Could CRT explain the increase in exercise capacity? Is CPET always required to assess the exercise capacity after CRT or is clinical evaluation accurate enough? Could an increase in peak VO₂ of 1 ml/kg/min be considered acceptable after CRT or is it inadequate?

Improvement of exercise capacity after CRT has been largely demonstrated [11, 13]. In heart failure patients with LBBB, the delayed activation of the left ventricular lateral wall induces a mechanical inter- and intraventricular dyssynchrony that additionally impairs the already decreased LVEF. Hemodynamic studies have shown, 1–3 months after CRT, improvement of the LVEF [14, 15], stroke volume, and SBP and reduction of the capillary pulmonary wedge pressure, mitral regurgitation [16], LV systolic and diastolic diameters [12, 17], and BNP concentrations [18]. Once these goals have been achieved, the neurohormonal blockade optimization [19] by drugs like beta-blockers, ACE inhibitors, or mineralocorticoid receptor antagonists becomes feasible.

In addition to cardiac hemodynamic improvement [20], CRT results in clinical benefits: increase of exercise capacity usually by one NYHA class, less hospitalizations [21], and better QoL scores [13]. All these benefits are usually recorded in the first 1–3 months after implantation [22].

Alongside enhanced cardiac hemodynamic, some peripheral mechanisms are also responsible for the increase in the patients’ exercise capacity; the acute increase in systolic blood pressure has a sympathoinhibitory effect, exerted through stimulation of the carotid baroreceptors and probably of the cardiopulmonary baroreceptors and muscular ergoreceptors [11]. The sympathetic nerve overstimulation, resulting in arteriolar constriction and decreased capillary blood flow, is the cornerstone of skeletal myopathy in heart failure, inducing reactive oxygen species release (favored by local hypoperfusion), inflammatory cytokine synthesis [4], with further protein loss, and abnormal apoptosis. Both direct assessment of MSNA (muscle nerve sympathetic activity) [23] or plasma epinephrine levels [24] and studies of HRV (heart rate variability) [25, 26] as marker of autonomic imbalance proved the decrease of sympathetic overstimulation after CRT. The latter was noted 3 months following the implantation and was associated with increase in 6 MWT distance or peak VO₂ during CPET [11].

The vascular endothelial function, impaired in HF patients, seems to be another pathway positively influenced by CRT in terms of exercise capacity improvement. Thus, RH-PAT (reactive hyperemia peripheral arterial tonometry) index increases with 20 % after CRT is added to optimal pharmacologic therapy [27, 28].

After CRT, the CPET is not imperative; however, the accurate assessment of exercise capacity gain [29] and prognosis as well as the best rehabilitation program outlines rely on the CPET parameters; therefore, it is recommended whenever possible.

In our patient, the exercise capacity was moderately increased (a VO₂ max improvement of only 1 ml/kg/min) at the lower border of the reported ranges (1.1–2.3 ml/kg/min), directly related to the baseline LVEF and duration of the disease [14, 30].

What are the possible determinants of less than expected improvement in exercise capacity after CRT?

In clinical trials, about 30 % of patients have no benefit from CRT (CRT non-responders) [31]. Certain documents concerning the best approach to CRT non-responders have shown that reevaluation of the CRT device (including pacing lead position and programmed parameters) should be considered along with optimization of the pharmacologic therapy as the main steps in this “troubleshooting algorithm” in order to achieve and maintain the clinical outcome [32].

The suboptimal technical results of CRT are primarily related to LV pacing lead placement limitations, caused by particular anatomy of the coronary sinus branches, scar proximity, or phrenic nerve stimulation, but also to suboptimal atrioventricular (AV) and right ventricle-to-left ventricle (RV-LV) delay [33].

In our patient, the poor improvement in exercise capacity was not determined by technical issues, all the parameters tested soon after implantation and at 4 weeks post-procedural evaluation being within normal range.

On the other hand, some clinical issues such as preexisting sedentary lifestyle and physical deconditioning could lead to a weaker and delayed response to CRT, but our patient has an active lifestyle.

Furthermore, the CRT non-responders should be evaluated for other well-known conditions such as chronic kidney disease, worsening of mitral regurgitation, new-onset atrial fibrillation, or myocardial ischemia (in the setting of coronary artery disease). All of them were ruled out in our case.

The third category includes conditions unrelated to abnormal cardiac performance, but certainly very common among HF patients [32]. These conditions are able to decrease the benefits of CRT.

Obesity increases oxygen consumption at rest; thus, the maximal effort capacity is reduced but our patient has normal weight. Chronic respiratory diseases, especially COPD [34, 35], contribute to the decrease in peak VO₂ by impairing the respiratory phase of oxygen transportation. Our patient performed spirometry, which showed normal values, and the ventilatory parameters were also within normal range during CPET; thus, a respiratory cause was improbable.

Anemia is another well-known cause for reduced effort capacity in heart failure patients. It could be the result of erythropoietin deficit, in this case erythropoietin treatment representing a feasible option for improving clinical status. More often anemia is due to iron deficit, which occurs long before the onset of anemia. This is why screening for iron deficiency by serum ferritin determination and parenteral iron replacement is largely recommended in HF patients [36].

In our patient, a moderate anemia was recorded (Hb = 10.3 g/dl, ferritin 30 ng/ml) as well as an iron deficiency of 489 mg. We therefore administered iv Ferinject (500 mg/10 ml), and after 4 weeks, the normalization of hemoglobin was achieved (Hb = 13.1 g/dl). An additional dose of 500 mg was administered to restore the iron reserve. This was followed by an improvement in clinical status. The patient noticed a better effort capacity and quality of life. Therefore we considered the patient can be included now in a physical training program.

What is the rationale of cardiac rehabilitation in CRT recipients considering that the resynchronization therapy by itself improves the exercise capacity?

The physical training in resynchronized HF patients is recommended because it further enhances exercise tolerance [37]. The COMPANION trial has reported an improvement of 24 % in exercise capacity [11], regardless of baseline characteristics of patients or disease severity.

These benefits result mainly from improvement of peripheral mechanisms involved during exercise, including skeletal muscle abnormalities (peripheral sympathetic nerve activity, inflammatory cytokines, endothelial dysfunction) [37, 38], the last being recorded after at least 3 months of cardiac rehabilitation [38]. Therefore, for the same myocardial oxygen consumption and cardiac output, endurance training provides additional benefits in terms of exercise capacity measured by parameters such as peak oxygen consumption (peak VO₂). Reverse left ventricular remodeling and increasing of cardiac output were also reported [12].

So, our patient was enrolled in a cardiac rehabilitation program designed for heart failure patients. The physical training was initiated in the Outpatient Department of the Clinical Rehabilitation Hospital.

A 6-month program consisting of three sessions/week was initiated. According to current guideline recommendations, each session was planned to consist of 5 mins warm-up and cool-down period and progressive 15–30 mins training on cycle, with progressive increase in exercise workload from 50 % peak VO₂ (HR = 80 bpm) to 70 % peak VO₂ (HR = 90–95 bpm). To calculate training HR, the heart rate reserve (HRR) was used because peak HR during CPET was low (treatment with carvedilol). During the rest of the days of the week, walking 2–3 km/hour, for 15–30 mins, was recommended.

Medical advice regarding lifestyle changes (dietary energy content, salt intake, smoking, and alcohol forbidden) was provided.

During cycle ergometer training, even if the heart rate increased appropriately, he tolerated the exercise poorly and complained of dyspnea, especially once the HR exceeded 80 bpm.

How can the unexpectedly decreased exercise tolerance be explained?

The debate comprises several issues: