0.03) and QoL (p=0.03). CONCLUSIONS: ARIS training was safe and resulted in incremental benefits in both peripheral and respiratory muscle weakness, cardiopulmonary function and QoL compared to that of AT. The present findings may add a new prospective to cardiac rehabilitation programs of heart failure patients whilst the clinical significance of these outcomes need to be addressed in larger randomised studies.

Prognostic value of NT-proBNP at rest and peak exercise in patients with impaired left ventricular function.

We aimed to identify whether N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) at peak exercise can provide incremental clinical information over resting levels. A total of 90 patients with systolic heart failure were prospectively studied. Levels of plasma NT-proBNP were assessed at rest and at peak exercise during a cardiopulmonary exercise test. Patients were followed-up for 30 ± 10 months. Levels of NT-proBNP at baseline and peak exercise were significantly correlated with left ventricular ejection fraction ([LVEF] r = -.629, P < .001 and r = -.630, P < .001, respectively) and peak oxygen uptake ([Vo (2)] r = -.752, P < .001 and r = -.740, P < .001, respectively). Levels of plasma NT-proBNP at peak exercise demonstrated similar predictive ability for the detection of patients with low peak Vo (2) and LVEF <28%. Levels of plasma NT-proBNP can detect low-functional class patients and patients who may be the candidates for heart transplantation with high sensitivity and specificity. At baseline and peak exercise, NT-proBNP demonstrates similar prognostic and predictive ability.

High plasma adiponectin is related to low functional capacity in patients with chronic heart failure.

We evaluated the association between plasma adiponectin and functional capacity in patients with chronic heart failure (CHF). Similarly to NT-proBNP, plasma adiponectin was elevated in CHF compared to healthy controls. Adiponectin correlated inversely with peak oxygen consumption and 6-minute walking distance and was able to identify CHF patients with impaired exercise capacity. Our findings support a role of adiponectin as an index of heart failure severity.

Chronotropic and neurohumoral markers for the evaluation of functional capacity in patients with impaired left ventricular function.

INTRODUCTION: Brain natriuretic peptide (BNP) levels correlate with functional capacity in patients with heart failure. Autonomic dysfunction and baro-chemo reflex balance play a role in conditioning exercise tolerance and chronotropic competence in heart failure. In this study we examined the relationship between N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and heart rate (HR) response during cardiopulmonary exercise testing and the ability of those two markers to detect low functional class patients. METHODS: We studied 100 patients (age 59 +/- 13 yrs) with heart failure and left ventricular ejection fraction 35 +/- 9% who underwent treadmill cardiopulmonary exercise testing using the Dargie protocol. HR response was assessed by the chronotropic response index (CRI), which is calculated using the formula CRI = (peak HR - rest HR) /(220 - age - rest HR) x 100 (%). Blood samples for NT-pro-BNP assessment were taken before exercise. RESULTS: The overall peak VO2 achieved was 18 +/- 5 ml/kg/mm and CRI was 70 +/- 26% (normal value >80%). CRI correlated both with peak VO2 (r = 0.50, p < 0.001) and VE/VCO2 (r = -0.24, p < 0.05). Peak VO2 correlated strongly with NT-pro-BNP (r = -0.77, p < 0.001). NT-pro-BNP values >335 pg/ml showed 83% sensitivity and 76% specificity for detecting peak VO2 values <20 ml/kg/mm (AUC=86%, p < 0.001). CRI values >79% showed 70% sensitivity and 60% specificity for detecting peak VO2 values <20 ml/kg/mm (AUC=72%, p < 0.001). CRI correlated well with NT-pro-BNP at rest (r = -0.31, p < 0.001). CONCLUSIONS: In patients with heart failure, CR1 correlates significantly with both functional capacity derived from cardiopulmonary exercise testing and NT-pro-BNP levels. These findings may support the use of CR1 as a simple noninvasive marker of heart failure severity.

N-terminal prohormone brain natriuretic peptide plasma levels in heart failure are affected both directly and indirectly by carvedilol.

N-terminal prohormone brain natriuretic peptide (NT Pro BNP) is a sensitive marker of left ventricular function in patients with heart failure. The influence of carvedilol on NT Pro BNP plasma levels was analyzed in 21 heart failure patients. Blood samples were taken before administration and after 12 months of treatment with low-dose carvedilol. Peak oxygen consumption did not change after carvedilol treatment, left ventricular ejection fraction improved (P < .005) in 11 patients (52%), did not change in 9 (43%), and decreased in 1 (5%). In patients where left ventricular ejection fraction improved, NT Pro BNP tended to decrease; however, in patients without improvement, NT Pro BNP increased at follow-up. A correlation exists between magnitude of change in BNP and magnitude of improvement in ventricular function during carvedilol therapy. Patients without noticeable changes in left ventricular ejection fraction with a low to moderate carvedilol dosage show an increase in NT Pro BNP plasma levels.

Incremental value of N-terminal pro-brain natriuretic peptide over left ventricle ejection fraction and aerobic capacity for estimating prognosis in heart failure patients.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels have been associated with indices of left ventricular (LV) function and aerobic capacity in heart failure. METHODS: We prospectively followed-up 149 patients with impaired left ventricular function for 30 +/- 10 months. During this period, 22 patients died and 5 underwent heart transplantation. Blood samples for NT-proBNP assessment were taken at baseline and before cardiopulmonary exercise to estimate peak oxygen consumption (Vo(2)). LV cavity diameter, left atrial size and LV ejection fraction (LVEF) were measured by echocardiography. RESULTS: NT-proBNP plasma levels >1,164 pg/ml showed 85% sensitivity and 82% specificity for detecting Vo(2)<14 ml/kg/min (area under the curve [AUC] = 90%, p < 0.001). Patients above this cutoff showed a 13.6-fold greater hazard ratio compared with those with values below this cutoff (p < 0.001). NT-proBNP plasma levels of >760 pg/ml showed 77% sensitivity and 69% specificity for detecting LVEF <28% (AUC = 77%, p < 0.001). Patients with values above this cutoff showed a 15.85-fold greater hazard ratio compared to those with values below this cutoff (p < 0.001). The addition of NT-proBNP to an assessment model that includes peak Vo(2), LVEF and New York Heart Association (NYHA) classification can significantly improve predictive ability. CONCLUSIONS: Assessment of NT-proBNP should be performed to detect candidates for heart transplantation because of the useful prognostic information that it can provide.