It remains unclear how cardiac resynchronization therapy (CRT) improves symptom status in heart failure population. CRT is one of the major treatment for patients suffering from refractory heart failure (HF) despite an optimal drug regimen [
Physiopathological determinants of such an hyperventilation remain unclear. Nevertheless, an important cause of hyperpnea during effort is the enlargement of physiological dead space and ventilation-perfusion mismatch by alveolar hypoperfusion from hemodynamic dysfunction. Another determinant is the early cardiorespiratory reflex dysregulation. This was evidenced by increased peripheral and central chemosensitivity, impaired sympathovagal balance with sympathetic predominance, and depressed baroreflex circulation control [
We suggest that reduction in exaggerated hyperventilation during exercise in HF population after CRT is linked to an improvement in musculature metabolism, which results in increasing oxidative metabolism, reducing the respiratory exchange ratio at peak of the exercise, and improving the time to anaerobic threshold (AT).
Fifty consecutive refractory HF patients were enrolled in this single center investigation. All those patients matched the following criteria: indication for CRT implantation according to current indications (QRS duration >120 ms, LV ejection fraction <35%, NYHA symptom class II-III or IV, and optimal heart failure medical regimen) [
Echocardiograms were loaded into a computer system (Echopac, GE), and all measurements were obtained for all patients at baseline and 6 months after implantation. Echocardiograms were analyzed by a single experienced sonographer.
Sample loops were analyzed off line on an Echopac computer workstation to obtain end-diastolic (EDV) and end-systolic LV (ESV) volumes using the methods of disks. Ejection fraction was calculated as follows:
A symptom-limited exercise test with ventilatory expired gas analysis using a cycle ergometer with a 10 Watts/minute protocol was performed in all patients in an air conditioned room (Ergo Card, Medisoft, Sorinnes, Belgium). Continuous standard 12 lead electrocardiograms, manual blood pressure measurements, and heart rate recordings were monitored at every stage. Data for oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), respiratory rate (RR), and work load were collected continuously throughout the exercise. Oxygen and carbon dioxide sensors were calibrated using gases with known oxygen, nitrogen, and carbon dioxide concentrations prior to each test. Ventilatory efficiency was obtained by the linear regression slope relating VE to VCO2 from the beginning to the peak of the effort [
The peak circulatory power was measured as an evaluation of the cardiac pumping function by the product of the peak VO2 and the systolic blood pressure as described by Cohen-Solal et al. [
the responders and the nonresponders to the CRT were characterized. The responder subgroup was defined as having a telesystolic LV volume reduction greater than 15% after CRT [
Paired t tests were used to compare differences between parameters at baseline and after CRT. All statistical tests with a
Baseline characteristics of patients included are summarized in Table
Population characteristics before and after CRT.
Baseline | 6-month followup | ||
---|---|---|---|
Subjects | 50 | ||
38 (76%) | |||
12 (24%) | |||
Age, yrs | |||
Left ventricular ejection fraction, % | <.01 | ||
Etiology | |||
23 (46%) | |||
27 (54%) | |||
SBP at rest, mmHg | >.05 | ||
SBP at peak, mmHg | >.05 | ||
HR at rest, bpm | <.05 | ||
HR at peak, bpm | >.05 | ||
Peak of VO2, ml/kg/min | <.05 | ||
VE/VCO2 slope | <.05 | ||
AT (seconds) | .01 | ||
AT VO2 | <.05 | ||
Peak CP, mmHg | <.01 | ||
Maximal work load, Watts | <.05 | ||
Peak RER | <.05 | ||
Peak respiratory rate, /min | .01 | ||
Exercise duration, seconds | .01 | ||
NYHA class | <.01 | ||
Left ventricular end-systolic volume, ml | <.01 | ||
Left ventricular end-diastolic volume, ml | <.01 | ||
Mitral regurgitation, grade | <.05 | ||
QRS duration, ms | |||
Beta-blocker, % | 95 | ||
Diuretic, % | 83 | ||
Angiotensin-converting enzym inhibitor, % | 85 |
AT: anaerobic threshold, CP: circulatory power, HR: heart rate, Ms: milliseconds, NYHA: New York Heart Association, RER: respiratory exchange ratio, SBP: Systolic blood pressure, VCO2: carbon dioxide production, VE: minute ventilation, VO2: oxygen consumption, and yrs: years.
At 6 months, mean values of NYHA,peak VO2, VE/VCO2 slope and RER at the peak were
23 patients (18 males,
In this population, NYHA symptom was improved from
27 patients (20 males,
NYHA symptom class was improved from
Reduction in the RER at peak (despite significant increase in exercise parameters) and improvement in the time to AT suggest a postponed muscular anaerobic metabolism during exercise 6 months after CRT, in particular in responder subgroup.
It was clearly confirmed that patients suffering from heart failure have muscular dysfunctions leading to an early anaerobic metabolism with a high production in carbon dioxide and a reduction in the oxygen consumption during exercise [
In our investigation, the ventilatory response evaluated by the linear regression slope relating the minute ventilation to the carbon dioxide production was significantly improved in particular in the responder subgroup as previously described [
In addition, left ventricular volumes and ejection fraction were improved as well as the peak circulatory power. This simple haemodynamic noninvasive parameter was described to be a close approach of the “cardiac power” (production of both the cardiac output and the main blood pressure) for the evaluation of the cardiac pumping function. The peak CP was measured by the product of the peak VO2 and the SBP at peak of the exercise as described previously. It was confirmed that the peak CP is a strong prognostic marker in heart failure population. It incorporates arteriovenous difference, heart rate, stroke volume, and blood pressure responses at peak of the exercise [
In the nonresponder subgroup, no significant improvement was found in the haemodynamic parameters (LV ejection fraction, peak circulatory power) associated with a nonsignificant improvement in both exercise capacity and ventilatory response. In addition, in this population no significant decrease in peak RER and in time to AT was found, suggesting a persistent early muscular anaerobic metabolism.
We suggest that CRT leads to an improvement in peripheral blood flow by better haemodynamic conditions. It could lead to a shift from fast-twitch-type 2 B fibres to slow-twitch-type 1 fibres with an increase in oxidative metabolism, in mitochondrial density, and in oxygen consumption and in reduction in carbon dioxide production resulting in a postponed AT and in lower peak RER.
Muscular biopsies with mitochondrial density, oxidative enzymes, and capillary density measurements are needed to confirm our data. We could correlate biopsy results with ventilatory response and time to AT after CRT. The lack of histology support was the main limitation in our investigation. In addition, this prospective study was not a randomized control trial.
CRT improves haemodynamic condition and exercise capacity and reduces the ventilatory response during effort. In addition, CRT decreases the peak respiratory exchange ratio suggesting the possibility of increased efficiency of energy production in skeletal muscle with less anaerobic metabolism by a shift from a glycolytic to an oxidative metabolism. Link between the improvement in the peak RER, the ventilatory data, and the haemodynamic parameters suggests a reduction in the sympathetic tone explained by a decrease in the ergoreflex activity. But, large further studies are needed to confirm our data.