Margherita Padeletti

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Vascular Inflammation in Obesity and Sleep Apnea

Background— Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA. Methods and Results— Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-&kgr;B and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-&kgr;B was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-&kgr;B significantly decreased in OSA patients who adhered to continuous positive airway pressure ≥4 hours daily. Conclusions— Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.

Early Detection of Left Atrial Strain Abnormalities by Speckle-Tracking in Hypertensive and Diabetic Patients with Normal Left Atrial Size

BACKGROUND Systemic hypertension and type 2 diabetes mellitus are associated with impaired left atrial (LA) function, but whether LA functional abnormalities also occur in patients with hypertension and diabetes who have normal LA sizes is unknown. The aim of this study was to explore LA strain using speckle-tracking echocardiography in patients with hypertension or diabetes and normal LA size. METHODS LA strain was studied by speckle-tracking echocardiography in 155 patients with hypertension or diabetes with LA volume indexes < 28 mL/m(2) (83 with hypertension, 34 with diabetes, and 38 with both diabetes and hypertension) and 36 age-matched controls. The following indexes were measured: peak atrial longitudinal strain, time to peak atrial longitudinal strain, atrial longitudinal strain during early diastole and late diastole, and peak LA strain rate during ventricular systole, early diastole, and late diastole. RESULTS Peak atrial longitudinal strain was lower in patients with hypertension (29.0 ± 6.5%) and those with diabetes (24.7 ± 6.4%) than in controls (39.6 ± 7.8%) and further reduced in patients with diabetes and hypertension (18.3 ± 5.0%) (P < .0001). Similar results were found for atrial longitudinal strain during early diastole, atrial longitudinal strain during late diastole, and peak LA strain rate during ventricular systole and early diastole (P < .0001 for all). An inverse trend was found for time to peak atrial longitudinal strain, whereas no differences in peak LA strain rate during late diastole were observed. Two-way analysis of variance showed no interactions between hypertension and diabetes. In multivariate analyses, hypertension and diabetes were both independently associated with decreases in all LA strain and strain rate indexes, with the exception of peak LA strain rate during late diastole. CONCLUSIONS LA deformation mechanics are impaired in patients with hypertension or diabetes with normal LA size. The coexistence of both conditions further impairs LA performance in an additive fashion. Speckle-tracking echocardiography may be considered a promising tool for the early detection of LA strain abnormalities in these patients.

Left atrial longitudinal strain by speckle tracking echocardiography correlates well with left ventricular filling pressures in patients with heart failure

BackgroundThe combination of early transmitral inflow velocity and mitral annular tissue Doppler imaging (E/Em ratio) is widely applied to noninvasively estimate left ventricular (LV) filling pressures. However E/Em ratio has a significant gray zone and its accuracy in patients with heart failure is debated. Left atrial (LA) deformation analysis by speckle tracking echocardiography (STE) was recently proposed as an alternative approach to estimate LV filling pressures. This study aimed at exploring the correlation of LA longitudinal function by STE and Doppler measurements with direct measurements of LV filling pressures in patients with heart failure.MethodsA total of 36 patients with advanced systolic heart failure (ejection fraction ≤35%), undergoing right heart catheterization, were studied. Simultaneously to pulmonary capillary wedge pressure (PCWP) determination, peak atrial longitudinal strain (PALS) and mean E/Em ratio were measured in all subjects by two independent operators. PALS values were obtained by averaging all segments (global PALS), and by separately averaging segments measured in the 4-chamber and 2-chamber views.ResultsNot significant correlation was found between mean E/Em ratio and PCWP (R = 0.15). A close negative correlation between global PALS and the PCWP was found (R = -0.81, p < 0.0001). Furthermore, global PALS demonstrated the highest diagnostic accuracy (AUC of 0.93) and excellent sensitivity and specificity of 100% and 93%, respectively, to predict elevated filling pressure using a cutoff value less than 15.1%. Bland-Altman analysis confirmed this close agreement between PCWP estimated by global PALS and invasive PCWP (mean bias 0.1 ± 8.0 mmHg).ConclusionIn a group of patients with advanced systolic heart failure, E/Em ratio correlated poorly with invasively obtained LV filling pressures. However, LA longitudinal deformation analysis by STE correlated well with PCWP, providing a better estimation of LV filling pressures in this particular clinical setting.

Coexistent chronic obstructive pulmonary disease and heart failure in the elderly

The prevalence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases substantially with age. The coexistence of COPD and CHF is common but often unrecognized in elderly patients. To avoid overlooking COPD in elderly patients with known CHF pulmonary function tests should be routinely obtained. Likewise, to avoid overlooking CHF in elderly patients with known COPD left ventricular (LV) function should be routinely assessed. Plasma brain natriuretic peptide levels are useful to differentiate COPD exacerbation from CHF decompensation in patients presenting with acute dyspnea. Aging exacerbates skeletal muscle alterations that occur in patients with CHF and COPD. Skeletal muscle metabolic alterations and atrophy and the resulting deterioration of functional capacity progress rapidly in elderly patients with COPD and CHF. Physical conditioning reverses rapidly progressing skeletal muscle metabolic alterations and atrophy and promotes independence and life quality in the elderly. Physical conditioning is clearly an essential component of the management of elderly patients with COPD and CHF. The pharmacological management of patients with coexistent COPD and CHF should focus on not depriving these patients from long-term beta adrenergic blockade. Long-term beta adrenergic blockade has been repeatedly shown to improve survival in elderly patients with CHF due to LV systolic dysfunction and, contrary to conventional belief, is well tolerated by patients with COPD.

Endothelial repair capacity and apoptosis are inversely related in obstructive sleep apnea

Purpose: To investigate the impact of obstructive sleep apnea (OSA) on endothelial repair capacity and apoptosis in the absence of potentially confounding factors including obesity. Patients and methods: Sixteen patients with a body mass index <30 and newly diagnosed OSA and 16 controls were studied. Circulating levels of endothelial progenitor cells, a marker of endothelial repair capacity, and endothelial microparticles, a marker of endothelial apoptosis, were quantified before and after four-week therapy with continuous positive airway pressure (CPAP). Endothelial cell apoptotic rate was also quantified in freshly harvested venous endothelial cells. Vascular reactivity was measured by flow-mediated dilation. Results: Before treatment, endothelial microparticle levels were greater and endothelial progenitor cell levels were lower in patients with OSA than in controls (P < 0.001 for both). Levels of endothelial microparticles and progenitors cells were inversely related (r = −0.67, P < 0.001). Endothelial progenitor cell levels increased after effective treatment (P = 0.036). Conclusions: In the absence of any co-morbid conditions including obesity, OSA alone impairs endothelial repair capacity and promotes endothelial apoptosis. These early endothelial alterations may underlie accelerated atherosclerosis and increased cardiovascular risk in OSA.

Reference Values of Right Atrial Longitudinal Strain Imaging by Two‐Dimensional Speckle Tracking

Background: The role of speckle tracking in the assessment of right atrial (RA) deformation dynamics has not been established yet. The reference ranges of RA longitudinal strain indices were measured by speckle tracking in a population of normal subjects. Methods: In 84 healthy individuals, peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and time to peak longitudinal strain (TPLS) were measured using a six‐segment model for the RA. Strain rate (SR) was also measured starting from the QRS‐wave onset, peak positive (x‐wave), first peak negative (y‐wave), and second negative peak (z‐wave). The time from the QRS onset was measured to each wave peak. Results: Adequate tracking quality was achieved in 64% of segments analyzed. Inter‐ and intraobserver variability coefficients of measurements ranged between 6% and 11%. Global PALS was 49 ± 13%, global TPLS was 363 ± 59 msec, x‐wave was 2.12 ± 0.58 sec−1, y‐wave was −1.91 ± 0.63 sec−1, and z‐wave was −2.18 ± 0.78 sec−1. Conclusion: Speckle tracking is a feasible technique for the assessment of longitudinal myocardial RA deformation. Reference ranges of strain indices were reported. (Echocardiography 2012;29:147‐152)

Right Atrial Speckle Tracking Analysis as a Novel Noninvasive Method for Pulmonary Hemodynamics Assessment in Patients with Chronic Systolic Heart Failure

Background: The right atrium (RA) plays multiple roles in the cardiac cycle. The reservoir phase of the RA is a dynamic rather than a static phase of cardiac cycle and RA deformation is dependent on pulmonary pressures exerted on the right ventricle and, therefore, backwards on the RA. The purpose of this study was to assess the accuracy and the clinical applicability of the speckle tracking echocardiography (STE) evaluation of the RA in predicting the invasive systolic pulmonary artery pressure (SPAP) in patients with systolic heart failure (HF) undergoing right heart catheterization (RHC). Methods: Thirty‐one hemodynamically stable, in‐clinic HF patients who were undergoing RHC were included. Doppler echocardiography and RHC catheterization were simultaneously performed. Echocardiographic measures and STE where obtained as peak atrial longitudinal strain (PALS), RA strain rate, and time to peak longitudinal strain (TPLS). RA PALS was inversely correlated with invasively assessed SPAP (r =–0.81; P < 0.001) while RA strain directly correlated with SPAP (r = 0.82; P < 0.001). RA PALS and strain rate retained this correlation even after nitroprusside challenge test (r =–0.81; P < 0.001 and r = 0.91; P < 0.001, respectively). Area under the curve optimal cutoffs for predicting the SPAP > 50 mmHg were for RA PALS 10.3% (AUC:0.93, sensitivity: 100%, specificity: 78%). Conclusion: RA STE showed a significant correlation with pulmonary pressure. RA assessment with STE can predict pulmonary artery hypertension in HF patients. This result is consistent with nitroprusside challenge test. Although RA STE is not routinely used, its evaluation may implement right heart evaluation in HF patients. (Echocardiography 2011;28:658‐664)

Sleep disordered breathing in patients with acutely decompensated heart failure

OBJECTIVE The purpose of this study is to systematically characterize sleep disordered breathing (SDB) during acute heart failure (HF) decompensation. BACKGROUND SDB, both Cheyne-Stokes breathing (CSB) and obstructive sleep apnea, is common in stable congestive HF patients, but its presence and characteristics in decompensated HF is unknown. METHODS Eighteen men and 11 women (mean age 57+/-17 years, plasma brain-natriuretic peptide 1660+/-1179pg/ml, left ventricular ejection fraction 20+/-6%) admitted with decompensated systolic HF without other active cardiorespiratory morbidity underwent echocardiography and overnight bedside polysomnography within 48h of admission. Ten patients underwent follow-up polysomnography just before or immediately after hospital discharge. RESULTS Twenty-eight of 29 patients demonstrated an apnea+hypopnea index (AHI)>5 events/h (mean AHI 41+/-29/h); 22 patients had an AHI>15/h. SDB was predominantly CSB (central events 39+/-29/h; obstructive events 2+/-2/h, p<0.001). Time in CSB was 51+/-33% of total sleep time (TST); nadir oxygen saturation (SaO2) was 81+/-10%. SDB was similar on admission vs. follow-up polysomnography (mean AHI 44+/-39/h vs. 38+/-31/h; CSB 53+/-38% vs. 46+/-37% TST). Follow-up polysomnography showed a higher nadir SaO2 than admission (84+/-11% vs. 79+/-12%, p=0.05), but TST with SaO2<90% was not reduced. CONCLUSIONS CSB is common and severe in patients hospitalized with decompensated HF. Acute treatment of HF does not consistently improve CSB. The effect of CSB on ventricular function and prognosis in decompensated HF remains to be demonstrated.

Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure

A broad spectrum of concomitant disorders may complicate heart failure adding further morbidity and mortality risk. Comorbidities may be subdivided into cardiovascular and noncardiovascular. The first group includes hypertension, coronary artery disease, peripheral artery disease, cerebrovascular disease, arrhythmias and valvular heart disease. Noncardiovascular comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. In recent years, advances in the treatment of heart failure have not been attended by important changes in management of its comorbidities. They now seem to be major causes of the poor prognosis of heart failure patients. In this review we provide an updated summary of the epidemiological, pathophysiological and clinical characteristics of comorbidities as well as their potential impact for heart failure treatment.