Pulmonary congestion due to heart failure causes abnormal lung function. Cardiac resynchronization therapy (CRT) is a proven effective treatment for heart failure. The aim of this study was to test the hypothesis that CRT promotes increased lung volumes, bronchial conductance, and gas diffusion. Forty-four consecutive patients with heart failure were prospectively investigated before and after CRT. Spirometry, gas diffusion (diffusing capacity for carbon monoxide), cardiopulmonary exercise testing, New York Heart Association class, brain natriuretic peptide, the left ventricular ejection fraction, left atrial volume, and right ventricular systolic pressure were assessed before and 4 to 6 months after CRT. Pre- and post-CRT measures were compared using either paired Student’s t tests or Wilcoxon’s matched-pair test; p values <0.05 were considered significant. Improved New York Heart Association class, left ventricular ejection fraction, left atrial volume, right ventricular systolic pressure, and brain natriuretic peptide were observed after CRT (p <0.05 for all). Spirometry after CRT demonstrated increased percentage predicted total lung capacity (90 ± 17% vs 96 ± 15%, p <0.01) and percentage predicted forced vital capacity (80 ± 19% vs 90 ± 19%, p <0.01). Increased percentage predicted total lung capacity was significantly correlated with increased peak exercise end-tidal carbon dioxide (r = 0.43, p = 0.05). Increased percentage predicted forced vital capacity was significantly correlated with decreased right ventricular systolic pressure (r = −0.30, p = 0.05), body mass index (r = −0.35, p = 0.02) and creatinine (r = −0.49, p = 0.02), consistent with an association of improved bronchial conductance and decreased congestion. Diffusing capacity for carbon monoxide did not significantly change. In conclusion, increased lung volumes and bronchial conductance due to decreased pulmonary congestion and increased intrathoracic space contribute to an improved breathing pattern and decreased hyperventilation after CRT. Persistent alveolar-capillary membrane remodeling may account for unchanged diffusing capacity for carbon monoxide.
Previous studies regarding the effects of cardiac resynchronization therapy (CRT) on pulmonary function have been limited. The hallmark of symptom alleviation subsequent to heart failure (HF) therapy is decreased dyspnea. We hypothesized that CRT promotes increased lung volumes, bronchial conductance, and gas diffusion. Accordingly, the aim of this study was to quantify pulmonary function in patients with HF before and after clinically indicated CRT.
Methods
Patients referred for clinically indicated CRT were screened for recruitment. All subjects met established clinical criteria for CRT, including QRS duration ≥130 ms, New York Heart Association class II to IV HF, and a left ventricular ejection fraction ≤35% despite optimal pharmacotherapy for ≥3 months. All participants gave written informed consent after being provided a description of study requirements. This study was approved by the Mayo Clinic Institutional Review Board.
Pulmonary function testing measurements were performed at baseline 1 to 2 days before CRT implantation and at clinically indicated follow-up 4 to 6 months after CRT. Pulmonary function measurements included total lung capacity, vital capacity, residual volume, alveolar volume, forced vital capacity (FVC), forced expiratory volume at 1 second, maximal forced expiratory flow (FEF), FEF at 25% to 75% of vital capacity (FEF 25%–75%), and single-breath diffusing capacity for carbon monoxide. Spirometric and diffusing capacity for carbon monoxide data were collected in accordance with American Thoracic Society standards.
Exercise ventilation and gas exchange were assessed by metabolic cart (Medical Graphics, St. Paul, Minnesota) during cardiopulmonary exercise testing. Measures included peak oxygen consumption, carbon dioxide output, end-tidal carbon dioxide, tidal volume, minute ventilation, and breathing frequency. Derived measures included ventilatory efficiency, defined as minute ventilation/carbon dioxide output. Tidal volume and minute ventilation were also normalized to vital capacity to evaluate changes of breathing pattern during exercise in patients before and after CRT.
For statistical analysis, the Shapiro-Wilk test, paired Student’s t test or Wilcoxon’s test, Mann-Whitney U test or unpaired Student’s t test, 2-tailed Fisher’s exact test, and Pearson’s or Spearman’s rank correlation were used. Data are summarized as mean ± SD; p values <0.05 were considered statistically significant. Statistical analysis was performed using Statistica version 10.0 (StatSoft Inc., Prague, Czech Republic) and SAS (SAS Institute Inc., Cary, North Carolina).
Results
The mean age of the pre-CRT subjects (n = 44) was 66 ± 12 years. They were predominantly men (75%) in New York Heart Association class III (89%), with low left ventricular ejection fractions (24 ± 7%), markedly decreased peak oxygen consumption (13 ± 3 ml/kg), and elevated brain natriuretic peptide (2,216 ± 7,093 pg/ml). The cause of HF was ischemic in 49%. Changes after 4 to 6 months are listed in Table 1 . There were no changes in HF medications ( Table 1 ), including mean furosemide dose, after CRT (51 ± 46 vs 55 ± 50 mg/day, p = 0.33). New York Heart Association class improved by ≥1 functional class in 66% of patients, which is similar to the response rates previously published in larger studies.
| Parameter | Pre-CRT | Post-CRT | p Value |
|---|---|---|---|
| BMI (kg/m 2 ) | 28 ± 5 | 28 ± 4 | 0.45 |
| New York Heart Association class | 3 ± 0.3 | 2 ± 0.8 | <0.01 |
| Left ventricular ejection fraction (%) | 24 ± 7 | 32 ± 13 | <0.01 |
| Left atrial volume (n = 41) (cm 3 ) | 123 ± 52 | 110 ± 50 | 0.02 |
| Left ventricular diastolic diameter (mm) | 67 ± 10 | 64 ± 12 | <0.01 |
| Right ventricular systolic pressure (n = 42) (mm Hg) | 46 ± 13 | 40 ± 12 | <0.01 |
| Brain natriuretic peptide (n = 40) (pg/ml) | 2,216 ± 7,093 | 977 ± 1,616 | <0.01 |
| Creatinine (mg/dl) | 1.3 ± 0.4 | 1.2 ± 0.4 | 0.10 |
| Medications | |||
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 41 (93%) | 40 (91%) | 0.99 |
| Digoxin | 21 (48%) | 24 (55%) | 0.67 |
| β blockers | 42 (95%) | 42 (95%) | 1.00 |
| Diuretics | 35 (80%) | 36 (82%) | 1.00 |
Pulmonary function testing after CRT showed improvements in static and dynamic parameters for absolute and percentage predicted values ( Tables 2 and 3 ). Mean expiratory maximal flow-volume loops after CRT demonstrated decreased pulmonary restriction and increased bronchial conductance ( Figure 1 ). The improvement of static and dynamic pulmonary function parameters after CRT was significantly correlated with the changes in several exercise parameters, body mass index (BMI), creatinine concentration, and right ventricular systolic pressure ( Table 4 ).
| Parameter | Pre-CRT | Post-CRT | p Value |
|---|---|---|---|
| Total lung capacity (n = 40) (L) | 5.7 ± 1.3 | 6.0 ± 1.2 | <0.01 |
| Residual volume (n = 40) (L) | 2.5 ± 0.8 | 2.7 ± 0.9 | <0.01 |
| Vital capacity (L) | 3.3 ± 0.9 | 3.4 ± 0.8 | 0.10 |
| Alveolar volume (L) | 4.8 ± 1.0 | 4.9 ± 1.0 | 0.04 |
| FVC (L) | 3.2 ± 0.8 | 3.2 ± 0.8 | 0.76 |
| Forced expiratory volume at 1 second (L) | 2.3 ± 0.7 | 2.4 ± 0.7 | 0.11 |
| FEF 25%–75% (L/s) | 1.7 ± 0.9 | 1.8 ± 1.1 | 0.04 |
| Maximal FEF (L/s) | 7.4 ± 1.9 | 7.6 ± 2.0 | 0.08 |
| Diffusing capacity for carbon monoxide (ml/min/mm Hg) | 18 ± 7 | 17 ± 5 | 0.18 |
| Parameter | Pre-CRT | Post-CRT | p Value |
|---|---|---|---|
| Total lung capacity (%) (n = 40) | 90 ± 17 | 96 ± 15 | <0.01 |
| Residual volume (%) (n=40) | 113 ± 31 | 121 ± 31 | <0.01 |
| Vital capacity (%) | 81 ± 18 | 82 ± 18 | 0.17 |
| Alveolar volume (%) | 79 ± 15 | 81 ± 14 | 0.08 |
| FVC (%) | 80 ± 19 | 90 ± 19 | <0.01 |
| Forced expiratory volume at 1 second (%) | 73 ± 19 | 75 ± 20 | 0.15 |
| FEF 25%–75% (%) | 59 ± 29 | 65 ± 36 | 0.04 |
| Maximal FEF (%) | 98 ± 23 | 101 ± 23 | 0.24 |
| Diffusing capacity for carbon monoxide (%) | 69 ± 16 | 68 ± 15 | 0.21 |
| Parameter (Δ) | r | p |
|---|---|---|
| Static parameters | ||
| Total lung capacity | ||
| Rest breathing frequency | −0.35 | 0.04 |
| Peak partial pressure of end-tidal carbon dioxide | 0.35 | 0.05 |
| Total lung capacity (%) | ||
| Peak partial pressure of end-tidal carbon dioxide | 0.43 | 0.05 |
| Residual volume | ||
| Peak partial pressure of end-tidal carbon dioxide | 0.43 | 0.05 |
| Residual volume (%) | ||
| Peak ventilatory efficiency | −0.35 | 0.05 |
| Alveolar volume | ||
| Rest breathing frequency | −0.35 | 0.03 |
| Dynamic parameters | ||
| FVC (%) | ||
| BMI | −0.35 | 0.02 |
| Creatinine | −0.49 | 0.02 |
| Right ventricular systolic pressure | −0.30 | 0.05 |
| FEF 25%–75% | ||
| BMI | −0.53 | <0.01 |
| FEF 25%–75% (%) | ||
| BMI | −0.51 | <0.01 |
Subjects after CRT had improved breathing patterns (higher tidal volume and lower breathing frequency; Figure 2 ), breathed more efficiently (lower minute ventilation/carbon dioxide output), and had less hyperventilation (higher end-tidal carbon dioxide) and higher oxygen consumption ( Table 5 ).
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