Peak Exercise Cardiac Output but Not Oxygen Uptake Increases in All Heart Failure Patients After Successful Resynchronization Therapy

Objectives and Background: Hemodynamic changes at rest and during exercise in heart failure (HF) after cardiac resynchronization therapy (CRT) are still undefined. Methods: In 93 HF patients, before and 8 ± 3 months after CRT, we assessed clinical conditions, ECG and standard echocardiography and we performed a maximal cardiopulmonary exercise test with nonCardiol Cardiovasc Med 2020; 4 (4): 386-395 DOI: 10.26502/fccm.92920135 Cardiology and Cardiovascular Medicine Vol. 4 No. 4 August 2020. [ISSN 2572-9292] 387 invasive measurement of cardiac output (CO) by inert gas rebreathing method. Results: At rest, CRT shortened QRS and improved NYHA class and left ventricular ejection fraction (LVEF), but not CO and stroke volume (SV). On average, at peak exercise, a significant improvement of oxygen uptake (VO2) (from 13.8 ±3.8 ml/min/kg to 14.9 ±4.6, p<0.0025), CO (from 6.19 ±1.82 L/min to 6.97 ±2.21, p<0.0001), and SV (from 62 ±18 mL to 71 ±19, p<0.0001) were detected. Regardless of HF severity, after CRT, patients showed a significant peak SV and CO increase, but a significant peak VO2 increase was observed only in patients with the lowest pre-CRT peak VO2 (5.9-11.3 ml/kg/min). Conclusions: Our data showed that: a) SV at rest was not affected by CRT, regardless of LVEF improvement; b) post-CRT peak VO2 improvement was limited to HF patients with low pre-CRT peak VO2; c) post-CRT, a similar peak CO increase was observed regardless of pre-CRT peak VO2. Consequently, the assessment of peak CO is preferable to analyze CRT effects on exercise.


Introduction
Cardiac resynchronization therapy (CRT) is nowadays an established treatment for heart failure (HF) [1][2][3][4][5][6]. In the chronic setting, CRT is associated with NYHA class reduction [7], LV inverse remodeling, LV ejection fraction increase (EF) [8], and peak oxygen uptake (VO 2 ) increase [9][10][11], leading to mortality and morbidity improvement [12]. However, the precise hemodynamic mechanism by which CRT improves HF patients' condition, both at rest and during exercise, is still undefined. This study was conceived to assess whether and how CRT improves HF patients' hemodynamic patterns at rest and during exercise.

Study Population
We studied subjects belonging to a cohort of HF

Post-CRT evaluation:
After at least 6 months of follow-up (range 6-16), all patients underwent clinical and instrumental re-evaluation, performing a CPET with CO measurement at rest and at peak exercise and using the same ramp workload protocol of the pre-CRT test. Data analysis was performed considering the entire population and assessing patients with different exercise performance. To do so, patients were grouped considering pre-CRT tertiles of peak VO 2 .

Echocardiography
Standard two-dimensional, color, and spectral Doppler measurements were performed. No specific data on ventricular dissynchrony were collected. LVEF was determined using the Simpson's rule algorithm by tracing the left ventricular 2D-area in standard apical two-and four-chamber view at end-systole and end-diastole [13].

Ramp Protocol CPET
CPET was performed on a cycle ergometer with progressive work-rate increase in a ramp pattern, after 3 minutes of rest and 3 minutes of unloaded cycling.
Expiratory O 2 , carbon dioxide (CO 2 ), and ventilation were measured breath by breath (Innocor ® rebreathing system, Innovision A/S, Odense, Denmark). A 12-lead ECG was recorded continuously during the test (Marquette, Case800, Milwaukee, WI). Patients were strongly encouraged to perform a maximal test, allowing the final 30 seconds for the rebreathing maneuver. The work-rate increase during the test was set to achieve peak exercise in 8 to 10 minutes during the increasing work-rate period [14,15]. Peak VO 2 is reported as a mean over the last 20 seconds [15].

CO measurement
Non-invasive CO measurements were performed during CPET at baseline and at peak exercise using the Innocor rebreathing system (Innovision A/S, Odense, Denmark) [16][17][18][19][20][21]. The IGR technique uses an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide-N 2 O) and an inert insoluble gas (0.1% Sulphur Hexafluoride-SF6) from a pre-filled bag. Patients breathe into a respiratory valve via a mouthpiece and a bacterial filter with a nose clip. At the end of the expiration, the valve is activated, so that the patient rebreaths from the pre-filled bag for a period of 10-20 seconds. After this period, the patient is switched back to ambient air, and CO measurement is terminated.
Photo-acoustic analyzers measure gas concentration over a 5-breath interval. SF 6 is insoluble in blood, and it is used to determine lung volume. N 2 O is soluble in blood, and its concentration decreases during rebreathing with a rate proportional to pulmonary blood flow (PBF), that is the blood flow that perfuses the active part of the alveoli. CO is equal to PBF when the arterial oxygen saturation measure (SpO 2 ) is high

Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD). Differences between before and after CRT were evaluated by paired t-test. The differences between patients in tertiles of pre-CRT peak VO2 were measured by ANOVA. Tests were two sided.
P-values <0.05 were considered statistically significant.
Analyses were performed by SAS version 9.4 (SAS Institute Inc., Cary, NC).

Results
Of  Figure 3).
In brief, at rest, CRT improves LVEF but not CO or SV in all categories of HF. At peak exercise, CRT improves SV and CO in all patients, but it increases peak VO 2 only in severe HF patients (Figure 3). carbon dioxide production; AT: anaerobic threshold

Discussion
Our study evaluated a typical population of HF patients We non-invasively measured CO at rest and at peak exercise using IGR method. As regards the response to exercise, improvement following CRT has been shown in HF patients in NYHA class II to IV, and also in a few class I patients, i.e. across virtually all patients with symptomatic HF, without significant differences between NYHA classes [23,24]. Differently, peak VO 2 , which is the gold standard of exercise performance evaluation, has been reported to increase after CRT only in patients with severely reduced exercise performance(10) , and specifically in subjects with a peak VO 2 <12 ml/kg/min [9,11], suggesting inconsistency between NYHA class improvement and peak VO 2 changes. Our data confirm these findings, suggesting a low threshold of peak VO 2 in CRT responders (peak VO 2 <11.3 ml/min/kg).
The simultaneous measurement of VO 2 and CO during exercise is an advance in the post-CRT evaluation of HF patients. Indeed, knowing both CO and VO 2 allows calculating the ΔC(a-v)O 2 and, in practice, to discriminate between post-CRT change due to LV pump function improvement and improvement due to peripheral causes such as blood flow distribution, O 2 extraction, and muscle function [25]. Our data showed that peak CO increase after CRT is similar in all patients and unaffected by pre-CRT peak VO 2 , while peak VO 2 showed no significant increase after CRT in patients with peak VO 2 >11.3 ml/min/kg. The difference is by necessity associated with the behavior of ΔC(a-v)O 2 , which reflects muscle O 2 extraction, muscle function, and blood flow distribution during exercise. Notably, very similar data were observed in the post-HF rehabilitation setting [26]. Specifically, knowing the hemodynamic response to CRT during exercise opens a new scenario for patients with improved CO but similar VO 2 . We believe that post-CRT patients who increase their peak CO but not their peak VO 2 are likely a suitable target of an intensive rehabilitation program, which was not performed in the studied patients.
In conclusion, CRT improves exercise performance in HF patients by changing peak exercise CO and SV in all classes of HF patients. However, post CRT peak CO improvement translates into peak VO 2 improvement only in patients with severe HF.