Digital Theses Archive


Tesi etd-03292023-115824

Type of thesis
Modulation of sympathetic nerve activity by central sleep apnea in systolic heart failure
Scientific disciplinary sector
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
relatore Prof. PASSINO, CLAUDIO
  • cardiovascular disease
  • sleep disordered breathing
  • Sympathovagal balance
Exam session start date
Systolic heart failure (HF), despite progress in the pathophysiological understanding and development of novel treatment options, is still associated with significant morbidity and mortality. Enhanced sympathetic nerve activity (SNA) is a key pathophysiological determinant of HF progression, being associated with worse symptoms, functional status, arrhythmias and increased mortality, and it is currently a major target of pharmacological treatments recommended by current guidelines. However, several patients on HF treatment still present adrenergic overactivity, a phenomenon called adrenergic escape with prognostic significance. <br>Central apneas (CAs) are highly prevalent in patients with HF, both during the day and the night, and have been associated with adrenergic escape, arrhythmias and worse clinical and prognostic outcomes. CAs in HF often present in the form of Cheyne Stokes respiration (CSR), where apneas alternate with phases of hyperventilation in a periodic fashion, so to be named also periodic breathing. Unlike hyperventilation, CAs have been suggested to be a key mechanism of adrenergic overactivity in HF and were therefore considered a promising therapeutic target. While several studies have shown that CAs are associated with increased adrenergic drive, some other studies have challenged this assumption, associating the autonomic imbalance to the severity of HF rather than to CA/CSR. Moreover, mask-based therapies of CAs have failed to show any relevant benefits on HF mortality in large randomized controlled trials. This may be due to the specific treatment applied or to a neutral/beneficial effects of CAs in patients with HF.<br>There are several methods for assessing SNA in HF. One widely used method consists of the evaluation of heart rate and blood pressure variability, even though some complexity arises in interpreting such data considering a potential overlap with the vagal drive and the counfounding effects of HF treatment, as well as heterogenities in end-organ responses (heart and peripheral vessels). Assessment of muscle sympathetic nerve activity (MSNA) is commonly considered the gold standard metric for sympathetic outflow in humans, overcoming the above mentioned limitations, but is only available in few centers worldwide because it is time consuming and requires a high level of training. <br>The present PhD project therefore contributes to the understanding of the association of CAs with sympathetic nerve activity (SNA) in HF and the effect of treatments by mask based therapies on those mechanisms. <br>We showed that using a simulation approach, CA reproduced by different periods of breath hold during the daytime, results in increased SNA, reflected both indirectly by assessing heart rate variability (HRV) and directly by assessing MSNA. However, based on analyses concucted at nighttime in a sleep laboratory environment we showed that spontaneously occurring CA at nighttime does not per se lead to a net increase in SNA compared to normal breathing in patients with HF and CA, at least with indirect methods (HRV). This highlights that very likely different phenotypes of CA produce different impacts on SNA. As such, strikingly, we showed for the first time by using MSNA analysis that CA only cause an overall increase in SNA when embedded in a periodic breathing pattern with short hyperventilation phases and not in the case of long hyperventilation phases. The background to this is that during hyperventilation, venous return and thus cardiac output are increased, and sympathetic drive is known to be inhibited by phasic (but not static) changes in lung volume and by hypocapnia. Conversely, central apneas are presumed to lead to increased sympathetic drive mainly in response to apnea-related hypoxemia and hypercapnia but also to a lack of inhibitory drive from the stretch receptors located in the airways, lungs and chest wall.<br>In line with this preliminary data on the impact of CAs on muscle sympathetic nerve activity in systolic heart failure we showed that increased MSNA in patients with HF and CA can be seen during the end of CAs and at the beginning of the subsequent hyperventilation phase when chemoreflex-activation for coincident hypoxia and hypercapnia is greatest in particular. <br>To determine the impact of mask-based treatment on SNA in HF patients with apneas dedicated split night studies in a sleep laboratory environment as well as the analysis of a RCT were used. Based on split night investigation we showed that at nighttime effective treatment of CA by mask-based therapies did not result in a decrease in SNA. Furthermore, the treatment by mask-based therapies of obstructive apneas (notably obstructive apneas had been clearly shown to be associated with increased SNA in HF) was found not to produce a decrease in SNA, even after 6 months of treatment. Therefore, we provided mechanistic data to support the notion that while treatment of apneas in HF might be effective from a respiratory perspective (i.e. reduction in apneas) this is not necessarily associated with a desired decrease in SNA, neither in HF patients with obstructive apneas nor in HF patients with CA. <br>Future studies should investigate whether certain phenotypes of HF patients with apneas (i.e. those with short hyperventilation phases) may benefit from different treatments beyond mask-based therapy (i.e. phrenic nerve stimulation, oxygen delivery or drugs) also in terms of a desired decrease in SNA. Such future research could also address whether, potentially, SNA response to acute treatment in the lab could help stratify long term reduction in SNA following therapy.