[Central apneas and cardiovascular diseases]. / Apnee centrali e malattie cardiovascolari.

Central apneas (CA) and periodic breathing (PB) are the most common related breathing disorders in heart failure, being observed in up to 50% of patients. Once considered only a sleep-related phenomenon, actually CA/PB occur across the whole 24 h period and their presence in the awake patient even in the upright position and during physical effort has been associated with a worse clinical profile and a greater mortality. Chemoreflex activation, circulatory time delay and altered plant gain are the pathophysiological determinants. While the use of guideline-recommended medical and device treatment represents the first step in the management of CA in heart failure patients, no specific therapy has been demonstrated to reduce CA-related impact on mortality. In particular, the use of non-invasive ventilation has yielded contradictory results in the context of large-scale randomized clinical trials. The design and testing of therapies targeting the pathophysiological triggers of CA, such as chemoreflex sensitivity, may prove valuable in the next future.

Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure.

BACKGROUND: Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era. OBJECTIVES: This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments. METHODS: Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization. RESULTS: A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05). CONCLUSIONS: In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.

Central Apneas Are More Detrimental in Female Than in Male Patients With Heart Failure.

Background Central apneas (CA) are a frequent comorbidity in patients with heart failure (HF) and are associated with worse prognosis. The clinical and prognostic relevance of CA in each sex is unknown. Methods and Results Consecutive outpatients with HF with either reduced or mildly reduced left ventricular ejection fraction (n=550, age 65±12 years, left ventricular ejection fraction 32%±9%, 21% women) underwent a 24-hour ambulatory polygraphy to evaluate CA burden and were followed up for the composite end point of cardiac death, appropriate implantable cardioverter-defibrillator shock, or first HF hospitalization. Compared with men, women were younger, had higher left ventricular ejection fraction, had lower prevalence of ischemic etiology and of atrial fibrillation, and showed lower apnea-hypopnea index (expressed as median [interquartile range]) at daytime (3 [0-9] versus 10 [3-20] events/hour) and nighttime (10 [3-21] versus 23 [11-36] events/hour) (all P<0.001), despite similar neurohormonal activation and HF therapy. Increased chemoreflex sensitivity to either hypoxia or hypercapnia (evaluated in 356 patients, 65%, by a rebreathing test) was less frequent in women (P<0.001), but chemoreflex sensitivity to hypercapnia was a predictor of apnea-hypopnea index in both sexes. At adjusted survival analysis, daytime apnea-hypopnea index ≥15 events/hour (hazard ratio [HR], 2.70; 95% CI, 1.06-7.34; P=0.037), nighttime apnea-hypopnea index ≥15 events/hour (HR, 2.84; 95% CI, 1.28-6.32; P=0.010), and nighttime CA index ≥10 events/hour (HR, 5.01; 95% CI, 1.88-13.4; P=0.001) were independent predictors of the primary end point in women but not in men (all P>0.05), also after matching women and men for possible confounders. Conclusions In chronic HF, CA are associated with a greater risk of adverse events in women than in men.

Central apnoeas and ticagrelor-related dyspnoea in patients with acute coronary syndrome.

AIMS: Dyspnoea often occurs in patients with acute coronary syndrome (ACS) treated with ticagrelor compared with other anti-platelet agents and is a cause of drug discontinuation. We aimed to explore the contribution of central apnoeas (CA) and chemoreflex sensitization to ticagrelor-related dyspnoea in patients with ACS. METHODS AND RESULTS: Sixty consecutive patients with ACS, preserved left ventricular ejection fraction, and no history of obstructive sleep apnoea, treated either with ticagrelor 90 mg b.i.d. (n = 30) or prasugrel 10 mg o.d. (n = 30) were consecutively enrolled. One week after ACS, all patients underwent two-dimensional Doppler echocardiography, pulmonary static/dynamic testing, carbon monoxide diffusion capacity assessment, 24-h cardiorespiratory monitoring for hypopnoea-apnoea detection, and evaluation of the chemosensitivity to hypercapnia by rebreathing technique. No differences were found in baseline demographic and clinical characteristics, echocardiographic, and pulmonary data between the two groups. Patients on ticagrelor, when compared with those on prasugrel, reported more frequently dyspnoea (43.3% vs. 6.7%, P = 0.001; severe dyspnoea 23.3% vs. 0%, P = 0.005), and showed higher apnoea-hypopnoea index (AHI) and central apnoea index (CAI) during the day, the night and the entire 24-h period (all P < 0.001). Similarly, they showed a higher chemosensitivity to hypercapnia (P = 0.001). Among patients treated with ticagrelor, those referring dyspnoea had the highest AHI, CAI, and chemosensitivity to hypercapnia (all P < 0.05). CONCLUSION: Central apnoeas are a likely mechanism of dyspnoea and should be screened for in patients treated with ticagrelor. A drug-related sensitization of the chemoreflex may be the cause of ventilatory instability and breathlessness in this setting.

Central and Obstructive Apneas in Heart Failure With Reduced, Mid-Range and Preserved Ejection Fraction.

Background: Although central apneas (CA) and obstructive apneas (OA) are highly prevalent in heart failure (HF), a comparison of apnea prevalence, predictors and clinical correlates in the whole HF spectrum, including HF with reduced ejection fraction (HFrEF), mid-range EF (HFmrEF) and preserved EF (HFpEF) has never been carried out so far. Materials and methods: 700 HF patients were prospectively enrolled and then divided according to left ventricular EF (408 HFrEF, 117 HFmrEF, 175 HFpEF). All patients underwent a thorough evaluation including: 2D echocardiography; 24-h Holter-ECG monitoring; cardiopulmonary exercise testing; neuro-hormonal assessment and 24-h cardiorespiratory monitoring. Results: In the whole population, prevalence of normal breathing (NB), CA and OA at daytime was 40, 51, and 9%, respectively, while at nighttime 15, 55, and 30%, respectively. When stratified according to left ventricular EF, CA prevalence decreased (daytime: 57 vs. 43 vs. 42%, p = 0.001; nighttime: 66 vs. 48 vs. 34%, p < 0.0001) from HFrEF to HFmrEF and HFpEF, while OA prevalence increased (daytime: 5 vs. 8 vs. 18%, p < 0.0001; nighttime 20 vs. 29 vs. 53%, p < 0.0001). In HFrEF, male gender and body mass index (BMI) were independent predictors of both CA and OA at nighttime, while age, New York Heart Association functional class and diastolic dysfunction of daytime CA. In HFmrEF and HFpEF male gender and systolic pulmonary artery pressure were independent predictors of CA at daytime, while hypertension predicted nighttime OA in HFpEF patients; no predictor of nighttime CA was identified. When compared to patients with NB, those with CA had higher neuro-hormonal activation in all HF subgroups. Moreover, in the HFrEF subgroup, patients with CA were older, more comorbid and with greater hemodynamic impairment while, in the HFmrEF and HFpEF subgroups, they had higher left atrial volumes and more severe diastolic dysfunction, respectively. When compared to patients with NB, those with OA were older and more comorbid independently from background EF. Conclusions: Across the whole spectrum of HF, CA prevalence increases and OA decreases as left ventricular systolic dysfunction progresses. Different predictors and specific clinical characteristics might help to identify patients at risk of developing CA or OA in different HF phenotypes.

Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure.

BACKGROUND: Large trials using noninvasive mechanical ventilation to treat central apnea (CA) occurring at night ("sleep apnea") in patients with systolic heart failure (HF) have failed to improve prognosis. The prevalence and prognostic value of CA during daytime and over an entire 24-h period are not well described. OBJECTIVES: This study evaluated the occurrence and prognostic significance of nighttime, daytime, and 24-h CA episodes in a large cohort of patients with systolic HF. METHODS: Consecutive patients receiving guideline-recommended treatment for HF (n = 525; left ventricular ejection fraction [LVEF] of 33 ± 9%; 66 ± 12 years of age; 77% males) underwent prospective evaluation, including 24-h respiratory recording, and were followed-up using cardiac mortality as an endpoint. RESULTS: The 24-h prevalence of predominant CAs (apnea/hypopnea index [AHI] ≥5 events/h, with CA of >50%) was 64.8% (nighttime: 69.1%; daytime: 57.0%), whereas the prevalence of predominant obstructive apneas (OA) was 12.8% (AHI ≥5 events/h with OAs >50%; nighttime: 14.7%; daytime: 5.9%). Episodes of CA were associated with neurohormonal activation, ventricular arrhythmic burden, and systolic/diastolic dysfunction (all p < 0.05). During a median 34-month follow-up (interquartile range [IQR]: 17 to 36 months), 50 cardiac deaths occurred. Nighttime, daytime, and 24-h moderate-to-severe CAs were associated with increased cardiac mortality (AHI of 

Prediction of the Chemoreflex Gain by Common Clinical Variables in Heart Failure.

BACKGROUND: Peripheral and central chemoreflex sensitivity, assessed by the hypoxic or hypercapnic ventilatory response (HVR and HCVR, respectively), is enhanced in heart failure (HF) patients, is involved in the pathophysiology of the disease, and is under investigation as a potential therapeutic target. Chemoreflex sensitivity assessment is however demanding and, therefore, not easily applicable in the clinical setting. We aimed at evaluating whether common clinical variables, broadly obtained by routine clinical and instrumental evaluation, could predict increased HVR and HCVR. METHODS AND RESULTS: 191 patients with systolic HF (left ventricular ejection fraction--LVEF--<50%) underwent chemoreflex assessment by rebreathing technique to assess HVR and HCVR. All patients underwent clinical and neurohormonal evaluation, comprising: echocardiogram, cardiopulmonary exercise test (CPET), daytime cardiorespiratory monitoring for breathing pattern evaluation. Regarding HVR, multivariate penalized logistic regression, Bayesian Model Averaging (BMA) logistic regression and random forest analysis identified, as predictors, the presence of periodic breathing and increased slope of the relation between ventilation and carbon dioxide production (VE/VCO2) during exercise. Again, the above-mentioned statistical tools identified as HCVR predictors plasma levels of N-terminal fragment of proBNP and VE/VCO2 slope. CONCLUSIONS: In HF patients, the simple assessment of breathing pattern, alongside with ventilatory efficiency during exercise and natriuretic peptides levels identifies a subset of patients presenting with increased chemoreflex sensitivity to either hypoxia or hypercapnia.

Influence of central apneas and chemoreflex activation on pulmonary artery pressure in chronic heart failure.

BACKGROUND: Pulmonary artery hypertension (PH), associated with increased left ventricular (LV) diastolic pressure and pulmonary vasoconstriction, is frequently observed in heart failure (HF), where it holds prognostic significance. We hypothesized that Cheyne-Stokes respiration (CSR) may contribute to increased pulmonary arterartery pressure (PAP) and right ventricular (RV) remodeling in HF, via hypoxia/hypercapnia cycles and adrenergic activation by the chemoreflex stimulation. METHODS: Seventy-two HF patients (57 males, aged 65.1 SD 12.3 years, LV ejection fraction<50%, 33.2 SD 7.5%), on guideline recommended pharmacological/device treatment underwent thorough clinical, echocardiographic and neurohormonal assessment, 24-hour cardiorespiratory screening for arrhythmias and CSR, and chemoreflex test for hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses. RESULTS: Twenty patients (28%) showed significant CSR (24-hour apnea-hypopnea index, AHI≥15). Patients with CSR presented with: a) higher systolic pulmonary artery pressure (sPAP: 42.8 standard deviation-SD 10.1 vs 32.3 SD 5.7 mmHg, p<0.001), despite similar LV systolic and diastolic function; b) indexes of right chamber remodeling (all p<0.05); c) enhanced HVR (median 0.78, interquartile range-IR 0.46-1.22 vs 0.42, IR 0.18-0.67 L/min/%, p=0.01) and HCVR (1.17, IR 0.97-1.29 vs 0.72, IR 0.47-0.93 L/min/mmHg, p=0.02); d) increased plasma norepinephrine levels (690, IR 477-868 vs 366, IR 226-508 ng/L, p<0.001). Univariate predictors of sPAP>35 mmHg were AHI, HVR, HCVR; only AHI maintained its predictive value at multivariate analysis (p=0.017). CONCLUSIONS: CSR may contribute to increased pulmonary artery pressure and right chamber remodeling in HF, independently of the severity of LV systolic and diastolic dysfunction, likely via recurrent hypoxia/hypercapnia cycles and chemoreflex mediated adrenergic discharge.

Effect of acetazolamide on chemosensitivity, Cheyne-Stokes respiration, and response to effort in patients with heart failure.

Increased chemosensitivity to hypoxia and hypercapnia, together with a prolonged circulatory time, are the main determinants of Cheyne-Stokes (C-S) respiration in heart failure. To evaluate the effect of acetazolamide, a carbonic anhydrase inhibitor, on chemosensitivity and respiratory dynamics in patients with heart failure with C-S respiration, 12 patients (mean age 62 ± 9 years, mean left ventricular ejection fraction 24 ± 9%) and C-S respiration (mean apnea-hypopnea index 23 ± 13) who underwent 4 consecutive days of oral acetazolamide treatment (250 mg twice daily) were enrolled in this study. Assessment of chemosensitivity to hypoxia and hypercapnia, cardiopulmonary stress testing, 24-hour cardiorespiratory polygraphy, and neurohormonal characterization were performed at baseline and at the end of treatment. Acetazolamide improved central apneas (apnea-hypopnea index 23 ± 13 to 15 ± 9, p = 0.012) and the percentage of time spent below an arterial oxyhemoglobin saturation of 90% (16 ± 23% to 10 ± 18%, p = 0.005). Chemosensitivity to hypoxia was blunted (1.03 ± 0.69 to 0.78 ± 0.55 L/min/mm Hg, p = 0.032), while chemosensitivity to hypercapnia increased after acetazolamide (1.27 ± 0.71 to 1.54 ± 0.78 L/min/% arterial oxygen saturation, p = 0.023); patients achieved a lower workload (90 ± 30 to 81 ± 30 W, p <0.001), with no differences in peak oxygen consumption, while there was an increment in the regression slope relating minute ventilation to carbon dioxide output (39 ± 10 to 43 ± 9, p = 0.010). In conclusion, in patients with heart failure, acetazolamide diminishes C-S respiration and improves oxyhemoglobin saturation, likely by decreasing chemosensitivity to hypoxia. However, it is associated with reduced maximal workload achieved during effort and increased chemosensitivity to hypercapnia, inducing a reduction in the ventilatory efficiency.

Combined increased chemosensitivity to hypoxia and hypercapnia as a prognosticator in heart failure.

OBJECTIVES: The aim of the present study was to investigate the prognostic significance of chemosensitivity to hypercapnia in chronic heart failure (HF). BACKGROUND: Increased chemosensitivity to hypoxia and hypercapnia has been observed in HF. The potential value of enhanced chemosensitivity to hypercapnia to risk prediction in systolic HF has not been specifically evaluated. METHODS: One hundred ten consecutive systolic HF patients (age 62 +/- 15 years, left ventricular ejection fraction [LVEF] 31 +/- 7%) underwent assessment of chemosensitivity to hypoxia and hypercapnia (rebreathing technique) and were followed up for a median period of 29 months (range 1 to 54 months). The end point was a composite of cardiac death and aborted cardiac death (ventricular tachyarrhythmia treated by cardioverter-defibrillator). RESULTS: At baseline, 31 patients (28%) had enhanced chemosensitivity to both hypoxia and hypercapnia. Although they had the same LVEF as the 43 patients (39%) with normal chemosensitivity, they were more symptomatic (New York Heart Association functional class), had higher plasma brain natriuretic peptide and norepinephrine, steeper regression slope relating minute ventilation to carbon dioxide output (V(E)/V(CO2) slope), more Cheyne-Stokes respiration, and more ventricular arrhythmias (all p < 0.05). Four-year survival was only 49%, in marked contrast to 100% for patients with normal chemosensitivity (p < 0.001). On multivariate analysis, combined elevation in chemosensitivity was the strongest independent prognostic marker, even when adjusted for univariate predictors (V(E)/V(CO2) slope, Cheyne-Stokes respiration, LVEF, and brain natriuretic peptide, p < 0.05). CONCLUSIONS: Increased chemosensitivity to both hypoxia and hypercapnia, eliciting neurohormonal derangement, ventilation instability, and ventricular arrhythmias, is a very serious adverse prognostic marker in HF.

Effects of Alzheimer's disease and mild cognitive impairment on driving ability: a controlled clinical study by simulated driving test.

OBJECTIVE: To assess the effects of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) on simulated car driving ability. METHODS: Twenty patients with a probable AD of mild severity (Clinical Dementia Rating, CDR = 1) were compared with 20 subjects with MCI (CD = 0.5), and a group of age-matched neurologically normal controls on a driving simulation task. Measures of driving competence included the length of run, the number of infractions (omission of stop at pedestrian crossings, speed limits violation), the number of stops at traffic lights, the mean time to collision, and the number of off-road events. Results in the driving competence measures were correlated with scores obtained from simple visual reaction times and mini-mental state examination (MMSE). RESULTS: The patients with mild AD performed significantly worse than MCI subjects and controls on three simulated driving measures, length of run and mean time to collision (p < 0.001), and number of off-road events (p < 0.01). MCI subjects had only a significantly shorter time-to-collision than healthy controls (p < 0.001). Simple visual reaction times were significantly longer (p < 0.001) in patients with AD, compared to MCI and healthy controls, and showed a borderline significant relation (p = 0.05) with simulated driving scores. Driving performance in the three groups did not significantly correlate with MMSE score as measure of overall cognitive function. CONCLUSIONS: Mild AD significantly impaired simulated driving fitness, while MCI limitedly affected driving performance. Unsafe driving behaviour in AD patients was not predicted by MMSE scores.