Tesi etd-03302020-145522
Link copiato negli appunti
Tipo di tesi
Dottorato
Autore
MIRIZZI, GIANLUCA
URN
etd-03302020-145522
Titolo
Central Chemoreceptor Modulation in Systolic Heart Failure
Settore scientifico disciplinare
MED/11
Corso di studi
Istituto di Scienze della Vita - TRANSLATIONAL MEDICINE
Commissione
Membro Prof. PASSINO, CLAUDIO
Membro Prof. EMDIN, MICHELE
Membro Dott. GIANNONI, ALBERTO
Membro Dott.ssa BIANCIARDI, MARTA
Membro Prof. RECCHIA, FABIO ANASTASIO
Membro Prof. VANELLO, NICOLA
Membro Prof. EMDIN, MICHELE
Membro Dott. GIANNONI, ALBERTO
Membro Dott.ssa BIANCIARDI, MARTA
Membro Prof. RECCHIA, FABIO ANASTASIO
Membro Prof. VANELLO, NICOLA
Parole chiave
- Nessuna parola chiave trovata
Data inizio appello
16/06/2020;
Disponibilità
completa
Riassunto analitico
Background: Systolic heart failure (HF) represent a growing concern due to its high prevalence and the still dismal prognosis, despite modern therapeutic advances. Central apnea and Cheyne-Stokes respiration (CSR)represent a frequent companion of HF and further worsen prognosis in this population. Heightened chemoreflex sensitivity to hypercapnia, or central chemoreflex sensitivity (CCS) has been shown to represent the pathophysiological pillar of CA/CSR. Animal models have shown that serotonergic neurotransmission in the brainstem plays a pivotal role in modulating CCS in the physiological setting and also in the pathophysiological setting of CA.
Aim: the aim of this Thesis is three-fold: 1) retrospective evaluation of the impact of drugs modulating serotonergic neurotransmission, commonly prescribed for anxiety and depression disorder, on CA/CSR occurrence in systolic HF patients; 2) prospective evaluation of the effect of buspirone, a negative modulator of central serotonergic neurotransmission, on CA occurrence via modulation of CCS in a population of systolic HF patients with a double blind, crossover trial; 3) evaluation of the pattern of brainstem activation in patiens with systolic HF with and without CA/CSR with functional magnetic resonance imaging (fMRI).
Methods:
Part 1: retrospective analysis of inpatients and outpatients with systolic HF who underwent 24-h cardiorespiratory polygraphic recording for apnea detection, with collection of psychoactive drug therapy (benzodiazepine, selective-serotonin reuptake inhibitors - SSRI- and serotonin/noradrenalin reuptake inhibitors -SNRI-, antipsychotics) .
Part 2: prospective double blind, crossover trial of buspirone in patients with systolic HF. Patients underwent a 4-week trial with 1-week each exposure to buspirone (up to 45 mg daily) or placebo followed by 1-week washout with evaluation of CA occurrence via 24-h cardiorespiratory polygraphic recording and CCS evaluation with hypercapnic ventilatory response (HCVR). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events.
Part 3: fMRI of the brainstem of patients with systolic HF, with and without CA/CSR defined as the presence of a daytime apnea/hypopnea index (AHI) >15 events/h, with simultaneous recording of thoracic excursion and end-tidal CO2. fMRI data were assessed with independent component analysis (ICA) for the identification of components associated with etCO2 temporal series.
Results:
Part 1: among 667 patients with systolic HF screened, 438 had prevalently CA (>50% CA during 24-h). On average they were old (67±12 years), males (82%) and had severe left ventricular dysfunction (left ventricular ejection fraction -LVEF- 30±9%). Median 24-h AHI was 25 events/h, interquartile range (i.r.) 14-37. Psychoactive treatments were prescribed to 25% of the patients, mainly SSRI/SNRI (11%) and benzodiazepines (11%). In patients with more severe forms of CA, identified by an AHI>15 events/H, either during nighttime, daytime of 24-h, no differences were found in psychoactive treatments; similarly, patients on and off psychoactive treatments had no differences in CA prevalence.
Part 2: sixteen consecutive patients with systolic HF and CA/CSR were enrolled. Patients were on average old (71.3±5.8 y), were all males and had a severe left ventricular dysfunction (LVEF 29.8±7.8 %). In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction > 0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%); difference between groups 43%, 95% CI 14-73%, p=0.016. Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (p=0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all p<0.01); no difference was observed after placebo administration (all p>0.05). No patient reported buspirone-related serious adverse events.
Part 3: twelve patients were enrolled; 3 patients were excluded for the detection of incidentalomas hampering fMRI acquisition and 1 was excluded for inadequate image quality. fMRI was then performed in all 8 patients (66±4 years, LVEF 33±8%, ischaemic cardiomyopathy 78%), 4 with and 4 without CA/CSR. ICA identified 5 component, 3 of which localized at the level of the rostral ventrolateral medulla, common to both CA/CSR patients and NB, and two at the level of the medulla oblongata, near the medullary raphe, specific of patients with CA/CSR.
Conclusions: in this thesis, for the first time the impact of therapies modulating CCS was assessed in patients with systolic HF. While commonly prescribed psychoactive drugs such as SSRI/SNRI had no apparent influence on CA occurrence, one week treatment with buspirone had consistent effects, both in magnitude and direction, on CCS and on CA occurrence; if confirmed on a larger scale and with harder endopoint, these observations could pave the way to a completely new treatment approach in patients with systolic HF and CA. Furthermore, the fMRI data, albeit obtained on a small cohort of patients, consistently evidence that areas known to include serotonergic neurons are more active in patients with systolic HF, especially in those with manifest CA/CSR.
Aim: the aim of this Thesis is three-fold: 1) retrospective evaluation of the impact of drugs modulating serotonergic neurotransmission, commonly prescribed for anxiety and depression disorder, on CA/CSR occurrence in systolic HF patients; 2) prospective evaluation of the effect of buspirone, a negative modulator of central serotonergic neurotransmission, on CA occurrence via modulation of CCS in a population of systolic HF patients with a double blind, crossover trial; 3) evaluation of the pattern of brainstem activation in patiens with systolic HF with and without CA/CSR with functional magnetic resonance imaging (fMRI).
Methods:
Part 1: retrospective analysis of inpatients and outpatients with systolic HF who underwent 24-h cardiorespiratory polygraphic recording for apnea detection, with collection of psychoactive drug therapy (benzodiazepine, selective-serotonin reuptake inhibitors - SSRI- and serotonin/noradrenalin reuptake inhibitors -SNRI-, antipsychotics) .
Part 2: prospective double blind, crossover trial of buspirone in patients with systolic HF. Patients underwent a 4-week trial with 1-week each exposure to buspirone (up to 45 mg daily) or placebo followed by 1-week washout with evaluation of CA occurrence via 24-h cardiorespiratory polygraphic recording and CCS evaluation with hypercapnic ventilatory response (HCVR). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events.
Part 3: fMRI of the brainstem of patients with systolic HF, with and without CA/CSR defined as the presence of a daytime apnea/hypopnea index (AHI) >15 events/h, with simultaneous recording of thoracic excursion and end-tidal CO2. fMRI data were assessed with independent component analysis (ICA) for the identification of components associated with etCO2 temporal series.
Results:
Part 1: among 667 patients with systolic HF screened, 438 had prevalently CA (>50% CA during 24-h). On average they were old (67±12 years), males (82%) and had severe left ventricular dysfunction (left ventricular ejection fraction -LVEF- 30±9%). Median 24-h AHI was 25 events/h, interquartile range (i.r.) 14-37. Psychoactive treatments were prescribed to 25% of the patients, mainly SSRI/SNRI (11%) and benzodiazepines (11%). In patients with more severe forms of CA, identified by an AHI>15 events/H, either during nighttime, daytime of 24-h, no differences were found in psychoactive treatments; similarly, patients on and off psychoactive treatments had no differences in CA prevalence.
Part 2: sixteen consecutive patients with systolic HF and CA/CSR were enrolled. Patients were on average old (71.3±5.8 y), were all males and had a severe left ventricular dysfunction (LVEF 29.8±7.8 %). In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction > 0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%); difference between groups 43%, 95% CI 14-73%, p=0.016. Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (p=0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all p<0.01); no difference was observed after placebo administration (all p>0.05). No patient reported buspirone-related serious adverse events.
Part 3: twelve patients were enrolled; 3 patients were excluded for the detection of incidentalomas hampering fMRI acquisition and 1 was excluded for inadequate image quality. fMRI was then performed in all 8 patients (66±4 years, LVEF 33±8%, ischaemic cardiomyopathy 78%), 4 with and 4 without CA/CSR. ICA identified 5 component, 3 of which localized at the level of the rostral ventrolateral medulla, common to both CA/CSR patients and NB, and two at the level of the medulla oblongata, near the medullary raphe, specific of patients with CA/CSR.
Conclusions: in this thesis, for the first time the impact of therapies modulating CCS was assessed in patients with systolic HF. While commonly prescribed psychoactive drugs such as SSRI/SNRI had no apparent influence on CA occurrence, one week treatment with buspirone had consistent effects, both in magnitude and direction, on CCS and on CA occurrence; if confirmed on a larger scale and with harder endopoint, these observations could pave the way to a completely new treatment approach in patients with systolic HF and CA. Furthermore, the fMRI data, albeit obtained on a small cohort of patients, consistently evidence that areas known to include serotonergic neurons are more active in patients with systolic HF, especially in those with manifest CA/CSR.
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