The link between sleep apnea and cardiovascular disease: time to target the nonsleepy sleep apneics?
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Cardiovascular Diseases↗
Biomedical subjects
J Hedner
Publications and source records attributed to J Hedner.
Impairment of vascular endothelial function and left ventricular filling : association with the severity of apnea-induced hypoxemia during sleep.
STUDY OBJECTIVE: To investigate whether a dose-effect relationship exists between the severity of obstructive sleep apnea (OSA) and subclinical indicators of myocardial or vascular dysfunction. DESIGN: Cross-sectional study using correlation analysis. PARTICIPANTS: Twenty subjects referred to our sleep laboratory for screening or therapy of OSA but without regular medication and without known cardiovascular disease. MEASUREMENTS: Severity of OSA was quantified by polysomnography. Moreover, nocturnal excretion of norepinephrine was determined. Left ventricular (LV) myocardial function was assessed with Doppler echocardiography. Using ultrasonographic measurements, endothelium-dependent and endothelium-independent conduit artery dilation were measured as flow-mediated and glyceryltrinitrate-induced changes in brachial artery diameter. RESULTS: Worsening nocturnal hypoxemia, measured as nocturnal oxygen saturation nadir or percentage of sleep time spent in hypoxemia (< 90% hemoglobin oxygen saturation), predicted increased interventricular septum thickness (corrected for age and body mass index), prolonged isovolumetric relaxation time, decreased ratio between peak early and late mitral flow velocities, as well as reduced endothelium-dependent dilatory capacity of the brachial artery (all relationships corrected for cofactor age and with p < 0.05) were observed. Associations between these cardiovascular function markers and nocturnal excretion of norepinephrine followed the same trend, but relations with interventricular septum thickness and flow-mediated artery dilation missed significance (p = 0.064 and p = 0.061, respectively). LV posterior wall thickness, measures of LV systolic function, early mitral flow deceleration time, and endothelium-independent artery dilation were not significantly related to the degree of nocturnal hypoxemia or norepinephrine excretion. None of the correlations with apnea-hypopnea index were statistically significant. CONCLUSIONS: The severity of apnea-related hypoxemia is associated with a gradual deterioration of LV diastolic function as well as large-artery endothelial function.
Adult↗
Treatment options for sleep apnoea.
Sleep apnoea (SA) is a common sleep disorder affecting 4 to 25% of the adult population. The most common form, obstructive SA, is characterised by recurrent upper airway obstruction during sleep associated with sleep disruption and hypoxaemia. There is increasing evidence that SA leads to impaired vigilance, quality of life, driving accidents and probably represents a vascular disease risk factor. Currently, the most effective treatments are aimed at increasing upper airway space by either air pressure [(continuous positive airway pressure (CPAP)], upper airway surgery or oral appliances. CPAP is the main treatment modality for moderate to severe SA but noncompliance approaches 50% in clinic populations. A number of pharmacological agents have been used in SA but at this stage, none are indicated in moderate to severe SA.
Acetazolamide↗
Regulation of systemic vasculature in obstructive sleep apnea syndrome.
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Atrial Natriuretic Factor↗
Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group.
Insomnia is a frequent complaint in the elderly population. Hypnotic agents, including benzodiazepines, with longer pharmacological half-lives have been associated with side effects, including residual sedation, memory impairment, and discontinuation effects. Zaleplon is a short-acting (elimination half-life of 1 hour), non-benzodiazepine hypnotic that acts on the benzodiazepine type 1 site of the gamma-aminobutyric acid type A (GABA(A)) receptor complex. The pharmacology and pharmacokinetics of Zaleplon suggest a safety profile that is improved over other hypnotics. The objective of this placebo-controlled study was to evaluate the efficacy and safety of Zaleplon (5 and 10 mg) in elderly (> or =65 years) outpatients with primary insomnia. This was a multicenter, double-blind, randomised, placebo-controlled 2-week outpatient study. Postsleep questionnaires were used to record subjective sleep variables: sleep latency, sleep duration, number of awakenings, and sleep quality. Zaleplon significantly reduced subjective sleep latency during both weeks of the study with both 5- and 10-mg doses. Subjective sleep quality was improved for significantly more patients treated with zaleplon 10 mg than those treated with placebo during both weeks of treatment. There was a weak indication of rebound insomnia after discontinuation of treatment with the 10-mg dose, but no significant difference in common treatment-emergent adverse events across treatment groups. Zaleplon is an effective and safe hypnotic for the treatment of insomnia in the elderly.
Acetamides↗
Association between blood pressure reduction with antihypertensive treatment and sleep apnea activity.
This study investigated whether a drug therapy-induced reduction in nocturnal blood pressure (BP) was associated with decreased sleep apnea activity. Two polysomnographies from 54 hospitalized male hypertensive, obstructive sleep apnea patients were analyzed in a double-blind, randomized, parallel-group trial of the angiotensin-converting enzyme inhibitor cilazapril (C), 2.5 mg once daily, or placebo (P). Blood pressure was measured by means of an intra-arterial catheter. Compared with P, C lowered mean arterial BP during non-rapid eye movement (NREM) (-8.3 +/- 10.7 mm Hg, P = .05) and REM sleep (-8.6 +/- 10.1 mm Hg, P = .02). Respiratory disturbance index (-8.6 +/- 3.2 events/h of sleep (n/h), P = .01) and apnea index (AI) (-6.6 +/- 3.0 n/h, P = .04) during NREM sleep were lowered by C and, to a lesser extent, by P (-5.9 +/- 3.2 n/h, P = .07 and -5.0 +/- 3.6 n/h, P = .18, respectively). The effect on AI and hypopnea index (HI) during REM sleep was not significant for C (-5.9 +/- 3.4 and 0.1 +/- 2.0, NS, respectively) and P (-2.6 +/- 3.9 and 1.6 +/- 2.0, NS, respectively). There was a significant linear correlation between the change in REM systolic BP and the change in REM AI (r = 0.28, P = .04); the mean BP change correlated negatively with the change in HI (-0.28, P = .04). During NREM sleep there was no significant correlation between changes in BP and the treatment effects on sleep apnea activity. Blood pressure reduction after short-term antihypertensive treatment did not affect sleep disordered breathing during NREM sleep. Reduced BP was associated with a weak reduction of AI and a slight increase of HI during REM sleep. It appears that elevated BP contributes only marginally to sleep apnea severity in hypertensive patients with obstructive sleep apnea.
Angiotensin-Converting Enzyme Inhibitors↗
Sleep-related breathing disorder is an independent risk factor for uncontrolled hypertension.
OBJECTIVE: To test the hypothesis that sleep-related breathing disorder (SRBD) is associated with poor blood pressure control in hypertensive patients independent from confounding factors such as age, body mass index, alcohol, smoking and daytime blood gases. DESIGN AND METHODS: This cross-sectional study of a sleep laboratory cohort was carried out at the University Hospital Sleep Disorders Centre, Marburg. The study comprised 599 patients referred for a sleep study, all of them with a documented history of systemic hypertension and/or previously initiated antihypertensive therapy. Data were obtained from a clinical interview, two unattended sleep studies and assessment of clinic blood pressure, cholesterol level, alcohol and nicotine consumption and daytime blood gases. The main outcome measure was a post hoc analysis of predictors for poor blood pressure control. RESULTS: Respiratory disturbance index (RDI) was significantly higher in patients with uncontrolled hypertension (blood pressure > or = 160 and/or 95 mmHg, n = 463) than in those with controlled hypertension (n = 136) (34.0 +/- 26.8 versus 27.0 +/- 23.5, P < 0.01). The relative proportion of patients with uncontrolled hypertension increased significantly as SRBD activity increased (chi2, P< 0.05). Body mass index was the only independent predictor (P = 0.006) of uncontrolled hypertension in the whole study sample. However, in the subset of patients aged < or = 50 years, RDI (P= 0.006) and age (P = 0.016) were the only independent predictors. The probability of uncontrolled hypertension increased by approximately 2% (B = 0.019, P= 0.006) for each RDI unit. CONCLUSION: SRBD should be considered, in addition to traditional confounders, as a risk factor for poor blood pressure control in younger hypertensive patients (< or = 50 years of age).
Adult↗
Increased vasoconstrictor sensitivity in obstructive sleep apnea.
We studied vasoconstrictor sensitivity and cholinergic responsiveness of the forearm vasculature in 10 male patients with obstructive sleep apnea (OSA) and 10 healthy controls. Subjects with regular medication, known arterial hypertension, diabetes mellitus, or dyslipidemia were not included in this study. Age, body mass index, blood pressure, blood glucose, serum lipids, and baseline forearm vascular conductance (derived from venous occlusion plethysmography and intra-arterial blood pressure measurement) did not differ significantly between these two groups. With use of three dosage steps each, angiotensin II and acetylcholine were successively infused into the brachial artery. During infusion of angiotensin II, mean conductance was 39.6% lower (P = 0.002) in the OSA patients compared with that in the control subjects. Vascular responsiveness to increasing dosages of acetylcholine was not significantly altered in the OSA group. These findings suggest an enhanced vasoconstrictor sensitivity in the forearm vasculature in OSA. The hypothesis that endothelial function in OSA is impaired independently of other cardiovascular risk factors is not supported by the present results.
Acetylcholine↗
Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea.
We compared the effects of atenolol (50 mg), amlodipine (5 mg), enalapril (20 mg), hydrochlorothiazide (25 mg), and losartan (50 mg) given in once-daily oral doses on office and ambulatory blood pressures (BPs) in patients with hypertension and obstructive sleep apnea (OSA). Each of 40 randomized patients was treated in sequence with two of the five agents (balanced incomplete block design). Treatment periods lasted 6 wk and were separated by a 3-wk washout period. Changes in BP from baseline with the study substances were compared through analysis of variance. Office diastolic BP, our primary outcome variable, was most effectively lowered by atenolol, with all four post hoc differences between atenolol and the remaining substances being statistically significant. Reductions in office systolic and daytime ambulatory BP were not significantly different among the five compounds. However, atenolol reduced mean nighttime ambulatory diastolic and systolic BP more effectively than did amlodipine, enalapril, or losartan (but not hydrochlorothiazide). Severity of sleep-disordered breathing and well-being during the day were not significantly influenced by any of the study compounds. Our findings are in accordance with the hypothesis that an overactivity of the sympathetic nervous system is an important mechanism behind the development or maintenance of hypertension in patients with OSA.
Adrenergic beta-Antagonists↗
Respiratory disturbance index: an independent predictor of mortality in coronary artery disease.
Cardiovascular mortality was prospectively investigated in consecutive coronary artery disease (CAD) patients with versus without obstructive sleep apnea (OSA) during a follow-up period of 5 yr. An overnight sleep/ventilatory study was performed in patients requiring intensive care (n = 62, mean age 67.6 +/- 10.4 yr, range 44 to 86) during a stable condition (New York Heart Association [NYHA] functional class I-II) 4 to 21 mo after discharge from the hospital. OSA, defined as a respiratory disturbance index (RDI) of 10/h or more was found in 19 patients (mean RDI 17.5 +/- 8.3). Three OSA subjects who were successfully treated with continuous positive airway pressure (CPAP) during the observation period were excluded from the final analysis. There was no statistically significant difference (Fisher two-tailed exact test) between the OSA and non-OSA patient groups in terms of number of elderly subjects (age >/= 65 yr), gender, obesity (body mass index [BMI] >/= 30 kg/m(2)), smoking history, presence of hypertension, diabetes mellitus, hypercholesterolemia, or history of myocardial infarction at the study start. During the follow-up period, cardiovascular death occurred in six of 16 OSA patients (37.5%) compared with 4 (9.3%) in the non-OSA group (p = 0.018). The univariate predictors of cardiovascular mortality were RDI (p = 0.007), OSA (p = 0.014), age at baseline (p = 0.028), hypertension at baseline (p = 0.036), history of never-smoking (p = 0.031), and digoxin treatment during the follow-up period (p = 0.013). In a Cox multiple conditional regression model, RDI remained as an independent predictor of cardiovascular mortality (exp beta = 1.13, 95% confidence interval [CI] 1.05 to 1.21, two-sided p < 0.001). We conclude that untreated OSA is associated with an increased risk of cardiovascular mortality in patients with CAD. Furthermore, it appears appropriate that RDI is taken into consideration when evaluating secondary prevention models in CAD.
Adult↗
Reduced alpha- and beta(2)-adrenergic vascular response in patients with obstructive sleep apnea.
Obstructive sleep apnea (OSA) has been associated with increased sympathetic activity. This study tested the hypothesis that the alpha- and beta(2)-receptor-mediated vascular response is altered in patients with OSA. Forearm vascular resistance was evaluated by venous occlusion plethysmography in 10 normotensive OSA patients and 10 normotensive controls (apnea/hypopnea index [mean +/- SD] 29.4 +/- 2.3 and 1.6 +/- 0.3 per hour, respectively) roughly matched for body mass index (BMI) and age. Forearm vascular resistance was measured after intraarterial infusion of norepinephrine (NE) (7.4, 31, 120, 472 and 1421 pmol/100 ml forearm volume [FAV]/min), before and after phentolamine infusion (2 microgram/100 ml FAV/min), and isoproterenol (ISO) (1, 2, 6, and 15 ng/100 ml FAV/min). NE-induced vasoconstriction was significantly attenuated in OSA patients compared with controls (65.0 +/- 36.6% versus 129.4 +/- 81.8%, p = 0.049). The reduction of vascular resistance after phentolamine was similar in patients and control subjects (-50.8 +/- 16.7% versus -43.4 +/- 20.0%, p = 0.38). During ongoing phentolamine infusion NE increased resistance to a similar extent in both groups (0.5 +/- 4.9% versus -0.9 +/- 10.1%, p = 0.96). Vasodilation following ISO was significantly attenuated in OSA patients compared with control subjects (-53.3 +/- 9.0% versus -64.7 +/- 10.3%, p = 0.049). Moreover, the vascular response to NE in OSA patients was negatively correlated with plasma NE concentration (r = -0.76, p < 0.05). The reduced vascular response to alpha- and beta-receptor stimulation suggests a functional downregulation of vascular sympathoadrenergic receptors in patients with sleep apnea.
Adult↗
Therapy with nCPAP: incomplete elimination of Sleep Related Breathing Disorder.
Correct assessment of the overall treatment effectiveness requires knowledge about therapy compliance and efficacy. This study aimed to determine overall long-term apnoea alleviation after continuous positive airway pressure (CPAP) in a complete sleep laboratory cohort. Out of 209 consecutive CPAP candidates (mean age 57+/-12 yrs, body mass index (BMI) 30.0+/-5.1 kg x m2, respiratory disturbance index (RDI) 32.9+/-29 h), follow-up treatment was performed in 149 of them at 9, 18 and 30 months after CPAP prescription. Compliance with CPAP (machine run time/days CPAP available) was adjusted for the individual subjective sleep-time. Apnoea alleviation was defined as adjusted compliance multiplied by the CPAP effect (RDI with CPAP applied), remaining RDI was calculated. The baseline RDI, age or BMI in 75 patients, who did not tolerate nasal continuous positive airway pressure (nCPAP), did not differ from those accepting CPAP (acceptors, n=74). In acceptors at 9 months follow-up RDI with CPAP applied was 1.4+/-2.6 (CPAP effect, n=66), mean CPAP use was 3.6+/-2.5 x 24 h(-1) (n=68), mean apnoea alleviation was 52.4+/-32.0% (range 1-100%, n=47), the average remaining whole-night RDI was 17.8+/-26. At 9, 18 and 30 months (n=47), the mean daily CPAP use increased from 3.6+/-2.5 h to 4.1+/-2.5 h and 4.4+/-2.4 h (p<0.01). Effectiveness of continuous positive airway pressure is potentially high but acceptance was low. When accounting for sleep-time, its actual effect and use, only 50% adjusted continuous positive airway pressure effectiveness was observed.
Adult↗
Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea.
Pharmacologic enhancement of serotonergic transmission by serotonin uptake inhibition has been suggested as one approach to improve upper-airway patency and thus nocturnal breathing in patients with obstructive sleep apnea (OSA). To test this hypothesis, we performed a double-blind, randomized, placebo-controlled crossover study testing the effect of paroxetine (20 mg od) on polysomnographic and psychopathologic outcomes in 20 male OSA patients (mean age 52.1 years, mean BMI 28.7 kg/m2, mean oxygen desaturation index on a previous screening 25.4/hour). The two treatment periods of 6 weeks and the separating washout period of 4 weeks were completed by 17 patients. Paroxetine reduced the apnea index during NREM sleep (-35%, p = 0.003), but not during REM sleep. No significant effect on hypopnea indices was found. With the exception of a previously described REM-postponing effect (p = 0.05), sleep architecture was not significantly influenced by paroxetine. Similarly, the effect of paroxetine on apnea was not associated with a significant overall alleviation of psychopathologic symptoms as rated on the Comprehensive Psychopathological Rating Scale or OSA-related daytime complaints assessed by visual analog scales. We conclude that enhanced serotonergic transmission improves breathing during NREM sleep in OSA. This effect is poorly related to effects on sleep architecture or daytime symptoms.
Adult↗
Latanoprost and respiratory function in asthmatic patients: randomized, double-masked, placebo-controlled crossover evaluation.
OBJECTIVE: To evaluate the effects of single and multiple administrations of the ocular hypotensive drug latanoprost on respiratory function, asthma symptoms, and use of asthma medication in patients with bronchial asthma. METHODS: Twenty-four stable patients with asthma (forced expiratory volume in 1 second: 70% to 90% of predicted and a minimum of 10% reversibility after inhalation of albuterol sulfate) with no previous exposure to inhaled corticosteroids participated in this randomized, double-masked crossover trial. Patients received latanoprost, 0.005%, or placebo, 1 drop per day, in each eye during two 6-day treatment periods separated by a 2-week washout period. Acute latanoprost or placebo provocation, methacholine chloride airway reactivity, and 12-stimulator reversibility tests were performed. MAIN OUTCOME MEASURES: Morning and evening peak expiratory flow, spirometric performance throughout treatment periods and during different provocation tests, asthma symptoms, and use of asthma medications were evaluated. RESULTS: There were no statistically significant differences between treatments in morning and evening peak expiratory flow, scored daytime and nocturnal asthma symptoms, or daily consumption of asthma medication. During placebo provocation, there was a small increase in forced expiratory volume in 1 second that was not seen during latanoprost provocation. This small difference (-0.09 L) was statistically significant but without clinical importance. CONCLUSIONS: Resting and provoked airway function and asthma symptoms were unaffected by latanoprost treatment in patients with asthma with no previous exposure to corticosteroids. Latanoprost can be used in patients with glaucoma and concomitant bronchial asthma.
Adolescent↗
An independent association between obstructive sleep apnoea and coronary artery disease.
Previous studies of sleep and breathing suggest an independent association between coronary artery disease (CAD) and obstructive sleep apnoea (OSA) in middle-aged males and females. These studies, however, were criticized because they did not properly adjust for all important confounding factors. In order to better control for the impact of these confounders, a case-control study was performed, matching for age, sex and body mass index (BMI), and additionally adjusting for hypertension, hypercholesterolemia, diabetes mellitus and current smoking. A consecutive selection of 62 patients (44 males and 18 females, mean age 69 yrs, range 44-88 yrs) requiring intensive care for angina pectoris or myocardial infarction at the County Hospital of Skaraborg, Skövde, Sweden, as well as 62 age-, sex- and BMI- matched control subjects without history or signs of heart disease underwent an overnight sleep/ventilatory monitoring study. The time interval between discharge from the intensive care unit and the overnight study ranged between 4 and 21 months. OSA, defined as a Respiratory Disturbance Index (RDI) of > or =10 x h(-1), was present in 19 CAD patients but only in eight control subjects (p=0.017). Using a univariate logistic regression analysis, current smoking (odds ratio (OR) 8.1, 95% confidence interval (CI) 2.2-29.0), diabetes mellitus (OR 4.2, 95% CI 1.1-16.1) and OSA (OR 3.0, 95% CI 1.2-7.5), but not hypertension (OR 1.5, 95% CI 0.7-3.2) and hypercholesterolaemia (OR 1.8, 95% CI 0.7-4.1) were significantly correlated with CAD. In a multiple logistic regression model, current smoking (OR 9.8, 95% CI 2.6-36.5), diabetes mellitus (OR 4.2, 95% CI 1.1-17.1) and OSA (OR 3.1, 95% CI 1.2-8.3) all remained independently associated with CAD. In summary, these data suggest a high occurrence of obstructive sleep apnoea in middle-aged and elderly patients with coronary artery disease requiring intensive care, which should be taken into account when considering risk factors for coronary artery disease.
Adult↗
Plasma noradrenaline and neuropeptide-Y may not be of primary importance in the pathophysiology of cardiac involvement in systemic sclerosis.
OBJECTIVE: The present study was performed to measure concentrations of plasma noradrenaline and neuropeptide-Y-like immunoreactivity in relation to cardiac function in patients with systemic sclerosis (SSc). METHODS: Plasma noradrenaline was measured by high performance liquid chromatography and neuropeptide-Y by radioimmunoassay in 30 consecutive patients with SSc and 48 sex and age matched controls. Left ventricular (LV) function was evaluated by Echocardiography. RESULTS: There were no significant differences between patients and controls in either plasma noradrenaline or plasma neuropeptide-Y. LV dysfunction and hypertrophy were common among patients. Plasma Neuropeptide-Y was related only to systolic function, while noradrenaline was related to both systolic and diastolic function as well as to LV hypertrophy. CONCLUSION: Patients with SSc develop different forms of myocardial dysfunction without activation of the sympathetic nervous system as evaluated by plasma noradrenaline and neuropeptide-Y; leaving vascular disease of the heart to be a main candidate.
Adult↗
Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by long-term intermittent hypoxia.
We investigated whether the effect of long-term intermittent hypoxia (LTIH) on cardiovascular function may be modified by preexisting genetic traits. To induce LTIH experimentally, cycles of 90-s hypoxia (nadir 6%) followed by 90-s normoxia were applied to six Wistar-Kyoto and six spontaneously hypertensive rats during 8 h daily. Comparison with the same number of control animals after 70 days revealed no alteration of intra-arterial blood pressure or heart rate. Blood pressure responsiveness to a brief hypoxic stimulus was enhanced in the LTIH animals, regardless of strain, whereas the hypoxia-induced increase in heart rate was abolished. In the spontaneously hypertensive but not the Wistar-Kyoto rats, LTIH increased left ventricular weight-to-body weight ratio and content of atrial natriuretic peptide mRNA. Expression of B-type natriuretic peptide was unchanged (Northern blot). Slightly increased right ventricular weight-to-body weight ratios in the LTIH animals were associated with higher right ventricular atrial natriuretic peptide and B-type natriuretic peptide mRNA amounts. Consequently, the effects of LTIH on different components of cardiovascular function appear incompletely related to each other and differentially influenced by constitutional traits.
Animals↗
Endothelin may be pathogenic in systemic sclerosis of the heart.
We evaluated 30 consecutive patients and 48 age- and sex-matched controls to explore the possibility of a pathogenic contribution by plasma endothelin-1 in the cardiac expression of systemic sclerosis. Venous plasma endothelin-1 was measured by radio-immunoassay and left ventricular function by echocardiography. The patient group had elevated plasma endothelin-1 (2.6 +/- 0.2 vs. 1.8 +/- 0.1 pmol/1, P < 0.001), but endothelin-1 was not related to age, heart rate, blood pressure, total peripheral resistance, disease duration or systemic sclerosis score. Endothelin-1 was related to left ventricular hypertrophy in terms of septal thickness (r = 0.33, P < 0.01) and left ventricular mass index (r = 0.32, P < 0.01). Plasma endothelin-1 was further related to measures indicating reduced left ventricular filling; left atrial emptying index (r = -0.50, P < 0.0005), the first third filling fraction (r = -0.31, P < 0.05) and the time velocity integral of Doppler early/late filling velocity (r = -0.40, P < 0.001). Furthermore, circulating endothelin-1 was related to impaired left ventricular contractility as estimated by pre-ejection period/left ventricular ejection time (r = 0.32, P < 0.01) and end-systolic wall stress/volume index (r = -0.30, P < 0.05). We conclude that plasma endothelin-1 is elevated in relation to the degree of left ventricular hypertrophy, diastolic dysfunction and impaired contractility in systemic sclerosis. It may be of pathogenic importance to the cardiac involvement in systemic sclerosis which is not mediated via an increase in systemic blood pressure. It is not yet clear whether our findings are exclusive to systemic sclerosis patients or represent a generalized phenomenon in patients with impaired left ventricular function.
Adult↗