SEARCH

SEARCH BY CITATION

Keywords:

  • CRT;
  • autonomics;
  • congestive heart failure

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Introduction

Muscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable.

Objectives

In this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF.

Methods

We assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III–IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied.

Results

CRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = –0.74, P = 0.01) was observed.

Conclusions

In patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Cardiac resynchronization therapy (CRT) is now an adjuvant therapy option to selected heart failure (HF) patients.[1] Several randomized clinical trials[2-10] have demonstrated that CRT clearly improves functional capacity, peak oxygen consumption (VO2), and a 6-minute walking test in HF patients with delayed intraventricular conduction.

Although exercise intolerance is a hallmark of HF, the mechanisms of this abnormality are not completely understood. Several studies have shown that changes in peripheral hemodynamic variables and skeletal muscles abnormalities, rather than left ventricular (LV) ejection fraction and intracardiac hemodynamic changes, seem to play an important role in the cause of exercise intolerance in HF patients.[11-14] According to a statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention,[15] the reduced skeletal muscle blood flow at rest and during exercise, endothelial dysfunction, early anaerobic metabolism of skeletal muscle, and metaboreflex activation are some of the peripheral events that occur in HF and explain, in part, the exercise intolerance.

Our laboratory[16] has previously demonstrated that the typical increase in muscle sympathetic nerve activity (MSNA) and peripheral vasoconstriction at rest and during moderate exercise in HF patients occur progressively. Notarious et al.[17] also found an inverse relationship between the percentage of predicted peak VO2 and resting MSNA in patients with HF.

Some studies have suggested that CRT elicits MSNA reduction at rest,[18-20] but there is no consistent evidence of sympathetic neural behavior during exercise in these patients.

The objective of this study was to evaluate the role of CRT on sympathetic neural activity at rest and during moderate exercise and on exercise capacity compared to HF patients submitted to optimal medical therapy.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Study Population

After written informed consents were obtained, 11 HF patients with an indication for CRT, eight age-matched HF control patients, and 12 healthy control subjects were studied. This study was approved by the Ethical Committee on Human Research Protocols of the University of São Paulo Medical School, and all participants signed a written informed consent. We included HF patients with New York Heart Association (NYHA) functional class III or IV and an ejection fraction ≤35% receiving optimal pharmacological treatment for at least 1 month. All patients received appropriate pharmacological treatment for HF, which included diuretics, β-blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at the maximal tolerated dose. The healthy control participants were not taking any medications. The exclusion criteria were: recent acute coronary or cerebrovascular syndromes and/or coronary revascularization (3 months prior to study enrollment); indication for pacemaker implantation; chronic atrial tachy-arrhythmias; sinus node dysfunction; insulin-dependent diabetes; neuropathies; inability to walk; pregnancy; and reduced life expectancy (less than 1 year) not associated with cardiovascular disease. The indication for CRT was made by the patients’ attending physician and was based on the following: drug-refractory HF with NYHA functional class III or IV in the presence of left bundle branch block with a QRS interval ≥150 ms.

Study Protocol

HF patients underwent echocardiography to assess LV ejection fraction. The three groups underwent cardiopulmonary exercise testing to determine the peak VO2. MSNA blood pressure (BP), and heart rate (HR) measurements were obtained at rest and during moderate static exercise. The CRT and HF control groups were subjected to the same procedures after a 3-month follow-up.

Device Implantation and Programming

Patients with CRT indication underwent implantation of a pacemaker with three pacing leads: a standard right atrial lead, a standard right ventricular lead, and a specialized LV lead, which was placed into a distal cardiac vein in the coronary sinus using a guiding catheter, or by the epicardial stimulation lead placed at the lateral or posterolateral LV free wall using a limited thoracotomy approach. All CRT devices were programmed in DDD (atrioventricular pacing) or VDD (ventricular pacing with atrial synchronism) pacing mode with the lower rate limit set at 50 beats/min and the upper rate limit set at 130 beats/min. Atrioventricular delay was optimized by echocardiography, and transmitral flow was evaluated. Interventricular delay was not optimized and programmed simultaneously. CRT implantation was carried out 1 to 3 days after the baseline measurements.

Measurements and Procedures

Cardiopulmonary Exercise Testing

Maximal exercise capacity was determined by means of a progressive maximal exercise test on an electromagnetically braked cycle ergometer (Medifit 400L, Medical Fitness Equipment, Maarn, The Netherlands), with workload increments of 5 W/min or 10 W/min at 60 revolutions per minute (rpm) until exhaustion. VO2 and carbon dioxide production were determined by means of gas exchange on a breath-by-breath basis in a computerized system (CAD/Net Medical Graphics Corporation, St. Paul, MN, USA, 2001). Peak VO2 was defined as the maximum VO2 attained at the end of the exercise period in which the patient could no longer maintain the cycle ergometer speed at 60 rpm. This method is considered the gold standard for assessing patients’ exercise capacity.[21] The reproducibility of the peak VO2 measured at different time intervals in the same individual expressed as mL/kg/min in our laboratory is r = 0.95.

MSNA

MSNA was directly measured from the peroneal nerve using microneurography technique, as previously described.[22] MSNA was analyzed in bursts per minute. The reproducibility of MSNA measured at different time intervals in the same individual, expressed as bursts per minute, is r = 0.88.

Other Measurements

BP was noninvasively monitored every minute with an automatic and oscillometric cuff (Dixtal, DX 2710, Manaus, Brazil) placed on the ankle with cuff width adjusted to ankle circumference. HR was continuously monitored using lead II of the electrocardiogram.

Experimental Protocol

Baseline Measurements

All studies were performed with the patients in supine position in a quiet air-conditioned room (22°C–24°C). After obtaining an adequate microneurography nerve-recording site, all patients rested for 10 minutes, and MSNA, BP, and HR were subsequently monitored for a baseline period of 5 minutes.

Moderate Isometric Exercise

The purpose of this experiment was to determine the magnitude of changes in muscle neurovascular control during central command activation, mechanoreceptor, and metaboreceptor controls. After a 10-minute period, baseline MSNA, BP, and HR were recorded for 3 minutes. Handgrip exercise was then performed with the dominant arm at 30% maximal voluntary contraction for 3 minutes. The patients were instructed to breathe normally during exercise in order to avoid an accidental Valsalva maneuver.

Statistical Analysis

Data were summarized as frequencies for categorical variables and means with standard errors (mean ± SE) for continuous variables. A two-way analysis of variance with repeated measures was performed to test possible differences within-groups and between-groups, both pre- and postinterventions. The Scheffé's post hoc comparison test was carried out when any significance was found. The Spearman correlation coefficient was applied to measure correlations between the variables. For all comparisons, P < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Nineteen HF patients and 12 healthy volunteers have been enrolled in this study. CRT and HF control patients were older than healthy volunteers (mean age, 51.4 ± 11.3 years vs 52.0 ± 6.7 years vs 43.4 ± 3.5 years, respectively, P = 0.029). The mean body mass index was lower in the HF control compared to the CRT group and healthy volunteers (22.8 ± 3.4 vs 26.8 ± 1.0 vs 25.4 ± 2.9, respectively, P = 0.040). CRT and HF control groups presented different baseline functional classes (P = 0.004). The characteristics of patients and controls are showed in Table I.

Table I. Participant Characteristics
 CRT (n = 11)CHF Control (n = 8)P CRT vs CHFNormal Control (n = 12)P HF × Normal
  1. *Values are given as means ± SE.

  2. BMI = body mass index; CHF = congestive heart failure; CRT = cardiac resynchronization therapy; HF = heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SE = standard errors.

Age (years)*51.4 ± 11.352.0 ± 6.70.90543.4 ± 3.50.029
Male (gender)6 (54.5%)6 (75%)0.6335 (41.7%)0.274
Weight (kg)*74.1 ± 2.964.9 ± 120.08268.9 ± 10.50.740
BMI (kg/m2)*26.8 ± 1.022.8 ± 3.40.02225.4 ± 2.90.040
Functional class  0.004  
NYHA II, n (%)05 (62.5%) Not applicable 
NYHA III, n (%)10 (90.9%)3 (37.5%) Not applicable 
NYHA IV, n (%)1 (9.1%)0 Not applicable 
Cardiomyopathy  0.192  
Idiopathic7 (63.6%)3 (37.5%) Not applicable 
Ischemic2 (18.2%)0 Not applicable 
Hypertensive2 (18.2%)4 (50%) Not applicable 
Chagas’ disease01 (12.5%) Not applicable 
LVEF (%)*27.8 ± 2.230 ± 4.80.600Not performed 

One patient in the CRT group refused to undergo the cardiopulmonary exercise testing, and the resting MSNA data at the 3-month follow-up was not obtained for one HF control patient due technical reasons. The patients received optimal drug treatment including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (100%), spironolactone (100%), β-blockers (90.9%), furosemide (90.9%), and digoxin (63.6%). All patients continued to receive the assigned treatment for the intended length of the study, except for one patient who had an increase in furosemide dose 1 month after beginning CRT.

Only one patient required epicardial LV lead placement via thoracotomy. In eight patients, LV lead was positioned at the lateral wall, and in three at the posterolateral wall.

Both groups of HF patients showed a similarly marked and significant reduction of peak VO2 compared with normal control subjects. Patients enrolled to CRT showed a significant improvement in NYHA functional class and peak VO2 after a 3-month follow-up (Fig. 1). In contrast, a significant change was not observed in HF control patients. CRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05) (Table II).

Table II. NYHA Functional Class, Peak VO2, MSNA at Rest and at Handgrip in HF Groups (CRT and Control), and Healthy Control Subjects at Baseline and after a 3-Month Follow-Up
 CRT N = 11CHF Control N = 8Normal Control N = 12
 Baseline3-Month Follow-UpBaseline3-Month Follow-UpBaseline
  1. Values are means ± SE.

  2. *P < 0.05 vs healthy control.

  3. **P < 0.05 vs HF control.

  4. CHF = congestive heart failure; CRT = cardiac resynchronization therapy; HF = heart failture; MSNA = muscle sympathetic nerve activity; NYHA = New York Heart Association; VO2 = peak oxygen consumption.

NYHA class     
I00100Not applicable
II0090505Not applicable
III10010303Not applicable
IV01000Not applicable
Peak VO2 (mL/kg/min)12.9 ± 2.8*16.5 ± 3.9**13.4 ± 3.6*12.1 ± 3.5*23.3 ± 3
MSNA at rest (bursts/min)48.9 ± 11.1*33.7 ± 15.3**42.7 ± 19.6*54.6 ± 15.5*22.9 ± 3
MSNA at handgrip (bursts/min)62.3 ± 13.1*46.9 ± 14.3**54.9 ± 21.7*64.8 ± 17.4*32.3 ± 5.7
image

Figure 1. Correlation between VO2 and MSNA at rest before and after CRT.

CRT = cardiac resynchronization therapy; MSNA = muscle sympathetic nerve activity. Pre/post indicates measured prior to and 3 months after CRT; VO2 = peak oxygen consumption.

Download figure to PowerPoint

At baseline, MSNA was higher at rest and remained significantly higher throughout moderate static exercise in the two groups of HF patients compared with normal control subjects. There was no difference of resting and exercising MSNA between CRT and HF control patients (Fig. 2A).

image

Figure 2. Muscle sympathetic nerve responses during moderate static exercise in CHF patients (CRT and control) compared with normal control subjects. (A) Moderate static handgrip exercise at baseline. (B) Moderate static handgrip exercise after a 3-month follow-up. *P < 0.001 vs normal control. **P = 0.005 vs normal control. ***P = 0.003 vs normal control.

CHF = congestive heart failure, CRT = cardiac resynchronization therapy.

The bars represent the standard deviation.

Download figure to PowerPoint

After a 3-month follow-up, MSNA had significantly decreased at rest and during moderate static exercise in the CRT group. Consequently, MSNA became significantly lower in CRT patients compared with HF control patients, but remained significantly higher when compared with healthy control subjects (Fig. 2B).

Although both groups of HF patients have shown greater nerve activity at rest and during static moderate exercise compared with healthy control subjects, MSNA progressively and similarly increased during 3 minutes of moderate static exercise in all three groups (group effect P < 0.001, time effect P < 0.001, interaction P = 0.324). This exercise response did not change after a 3-month follow-up.

We observed an inverse correlation between VO2 peak and resting MSNA (r = –0.74, P = 0.01). We did not find statistical correlations between changes in exertion MSNA and VO2 peak.

Examples of MSNA before and after CRT at rest and during isometric exercise are shown in Figure 3.

image

Figure 3. MSNA before and after cardiac resynchronization therapy at rest and during isometric exercise. CRT = cardiac resynchronization therapy; MSNA = muscle sympathetic nerve activity; Pre/post = measured prior to and 3 months after CRT.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Increased sympathetic nerve activity may have several detrimental effects contributing to poor exercise tolerance in HF. This study demonstrates that in patients with HF, CRT significantly decreased MSNA at rest and during static exercise. To the best of our knowledge, this is the first study to show the effects of CRT in MSNA during isometric exercise, a condition in which central command and exercise pressor reflex (EPR), for example, metaboreflex and mechanoreflex, are simultaneously activated.

Besides this functional behavior, we observed that CRT improves exercise capacity as measured by peak VO2 and NYHA functional class, which is in accordance with findings of prior randomized clinical trials.[2-10] However, the mechanisms of this benefit are not well understood. Therefore, we consider that CRT effects on limb neurovascular control may contribute to a better understanding of this issue.

Although exercise intolerance is a hallmark of HF, the mechanisms of the symptoms are not completely understood. Evidence from the literature has shown that peripheral hemodynamic variables and skeletal muscles abnormalities, rather than ejection fraction and intracardiac hemodynamic alterations, seem to play an important role in exercise intolerance in patients with HF.[23-27] Moreover, previous studies including randomized controlled trials have shown that CRT improves peak VO2 without significant changes in systolic function.[6, 7] These findings are in accordance with the muscle hypothesis proposed by Coats et al.[28] in the early 1990s. In that paper, the authors suggested that exercise intolerance in HF patients is caused by increased ergoreflex activity (i.e., somatic afferents located in skeletal muscle sensitive to metabolic by-products), hyperventilation, increased sympathetic nerve activity, and peripheral vasoconstriction.

The concept that muscle mechanoreceptor sensitivity is increased in HF was postulated by several investigators after observing that the muscle metaboreflex is blunted in HF patients.[29, 30] Prior evidence suggests that this is the predominant mechanism leading to sympathetic activity observed in HF patients during exercise. Middlekauff et al.[31] demonstrated that MSNA increases during low-level rhythmic handgrip exercise in the first minute in HF patients and only in the third minute of exercise in healthy control individuals. These results confirm that muscle mechanoreceptor control is augmented in patients with HF. Moreover, it was also observed that MSNA increases during passive exercise in HF patients, but remained unchanged in healthy controls. In this sense, previous studies have also demonstrated that muscle mechanoreceptor control of renal vascular resistance during exercise is augmented in HF patients as well.[32]

Grassi et al.[18] have previously demonstrated that MSNA at rest was decreased 2 months after CRT. Interestingly, plasma norepinephrine levels were not decreased. Our findings are in agreement with that study, but we also observed MSNA decrease during moderate isometric exercise after CRT when central command and EPR are simultaneously activated.

The mechanism of sympathetic nerve activity attenuation during CRT is not entirely understood, but it may be related to increase in BP, contractility improvement, and activation of inhibitory cardiopulmonary baroreceptors.[33]

As an individual analysis approach, we also observed that the sympathoinhibitory effects were more remarkable in patients with a better clinical response to CRT. The two patients who showed a two NYHA functional class improvement have experienced a more significant reduction in peripheral sympathetic activity: MSNA at rest decreased from 46 bursts/min to 11 bursts/min (76% reduction) and from 54 to 18 (66% reduction) in those patients who experienced NYHA functional class improvement from III to I and from IV to II, respectively. On the other hand, it was interesting to observe that the patient with no improvement in NYHA functional class demonstrated a less significant reduction in MSNA at rest (63 bursts/min to 53 bursts/min, 16% reduction), while in two patients with NYHA functional class improvement from III to II, the MSNA at rest remained unchanged or showed a significantly smaller reduction in sympathetic activity: 50 bursts/min to 51 bursts/min (2% increase) and 47 bursts/min to 44 bursts/min (6% reduction). These findings suggest that the improvement in exercise tolerance after CRT can also be achieved by mechanisms that probably do not involve changes in peripheral sympathetic activation and skeletal muscle perfusion in patients with this disorder.

Another important and new finding in our study was a significant and inverse relationship between peak VO2 and reduction of MSNA at rest. According to previous data, this suggests that chronic sympathetic hyperactivity in skeletal muscle may play an important role in the development of exercise intolerance in HF patients. Adamapoulos et al.[34] evaluated patients with anterior myocardial infarction and low ejection fraction, decreased exercise capacity (low peak VO2 and low handgrip exercise performance), and reduction in phosphocreatine levels during submaximal exercise. They have demonstrated that the development of congestive heart failure (CHF) occurs only in patients with previous significantly high sympathetic activation, measured by reduced HR variability and noradrenaline spillover in early stage, before the onset of the symptoms. Notarius et al.[17] found a strong inverse correlation between the percentage of predicted peak VO2 and MSNA at rest in CHF patients submitted to pharmacological treatment, but not in healthy individuals. They proposed that interventions to reduce sympathetic hyperactivation in patients with CHF may result in improvement of exercise tolerance. Our study supports these previous studies by demonstrating that CHF patients with improvement in clinical status after CRT have shown a significant and uniform reduction in MSNA during moderate static exercise and a clearly inverse correlation between peak VO2 and MSNA at rest.

Conclusions and Perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Although the results of this study do not define the specific mechanism responsible for the improvement of exercise tolerance provided by CRT, our data enable us to add new information: (1) CRT provides a significant and uniform reduction of MSNA during moderate static exercise; and (2) there is a significant inverse correlation between peak VO2 and MSNA at rest after CRT.

Whether the significant reduction in MSNA can explain the improvement in exercise capacity provided by CRT in selected CHF patients remains an unsolved issue. However, based on the two aforementioned studies,[17, 34] as well as on the additional data of our study, it is possible to hypothesize that the chronic exposure to a stronger sympathetic activation could be directly responsible for skeletal muscle abnormalities that may contribute to exercise intolerance typically found in CHF patients.

Limitations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References

Potential limitations of our study include the small number of patients and the possibility of participation bias. However, we do not believe that the latter has interfered in our primary results. We used the static exercise protocol, so it is not possible to extend these findings to large skeletal muscle mass during isotonic exercise. Finally, our findings may not represent the long-term effects of CRT. Therefore, larger studies with a long-term follow-up are necessary to confirm our results.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions and Perspectives
  8. Limitations
  9. References
  • 1
    Strickberger SA, Conti J, Daoud EG, Havranek E, Mehra MR, Pina IL, Young J. Patient selection for cardiac resynchronization therapy: From the Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in collaboration with the Heart Rhythm Society. Circulation 2005; 111:21462150.
  • 2
    Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:18451853.
  • 3
    Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Bocker D, et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003; 42:21092116.
  • 4
    Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002; 39:20262033.
  • 5
    Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001; 344:873880.
  • 6
    Lozano I, Bocchiardo M, Achtelik M, Gaita F, Trappe HJ, Daoud E, Hummel J, et al. Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias. Pacing Clin Electrophysiol 2000; 23:17111712.
  • 7
    Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: The MIRACLE ICD Trial. JAMA 2003; 289:26852694.
  • 8
    Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:15391549.
  • 9
    Moss A, Hall J, Cannom DS, Klein H, Brown MW, Daubert JP, Mark Estes NA III, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361:13291338.
  • 10
    Tang ASL, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH et al. Cardiac-resynchronization therapy for mild-to-moderate heart-failure. N Engl J Med 2010; 363:23852395.
  • 11
    Maskin CS, Forman R, Sonnenblick EH, Frishman WH, LeJemtel TH. Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983; 51:177182.
  • 12
    Harrington D, Anker SD, Chua TP, Webb-Peploe KM, Ponikowski PP, Poole-Wilson PA, Coats AJ. Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol 1997; 30:17581764.
  • 13
    Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, Wilson JR. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992; 85:13641373.
  • 14
    Bekedam MA, Van Beek-Harmsen BJ, Boonstra A, Van Mechelen W, Visser FC, Van der Laarse WJ. Maximum rate of oxygen consumption related to succinate dehydrogenase activity in skeletal muscle fibres of chronic heart failure patients and controls. Clin Physiol Funct Imaging 2003; 23:337343.
  • 15
    Pina IL, Apstein CS, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, Fletcher BJ, et al. Exercise and heart failure: A statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation 2003; 107:12101225.
  • 16
    Negrao CE, Rondon MU, Tinucci T, Alves MJ, Roveda F, Braga AM, Reis SF, et al. Abnormal neurovascular control during exercise is linked to heart failure severity. Am J Physiol Heart Circ Physiol 2001; 280:H1286H1292.
  • 17
    Notarius CF, Ando S, Rongen GA, Floras JS. Resting muscle sympathetic nerve activity and peak oxygen uptake in heart failure and normal subjects. Eur Heart J 1999; 20:880887.
  • 18
    Grassi G, Vincenti A, Brambilla R, Trevano FQ, Dell'Oro R, Ciro A, Trocino G, et al. Sustained sympathoinhibitory effects of cardiac resynchronization therapy in severe heart failure. Hypertension 2004; 44:727731.
  • 19
    Hamdan MH, Barbera S, Kowal RC, Page RL, Ramaswamy K, Joglar JA, Karimkhani V, et al. Effects of resynchronization therapy on sympathetic activity in patients with depressed ejection fraction and intraventricular conduction delay due to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2002; 89:10471051.
  • 20
    Hamdan MH, Zagrodzky JD, Joglar JA, Sheehan CJ, Ramaswamy K, Erdner JF, Page RL, et al. Biventricular pacing decreases sympathetic activity compared with right ventricular pacing in patients with depressed ejection fraction. Circulation 2000; 102:10271032.
  • 21
    Cohen-Solal A. Cardiopulmonary exercise testing in chronic heart failure. In: Wasserman K (ed.): Cardiopulmonary Exercise Testing and Cardiovascular Health. Armonk, NY, Futura Publishing, 1996, pp. 1735.
  • 22
    Fagius J, Wallin BG. Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade. Clin Auton Res 1993; 3:201205.
  • 23
    Harrington D, Coats AJ. Skeletal muscle abnormalities and evidence for their role in symptom generation in chronic heart failure. Eur Heart J 1997; 18:18651872.
  • 24
    Sullivan MJ, Knight JD, Higginbotham MB, Cobb FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation 1989; 80:769781.
  • 25
    Drexler H. Skeletal muscle failure in heart failure. Circulation 1992; 85:16211623.
  • 26
    Kemp GJ, Thompson CH, Stratton JR, Brunotte F, Conway M, Adamopoulos S, Arnolda L, et al. Abnormalities in exercising skeletal muscle in congestive heart failure can be explained in terms of decreased mitochondrial ATP synthesis, reduced metabolic efficiency, and increased glycogenolysis. Heart 1996; 76:3541.
  • 27
    Chati Z, Zannad F, Jeandel C, Lherbier B, Escanye JM, Robert J, Aliot E. Physical deconditioning may be a mechanism for the skeletal muscle energy phosphate metabolism abnormalities in chronic heart failure. Am Heart J 1996; 131:560566.
  • 28
    Coats AJ, Clark AL, Piepoli M, Volterrani M, Poole-Wilson PA. Symptoms and quality of life in heart failure: The muscle hypothesis. Br Heart J 1994; 72(2 Suppl):S36S39.
  • 29
    Sterns DA, Ettinger SM, Gray KS, Whisler SK, Mosher TJ, Smith MB, Sinoway LI. Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation 1991; 84:20342039.
  • 30
    Sinoway LI, Li J. A perspective on the muscle reflex: Implications for congestive heart failure. J Appl Physiol 2005; 99:522.
  • 31
    Middlekauff HR, Chiu J, Hamilton MA, Fonarow GC, Maclellan WR, Hage A, Moriguchi J, et al. Muscle mechanoreceptor sensitivity in heart failure. Am J Physiol Heart Circ Physiol 2004; 287:H1937H1943.
  • 32
    Middlekauff HR, Sinoway LI. Point: Counterpoint: Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure. J Appl Physiol 2007; 102:492494.
  • 33
    Middlekauff HR. How does cardiac resynchronization therapy improve exercise capacity in chronic heart failure? J Card Fail 2005; 11:534541.
  • 34
    Adamopoulos S, Kemp GJ, Thompson CH, Arnolda L, Brunotte F, Stratton JR, Radda GK, et al. The time course of haemodynamic, autonomic and skeletal muscle metabolic abnormalities following first extensive myocardial infarction in man. J Mol Cell Cardiol 1999; 31:19131926.