Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases.

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.

Gut immune cells-A novel therapeutical target for cardiovascular disease?

Despite scientific and clinical advances during the last 50 years cardiovascular disease continues to be the main cause of death worldwide. Especially patients with diabetes display a massive increased cardiovascular risk compared to patients without diabetes. Over the last two decades we have learned that cardiometabolic and cardiovascular diseases are driven by inflammation. Despite the fact that the gastrointestinal tract is one of the largest leukocyte reservoirs of our bodies, the relevance of gut immune cells for cardiovascular disease is largely unknown. First experimental evidence suggests an important relevance of immune cells in the intestinal tract for the development of metabolic and cardiovascular disease in mice. Mice specifically lacking gut immune cells are protected against obesity, diabetes, hypertension and atherosclerosis. Importantly antibody mediated inhibition of leukocyte homing into the gut showed similar protective metabolic and cardiovascular effects. Targeting gut immune cells might open novel therapeutic approaches for the treatment of cardiometabolic and cardiovascular diseases.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

Effect of Atrial Fibrillation and Mitral Valve Gradients on Response to Percutaneous Mitral Valve Repair With the MitraClip System.

Both pre-existing atrial fibrillation (AF) and mitral valve pressure gradients (MVPG) created by MitraClip implantation have demonstrated predictive power for unfavorable outcomes. Therefore, we aimed to assess the impact of MVPG following MitraClip on outcomes in patients with and without AF. A total of 200 patients who underwent MitraClip implantation in our institution were enrolled. Echocardiography was obtained before and after the procedure. The primary endpoint of the study was all-cause mortality 1-year after MitraClip implantation. Secondary end points were clinical improvements in NYHA functional class and reduction in MR severity after MitraClip implantation. Two hundred patients (74 ± 10 years, left ventricular ejection fraction 41% ± 14%, logistic EuroSCORE I 21 ± 15) were enrolled into the final analysis. One hundred twelve patients (56%) had pre-existing AF. One-year all-cause mortality was 17% without any differences between patients with or without pre-existing AF. Comparing postprocedural MVPG of surviving and deceased patients, deceased patients with pre-existing AF exhibited significantly elevated postprocedural MVPG compared with surviving patients without AF (4.8 ± 2.1 mm Hg vs 3.6 ± 1.8 mm Hg; p = 0.010). ROC analysis and Kaplan-Meier survival curves identified significantly reduced survival in AF patients with postprocedural MVPG above 4.0 mm Hg (p = 0.011). After MitraClip, a MVPG above 4.0 mm Hg in patients with pre-existing AF was a significant outcome predictor in univariate and multivariate analysis. In conclusion, we identified a high-risk cohort characterized by postprocedural MVPG above 4.0 mm Hg and pre-existing AF predicting poor long-term outcome.

Microstructural cerebral lesions are associated with the severity of central sleep apnea with Cheyne-Stokes-respiration in heart failure and are modified by PAP-therapy.

This study investigated the association of microstructural cerebral lesions with central sleep apnea with Cheyne-Stokes-respiration (CSA-CSR) in heart failure (HF) patients and the effect of positive airway pressure therapy (PAP) of CSA-CSR on these lesions. PAP-therapy was initiated in patients with HF with midrange and with reduced ejection fraction (NYHA≥II; left ventricular ejection fraction <50%) and proven CSA-CSR. Cerebral magnetic resonance imaging (MRI) scans at 3T including diffusion tensor imaging were obtained before and after 4 months of PAP-therapy. Cerebral MRI scans revealed microstructural lesions in all 11 patients with HF with midrange or reduced ejection fraction and CSA-CSR (64±8years, 82% male, left ventricular ejection fraction 37±11%) that were focussed on the brainstem and frontal cerebral regions. This microstructural damage correlated with the severity of CSA-CSR and 4 months of PAP-therapy lead to voxel clusters of altered fiber integrity in these lesions. Microstructural cerebral lesions might contribute to the pathophysiology of CSA-CSR in HF. In these patients PAP-therapy induces neuronal plasticity.

The prognostic significance of serum sodium in a population undergoing cardiac resynchronisation therapy.

PURPOSE: To determine the prognostic implications of changes towards hyponatremia at varying time-points in the treatment of patients undergoing cardiac resynchronisation therapy (CRT). METHODS: A retrospective series of 249 patients was studied from 2002 to 2013. The population was categorized on the basis of serum sodium profile at baseline, at 1 month and at 6 month follow up visits following successful CRT implantation. The composite endpoint was all-cause mortality and heart failure hospitalisation (defined by the need for intravenous diuretic therapy) following CRT implantation. RESULTS: A total of 249 patients (67.8±12.5 years; NYHA class III/IV 75; LVEF 27.2±8.8%) were followed up for a median of 5.5 years. Hyponatremia at baseline, 1 month or 6 months follow up did not predict the composite endpoint. 26% of patients showed hyponatremia at baseline prior to CRT implantation, while it was present in 19.9% of patients 1 month (p=0.003) and in 16% (p<0.001) 6 months after CRT implantation. There was a significantly worse outcome for those patients who developed hyponatremia 6 months after CRT implantation. In multivariate analysis, the intake of loop diuretics (HR 1.76 [1.04-2.95], p=0.03) and renal impairment (urea>7.0mmol/l) (HR 1.61 [1.05-2.46], p=0.03) at baseline were associated with an increased risk of unplanned heart failure hospitalisation and all-cause mortality after CRT implantation. CONCLUSIONS: A change towards hyponatremia when observed 6 months after CRT implantation may predict a worse clinical outcome. Additionally, renal impairment and higher diuretic doses are associated with an increased risk of mortality in the population analysed.

Sleep duration and quality in heart failure patients.

PURPOSE: Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure and reduced left ventricular ejection fraction (HF-REF). SDB is classified as predominant obstructive (OSA) or central (CSA) and may alter sleep duration, sleep quality, and quality of life. This study describes sleep quality and duration in well-characterized cohorts of these patients. METHODS: Two hundred fifty consecutive patients with HF-REF (NYHA class ≥II, ejection fraction ≤45%) underwent cardiac and pulmonary examination, plus full attended in-hospital overnight polysomnography (PSG). PSG recordings were performed according to current recommendations and underwent independent, blinded analysis at a core laboratory. RESULTS: Patients with HF-REF and CSA were older and had more impaired cardiac function compared to those with OSA. With respect to sleep parameters, patients with CSA spent more time in bed than those with OSA (468 ± 52 vs 454 ± 46 min, p = 0.021) while sleep efficiency was lower (67 ± 14 vs 72 ± 13% of total sleep time (TST), p = 0.008). In addition, CSA patients spent more time awake after sleep onset (101 ± 61 vs 71 ± 46 min, p = 0.001) and had more stage N1 (light) sleep (33 ± 19 vs 28 ± 16% of TST, p = 0.017). Overall, the proportion of sleep spent in N3 (slow-wave/deep) sleep in HF-REF patients with SDB was low (4.1 ± 6.3% of TST) compared with healthy adults. CONCLUSIONS: HF-REF patients with CSA compared to OSA have worse sleep efficiency and quality. This could result in less restorative sleep, changes in sympathovagal balance, and impaired resetting of important reflexes, which might contribute to worse cardiovascular outcomes in HF-REF patients with SDB.

Improvements of central respiratory events, Cheyne-Stokes respiration and oxygenation in patients hospitalized for acute decompensated heart failure.

BACKGROUND: Sleep-disordered breathing (SDB), and Cheyne-Stokes respiration (CSR) in particular, are associated with reduced survival in patients with acute decompensated heart failure (ADHF). CSR cycle length (CL) has been shown to mirror heart failure severity and therefore may be a predictor of outcome. However, studies characterizing CSR in ADHF are rare and no study has investigated changes in CSR from admission to discharge in ADHF patients. METHODS: Consecutive patients admitted to our Academic Medical Center with ADHF were eligible. Study patients underwent two multichannel cardiorespiratory polygraphy (PG) recordings, one on admission and another during recompensation. RESULTS: 105 patients (age 71.5 ± 12.1 years, 66.7% male, NYHA class 3.2 ± 0.6, left ventricular ejection fraction 38.5 ± 13.3%, brain natriuretic peptide 1299 ± 1290 pg/ml); 77 had two fully analyzable PG recordings. CSA prevalence on the first PG was 77%. Based on the apnea-hypopnea index (AHI), CSA was mild, moderate or severe in 21%, 39% and 40% of patients, respectively. During ADHF treatment, AHI decreased non-significantly from 54 ± 17/h to 48 ± 9/h (p = 0.06), central hypopnea index from 20.9 ± 14/h to 17.1 ± 6.2/h (p < 0.01), and time spent in CSR from 65.5 ± 28.4 to 63.7 ± 17.8 min (p < 0.01); oxygenation improved from 91.4 ± 2.6% to 92.0 ± 1.5% (p < 0.05). There was no significant change in CL. CONCLUSIONS: Patients with ADHF have a high prevalence of central respiratory events, which decreased during cardiac recompensation. Cardiac recompensation also non-significantly improved the AHI and time spent in CSR and oxygenation, but had no clear impact on CSR CL, which leaves clinical account open to further investigation.

Impact of SERVE-HF on management of sleep disordered breathing in heart failure: a call for further studies.

Sleep disordered breathing (SDB) (obstructive sleep apnea, central sleep apnea/Cheyne-Stokes respiration or the combination of both) is highly prevalent in patients with a wide variety of cardiovascular diseases including hypertension, arrhythmia, coronary artery disease, myocardial infarction and stroke (reviewed previously in the September issue of this journal). Its close association with outcomes in chronic heart failure with reduced ejection fraction (HF-REF) suggests that it may be a potential treatment target. Herein, we provide an update on SDB and its treatment in HF-REF.

Acute improvement of pulmonary hemodynamics does not alleviate Cheyne-Stokes respiration in chronic heart failure-a randomized, controlled, double-blind, crossover trial.

OBJECTIVES: This randomized, controlled trial aimed to investigate whether acute improvement of pulmonary congestion would reduce the severity of Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF). METHODS: Twenty-one consecutive patients with CHF and CSR (apnea-hypopnea index [AHI] ≥15/h) underwent right heart catheterization with titration of intravenous (IV) glyceryltrinitrate (GTN) to a maximum tolerable dosage and inhalation of iloprost 10 µg/mL after a washout phase. Maximum tolerable dosages of GTN and iloprost were randomly applied during full cardiorespiratory polysomnography within two split-night procedures and compared with IV or inhaled sodium chloride (NaCl) 0.9 %, respectively. RESULTS: GTN (6.2 ± 1.5 mg/h) and iloprost significantly lowered \mean pulmonary artery pressure (20.1 ± 9.0 to 11.6 ± 4.2 mmHg, p < 0.001 and 16.9 ± 7.9 to 14.2 ± 6.4 mmHg, p < 0.01, respectively). Pulmonary capillary wedge pressure was only reduced by GTN (14.0 ± 5.6 to 7.2 ± 3.9 mmHg, p < 0.001), and there was no significant change in the cardiac index. Sleep studies revealed no significant improvement in markers of CSR severity, including AHI, central apnea index, and CSR cycle length following GTN or iloprost treatment. Significant decreases in blood pressure, mean oxygen saturation, and S3 sleep were documented during GTN infusion. CONCLUSIONS: Acute improvement of pulmonary congestion by GTN had no immediate impact on CSR severity. Future investigations must therefore include longer treatment periods and treatment regimens that have positive, rather than negative, additional effects on peripheral and central chemoreceptors and sleep structure. TRIAL REGISTRATION: German Clinical Trial Registry-ID:DRKS00000467 ( www.germanctr.de ).

Heterogenous haemodynamic effects of adaptive servoventilation therapy in sleeping patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers.

This study investigated the haemodynamic effects of adaptive servoventilation (ASV) in heart failure (HF) patients with Cheyne-Stokes respiration (CSR) versus healthy controls. Twenty-seven HF patients with CSR and 15 volunteers were ventilated for 1 h using a new ASV device (PaceWave™). Haemodynamics were continuously and non-invasively recorded at baseline, during ASV and after ventilation. Prior to the actual study, a small validation study was performed to validate non-invasive measurement of Stroke volume index (SVI). Non-invasive measurement of SVI showed a marginal overall difference of -0.03 ± 0.41 L/min/m(2) compared to the current gold standard (Thermodilution-based measurement). Stroke volume index (SVI) increased during ASV in HF patients (29.7 ± 5 to 30.4 ± 6 to 28.7 ± 5 mL/m(2), p < 0.05) and decreased slightly in volunteers (50.7 ± 12 to 48.6 ± 11 to 47.9 ± 12 mL/m(2)). Simultaneously, 1 h of ASV was associated with a trend towards an increase in parasympathetic nervous activity (PNA) in HF patients and a trend towards an increase in sympathetic nervous activity (SNA) in healthy volunteers. Blood pressure (BP) and total peripheral resistance response increased significantly in both groups, despite marked inter-individual variation. Effects were independent of vigilance. Predictors of increased SVI during ASV in HF patients included preserved right ventricular function, normal resting BP, non-ischaemic HF aetiology, mitral regurgitation and increased left ventricular filling pressures. This study confirms favourable haemodynamic effects of ASV in HF patients with CSR presenting with mitral regurgitation and/or increased left ventricular filling pressures, but also identified a number of new predictors. This might be mediated by a shift towards more parasympathetic nervous activity in those patients.

Respiratory effects of adaptive servoventilation therapy in patients with heart failure and Cheyne-Stokes respiration compared to healthy volunteers.

BACKGROUND: Nocturnal adaptive servoventilation (ASV) therapy is now frequently used to treat Cheyne-Stokes respiration (CSR), which is highly prevalent in patients with moderate-to-severe heart failure (HF) and characterized by periodical breathing (hyperventilation). OBJECTIVES: This study analyzed and compared the acute effects of a novel ASV device on carbon dioxide pressure (pCO2) and oxygen saturation (SaO2) in HF patients with CSR and healthy volunteers. The influence of being asleep or awake on the ASV algorithm was also determined. METHODS: All subjects underwent ASV (PaceWave™, ResMed) for 1 h. Transcutaneous pCO2 (PtcCO2) and SaO2 were assessed transcutaneously, while wakefulness was analyzed using EEG recordings. Assessments were made 30 min before and after ASV, and during 1 h of ASV. RESULTS: Twenty HF patients (19 male; age 79 ± 12 years) and 15 volunteers (13 male, age 25 ± 4 years) were included. When awake, ASV was associated with a trend towards a decrease in PtcCO2 and an increase in SaO2 versus baseline in HF patients (34.4 ± 3.2 to 33.7 ± 3.8 mm Hg and 93.8 ± 2.6 to 94.9 ± 2.6%, respectively) and volunteers (39.5 ± 3.0 to 38.2 ± 3.8 mm Hg and 96.9 ± 1.3 to 97.8 ± 0.9%). While asleep during ASV, PtcCO2 increased to 36.3 ± 3.8 mm Hg and SaO2 decreased to 93.8 ± 2.6% in HF patients, with similar changes in volunteers (PtcCO2 41.7 ± 3.0 mm Hg, SaO2 97.1 ± 1.2). All comparisons were statistically significant (p ≤ 0.05, except the PtcCO2 decrease in both groups when awake). CONCLUSIONS: ASV therapy might result in hyperventilation when subjects are awake, but while asleep, PtcCO2 increased to mid-normal values, effects that would be favorable in HF patients with CSR.

Performance of conventional and enhanced adaptive servoventilation (ASV) in heart failure patients with central sleep apnea who have adapted to conventional ASV.

PURPOSE: Adaptive servo-ventilation (ASV) is a positive pressure ventilator support system to normalize ventilation in patients with Cheyne-Stokes respiration (CSR). The latest generation enhanced ASV device (PaceWave; ResMed) has a new feature--auto-adjustment of EPAP. This study tested the hypothesis that enhanced ASV with auto-adjustment of EPAP (PaceWave) is non-inferior to conventional ASV (AutoSetCS). METHODS: This prospective, randomized, crossover, single-center study enrolled adult patients with stable heart failure (HF) and moderate-to-severe sleep-disordered breathing (SDB) who had been receiving conventional ASV therapy for at least 4 weeks. Patients received conventional ASV for one night and enhanced ASV on another night. Support settings for the two ASV devices were similar, with fixed expiratory positive airway pressure (EPAP) set to between 4 and 10 cm H2O and variable EPAP set to between 4 and 15 cm H2O. Full polysomnography was performed during ASV therapy on both nights. Endpoints were the number of nocturnal respiratory events and oxygen desaturations, and changes in blood pressure (BP). RESULTS: Levels of EPAP were comparable during the use of enhanced and conventional ASV, but minimum and maximum inspiratory pressure support values were significantly higher with the PaceWave device. All measures of apnea and hypopnea, and oxygen saturation, were significantly improved during ASV therapy with either device. There were no significant changes in BP or heart rate. CONCLUSIONS: Enhanced ASV is non-inferior to ASV with fixed EPAP in patients with chronic HF and CSR, with a trend towards better control of respiratory events.

Cheyne-Stokes respiration in heart failure: friend or foe? Hemodynamic effects of hyperventilation in heart failure patients and healthy volunteers.

OBJECTIVE: In patients with heart failure (HF), Cheyne-Stokes respiration (CSR) is characterized by chronic hyperventilation (HV) with low arterial partial pressure of carbon dioxide (pCO2). It is still unclear whether this HV represents a compensatory response to HF or an independent comorbidity. This study investigated the hemodynamic effects of HV in HF patients and volunteers. METHODS: A total of 15 volunteers [13 male, 25 ± 4 years, brain natriuretic peptide (BNP) <49 pg/mL, left ventricular rejection fraction (LVEF) >55 %) and 20 HF patients with reduced LVEF (15 male, 67.7 ± 12 years, NYHA class 2.6 ± 0.6, BNP 790 ± 818 pg/mL, LVEF 32.4 ± 7.3 %) were enrolled. Hemodynamics was monitored noninvasively in volunteers (TaskForce Monitor, CNSystems) and invasively in HF patients. RESULTS: During HV, the transcutaneous CO2 pressure in volunteers decreased from 38.7 ± 2.5 to 28.6 ± 3.3 mmHg (p < 0.001) and pCO2 in HF patients decreased from 33.6 ± 3.7 to 22.2 ± 3.2 mmHg (p < 0.001). There was a significant increase in cardiac output (CO) in both volunteers (6.2 ± 1.3-7.5 ± 1.3 L/min, p < 0.001) and HF patients (4.4 ± 1.3-5.0 ± 1.3 L/min), mainly as a result of an increase in heart rate (67.4 ± 7.6-82.8 ± 10.9/min, p < 0.001; and 77.2 ± 17.7-86.2 ± 22.4/min, p < 0.001, respectively); stroke volume (SV) was unchanged in volunteers (93.7 ± 19.6-93.8 ± 21.4 mL) and only slightly increased in HF patients (64.4 ± 28.7-68.5 ± 23.2 mL). CONCLUSIONS: CSR with associated HV may be a compensatory mechanism in patients with a failing heart. This compensatory mechanism includes an increase in heart rate, which might be deleterious in the long run.

Implications of revised AASM rules on scoring apneic and hypopneic respiratory events in patients with heart failure with nocturnal Cheyne-Stokes respiration.

STUDY OBJECTIVES: This study investigated the implications of the revised scoring rules of the American Academy of Sleep Medicine (AASM) in patients with heart failure (HF) with Cheyne-Stokes respiration (CSR). METHODS: Ninety-one patients (NYHA ≥II, LVEF ≤45 %; age 73.6 ± 11.3 years old; 81 male subjects) with documented CSR underwent 8 h of cardiorespiratory polygraphy recordings. Those were analyzed by a single scorer strictly applying the 2007 recommended, 2007 alternative, and the 2012 scoring rules. RESULTS: Compared with the AASM 2007 recommended rules, apnea-hypopnea index (AHI) and hypopnea index (HI) increased significantly when the 2007 alternative and 2012 rules were applied (AHI 34.1 ± 13.5/h vs 37.6 ± 13.2/h vs 38.3 ± 13.2/h, respectively; HI 10.2 ± 9.4/h vs 13.7 ± 10.7/h vs 14.4 ± 11.0/h, respectively; all p < 0.001). Duration of CSR increased significantly with the alternate versus recommended 2007 rules (182.2 ± 117.0 vs 170.1 ± 115.0 min; p ≤ 0.001); there was a significant decrease in CSR duration for the 2012 versus 2007 alternative rules (182.2 ± 117.0 vs 166.7 ± 115.4 min; p ≤ 0.001). CONCLUSION: AHI was higher using the AASM 2012 scoring rules due to a less strict definition of hypopnea. Data on the prognostic effects of CSR in patients with HF and the benefits of treatment are mostly based on the AASM 2007 recommended rules, so differences between these and the newer version need to be taken into account.

Validation of blood pressure monitoring using pulse transit time in heart failure patients with Cheyne-Stokes respiration undergoing adaptive servoventilation therapy.

PURPOSE: Using pulse transit time (PTT) and an ECG appears to be a promising alternative for invasive or noninvasive monitoring of blood pressure (BP). This study assessed the validity of PTT for BP monitoring in clinical practice. METHODS: Twenty-nine patients with chronic heart failure (HF; 27 male, 70.5 ± 9.9 years) and nocturnal Cheyne-Stokes respiration were noninvasively ventilated for one hour using adaptive servoventilation (ASV) therapy (PaceWave, ResMed). BP was measured using two devices (oscillometrically via Task Force Monitor, CNSystems and PTT via SOMNOscreen, Somnomedics) at least every 7 min for 30 min before, during, and after ASV. RESULTS: Mean systolic BP was 118.1 ± 14.4 mmHg vs. 115.9 ± 14.1 mmHg for oscillometric method vs PTT, respectively. Corresponding values for diastolic BP were 72.3 ± 10.3 mmHg and 69.4 ± 11.1 mmHg. While clinically comparable, differences between the two methods were statistically significant (p < 0.05). The difference between the two methods showed an increasing trend over time. A total of 18.5 % of PTT-based measurements could not be analyzed. The direction of a change in BP was opposite for PTT vs oscillometry for 17.0 % and 32.8 % of systolic and diastolic BP measurements, respectively. CONCLUSIONS: When monitoring BP in HF patients, overall BP monitoring using PTT is comparable to oscillometry for a period of 2 h (including a 1-h ASV phase). However, PTT shows a tendency to underestimate BP over time and during ASV.