Rami Khayat

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

An important determinant of [H+] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO2 would lead to hyperventilation and an increased ventilatory responsiveness to CO2. We used oral indomethacin to reduce the cerebrovascular reactivity to CO2 and tested the steady‐state hypercapnic ventilatory response to CO2 in nine normal awake human subjects under normoxia and hyperoxia (50% O2). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 ± 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm−1 s−1 mmHg−1, P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm−1 s−1 mmHg−1, P < 0.05). Concomitantly, indomethacin administration also caused 40–60% increases in the slope of the mean ventilatory response to CO2 in both normoxia (1.27 ± 0.31 versus 1.76 ± 0.37 l min−1 mmHg−1, P < 0.05) and hyperoxia (1.08 ± 0.22 versus 1.79 ± 0.37 l min−1 mmHg−1, P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO2 is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure

AIMS Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients. METHODS AND RESULTS Thirty-one patients from six centres underwent attempted transvenous lead placement. Of these, 16 qualified to undergo two successive nights of polysomnography-one night with and one night without phrenic nerve stimulation. Comparisons were made between the two nights using the following indices: apnoea-hypopnoea index (AHI), central apnoea index (CAI), obstructive apnoea index (OAI), hypopnoea index, arousal index, and 4% oxygen desaturation index (ODI4%). Patients underwent phrenic nerve stimulation from either the right brachiocephalic vein (n = 8) or the left brachiocephalic or pericardiophrenic vein (n = 8). Therapy period was (mean ± SD) 251 ± 71 min. Stimulation resulted in significant improvement in the AHI [median (inter-quartile range); 45 (39-59) vs. 23 (12-27) events/h, P = 0.002], CAI [27 (11-38) vs. 1 (0-5) events/h, P≤ 0.001], arousal index [32 (20-42) vs. 12 (9-27) events/h, P = 0.001], and ODI4% [31 (22-36) vs. 14 (7-20) events/h, P = 0.002]. No significant changes occurred in the OAI or hypopnoea index. Two adverse events occurred (lead thrombus and episode of ventricular tachycardia), though neither was directly related to phrenic nerve stimulation therapy. CONCLUSION Unilateral transvenous phrenic nerve stimulation significantly reduces episodes of CSA and restores a more natural breathing pattern in patients with heart failure. This approach may represent a novel therapy for CSA and warrants further study.

Sleep disordered breathing and post-discharge mortality in patients with acute heart failure

BACKGROUND Hospitalizations for heart failure are associated with a high post-discharge risk for mortality. Identification of modifiable predictors of post-discharge mortality during hospitalization may improve outcome. Sleep disordered breathing (SDB) is the most common co-morbidity in heart failure patients. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of patients hospitalized with acute heart failure (AHF) in a single academic heart hospital. Between January 2007 and December 2010, all patients hospitalized with AHF who have left ventricular ejection fraction (LVEF) ≤ 45% and were not already diagnosed with SDB were the target population. MAIN OUTCOMES AND MEASURES Patients underwent in-hospital attended polygraphy testing for SDB and were followed for a median of 3 years post-discharge. Mortality was recorded using national and state vital statistics databases. RESULTS During the study period, 1117 hospitalized AHF patients underwent successful sleep testing. Three hundred and forty-four patients (31%) had central sleep apnoea (CSA), 525(47%) patients had obstructive sleep apnoea (OSA), and 248 had no or minimal SDB (nmSDB). Of those, 1096 patients survived to discharge and were included in the mortality analysis. Central sleep apnoea was independently associated with mortality. The multivariable hazard ratio (HR) for time to death for CSA vs. nmSDB was 1.61 (95% CI: 1.1, 2.4, P = 0.02). Obstructive sleep apnoea was also independently associated with mortality with a multivariable HR vs. nmSDB of 1.53 (CI: 1.1, 2.2, P = 0.02). The Cox proportional hazards model adjusted for the following covariates: LVEF, age, BMI, sex, race, creatinine, diabetes, type of cardiomyopathy, coronary artery disease, chronic kidney disease, discharge systolic blood pressure <110, hypertension, discharge medications, initial length of stay, admission sodium, haemoglobin, and BUN. CONCLUSIONS This is the largest study to date to evaluate the effect of SDB on post-discharge mortality in patients with AHF. Newly diagnosed CSA and OSA during AHF hospitalization are independently associated with post-discharge mortality.

Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences

Sleep apnea is highly prevalent in patients with cardiovascular disease. These disordered breathing events are associated with a profile of perturbations that include intermittent hypoxia, oxidative stress, sympathetic activation, and endothelial dysfunction, all of which are critical mediators of cardiovascular disease. Evidence supports a causal association of sleep apnea with the incidence and morbidity of hypertension, coronary heart disease, arrhythmia, heart failure, and stroke. Several discoveries in the pathogenesis, along with developments in the treatment of sleep apnea, have accumulated in recent years. In this review, we discuss the mechanisms of sleep apnea, the evidence that addresses the links between sleep apnea and cardiovascular disease, and research that has addressed the effect of sleep apnea treatment on cardiovascular disease and clinical endpoints. Finally, we review the recent development in sleep apnea treatment options, with special consideration of treating patients with heart disease. Future directions for selective areas are suggested.

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

RATIONALE Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease. We hypothesized that patients with OSA and no cardiovascular disease have oxidant-related microcirculatory endothelial dysfunction. OBJECTIVES To evaluate the microcirculation in OSA. METHODS This study included seven patients with OSA and seven age- and weight-matched control subjects (mean age, 38 yr; mean body mass index, 32.5 kg/m²). All participants were free of cardiovascular risk factors. Participants received measurement of brachial artery flow-mediated dilation and forearm subcutaneous biopsy. Patients underwent repeated tests 12 weeks after treatment. Microcirculatory endothelial cells were isolated, and immunohistochemistry staining for peroxynitrite in the microcirculation was performed. MEASUREMENTS AND MAIN RESULTS Flow-mediated dilation was lower in patients than in control subjects at baseline (mean ± SEM: 5.7 ± 0.5 vs. 9.5 ± 0.6; P = 0.02) and increased after treatment (5.7-7.3; change, 1.7 ± 0.6; P = 0.04). Microcirculatory peroxynitrite deposit was higher in patients compared with control subjects (44.0 ± 1.6 vs. 21.8 ± 1.9 stain density units; P < 0.001) and decreased after treatment from 44.0 to 30.5 stain density units (change, -13.5 ± 2.9; P = 0.009). In patients, transcription of endothelial nitric oxide synthase decreased from 5.2 to -1.3 after treatment (change, 6.5 ± 2.5; P = 0.05), and transcription of superoxide dismutase1 decreased from -4.0 to -12.3 after treatment (change, -8.3 ± 2.1; P = 0.01). These changes persisted after adjustment for weight and underlying severity of OSA. CONCLUSIONS This is the first direct evaluation of the microcirculation in OSA. Patients with OSA with low cardiovascular risk status had increased oxidant production in the microcirculation and endothelial dysfunction, both of which improved with treatment. Endothelial nitric oxide synthase transcription decreased with treatment.

In-hospital Testing for Sleep-disordered Breathing in Hospitalized Patients With Decompensated Heart Failure: Report of Prevalence and Patient Characteristics

BACKGROUND Sleep-disordered breathing (SDB) is present in more than 50% of ambulatory patients with chronic heart failure. The prevalence and type of SDB in hospitalized patients with acutely decompensated heart failure (ADHF) are not known. METHODS AND RESULTS In-hospital sleep studies were performed on consecutive patients with ADHF who were not previously tested for SDB. A total of 395 consecutive patients with ADHF underwent successful sleep study recording during hospitalization. A total of 298 patients (75%, 95% CI [71-80%] had SDB; of these, 226 (57%, 95% CI [52-62]) had predominantly obstructive SDB and 72 (18%, 95% CI [14-22]) had predominantly central SDB. Only 25% (95% CI 20-29%) of patients were free of SDB. Validation polysomnography between 6 and 8 weeks after discharge on a subgroup of unselected patients with obstructive SDB revealed a 100 % positive predictive value (95% CI 94-100%) for obstructive sleep apnea (OSA). CONCLUSIONS Similar to stable chronic heart failure, ADHF is associated with a high prevalence of SDB. The prevalence of predominantly obstructive SDB exceeded that of predominantly central SDB in ADHF patients. The presence of obstructive SDB during hospitalization predicted a diagnosis of OSA on polysomnography.

Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease

Obstructive sleep apnea (OSA) is increasingly recognized as a novel cardiovascular risk factor. OSA is implicated in the pathogenesis of hypertension, left ventricular dysfunction, coronary artery disease and stroke. OSA exerts its negative cardiovascular consequences through its unique pattern of intermittent hypoxia. Endothelial dysfunction, oxidative stress, and inflammation are all consequences of OSA directly linked to intermittent hypoxia and critical pathways in the pathogenesis of cardiovascular disease in patients with OSA. This review will discuss the known mechanisms of vascular dysfunction in patients with OSA and their implications for cardiovascular disease.

Mechanisms and Clinical Consequences of Untreated Central Sleep Apnea in Heart Failure

Central sleep apnea (CSA) is a highly prevalent, though often unrecognized, comorbidity in patients with heart failure (HF). Data from HF population studies suggest that it may present in 30% to 50% of HF patients. CSA is recognized as an important contributor to the progression of HF and to HF-related morbidity and mortality. Over the past 2 decades, an expanding body of research has begun to shed light on the pathophysiologic mechanisms of CSA. Armed with this growing knowledge base, the sleep, respiratory, and cardiovascular research communities have been working to identify ways to treat CSA in HF with the ultimate goal of improving patient quality of life and clinical outcomes. In this paper, we examine the current state of knowledge about the mechanisms of CSA in HF and review emerging therapies for this disorder.

The Performance of Two Automatic Servo-Ventilation Devices in the Treatment of Central Sleep Apnea

INTRODUCTION This study was conducted to evaluate the therapeutic performance of a new auto Servo Ventilation device (Philips Respironics autoSV Advanced) for the treatment of complex central sleep apnea (CompSA). The features of autoSV Advanced include an automatic expiratory pressure (EPAP) adjustment, an advanced algorithm for distinguishing open versus obstructed airway apnea, a modified auto backup rate which is proportional to subjects baseline breathing rate, and a variable inspiratory support. Our primary aim was to compare the performance of the advanced servo-ventilator (BiPAP autoSV Advanced) with conventional servo-ventilator (BiPAP autoSV) in treating central sleep apnea (CSA). STUDY DESIGN A prospective, multicenter, randomized, controlled trial. SETTING Five sleep laboratories in the United States. PARTICIPANTS Thirty-seven participants were included. MEASUREMENTS AND RESULTS All subjects had full night polysomnography (PSG) followed by a second night continuous positive airway pressure (CPAP) titration. All had a central apnea index ≥ 5 per hour of sleep on CPAP. Subjects were randomly assigned to 2 full-night PSGs while treated with either the previously marketed autoSV, or the new autoSV Advanced device. The 2 randomized sleep studies were blindly scored centrally. Across the 4 nights (PSG, CPAP, autoSV, and autoSV Advanced), the mean ± 1 SD apnea hypopnea indices were 53 ± 23, 35 ± 20, 10 ± 10, and 6 ± 6, respectively; indices for CSA were 16 ± 19, 19 ± 18, 3 ± 4, and 0.6 ± 1. AutoSV Advanced was more effective than other modes in correcting sleep related breathing disorders. CONCLUSIONS BiPAP autoSV Advanced was more effective than conventional BiPAP autoSV in the treatment of sleep disordered breathing in patients with CSA.

In-Hospital Treatment of Obstructive Sleep Apnea During Decompensation of Heart Failure

BACKGROUND Treatment of obstructive sleep apnea (OSA) in outpatients with systolic heart failure improves cardiac function. We evaluated the impact of immediate inpatient diagnosis and treatment of OSA in hospitalized patients with acutely decompensated heart failure (ADHF) on in-hospital cardiac outcomes. METHODS A pilot randomized controlled trial was conducted in an academic heart hospital. Patients with ADHF underwent an attended in-hospital sleep study within 2 days of hospital admission to establish the diagnosis of sleep-disordered breathing. The participants were 46 consecutive patients with ADHF who had OSA (apnea-hypopnea index [AHI], >or= 15 events per hour). Participants were randomly assigned to either the intervention arm (n = 23), with in-hospital treatment of OSA using auto-adjusting positive airway pressure along with standard treatment of ADHF, or to the control arm (n = 23), in which they received only standard treatment for ADHF. The primary outcome was the change in left ventricular ejection fraction (LVEF) 3 nights postrandomization. RESULTS The change in LVEF from baseline to 3 days postrandomization in the intervention arm was significantly superior to that of the control group. The difference in LVEF improvement was 4.6% (p = 0.03). LVEF increased in the intervention group by 4.5% (SE, 1.7%). The LVEF change in the control arm was--0.3% (SE, 1.5%). The difference in LVEF improvement between the two groups persisted after adjustment for baseline LVEF, type of cardiomyopathy, BMI, AHI, and sex. CONCLUSIONS An approach of early identification and in-hospital treatment of OSA in patients with ADHF is feasible and resulted in improvement in systolic function. The impact of this approach on out-of-hospital outcomes requires further investigation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00701038.