Alena Shantsila

Left Ventricular Systolic and Diastolic Function in Obstructive Sleep Apnea: Impact of Continuous Positive Airway Pressure Therapy

Background— Previous studies in obstructive sleep apnea (OSA) were limited by study cohorts with comorbidities that confound assessment of left ventricular (LV) systolic and diastolic function. We comprehensively evaluated LV function using 2-dimensional echocardiography (2DE), tissue Doppler imaging (TDI), and 3-dimensional echocardiography (3DE) in subjects moderate-severe OSA, who were compared with disease (patients with hypertension, no OSA) and healthy control subjects. Methods and Results— A total of 120 subjects (n=40 each of matched OSA, hypertension and healthy cohorts) underwent echocardiographic examination for the assessment of septal and posterior wall thickness, LV mass index, LV volumes and ejection fraction, mitral valve inflow indices (E, A), mitral annular velocity (S, E′), and left atrial volume index (LAVI). OSA subjects were treated with continuous positive airway pressure (mean duration of 26 weeks), after which the echocardiographic parameters were reassessed. Posterior wall thickness and LV mass index were significantly higher in OSA and hypertensive groups compared with healthy. Systolic S velocity was reduced in OSA and hypertensive compared with healthy control subjects ( P <0.05). Diastolic function (E/A, IVRT, and E/E′) was impaired in both OSA and hypertensive groups. On 3DE, mean LAVI was significantly greater in OSA and hypertensive compared with healthy. In OSA patients, continuous positive airway pressure therapy resulted in reduction of the posterior wall thickness ( P =0.02) and improvement in LV ejection fraction ( P <0.05), systolic S velocity ( P <0.05), and diastolic LV impairment parameters. Conclusions— Moderate to severe OSA causes structural and functional changes in LV function and are comparable to that seen in hypertension. These abnormalities significantly improve after CPAP therapy.Background—Previous studies in obstructive sleep apnea (OSA) were limited by study cohorts with comorbidities that confound assessment of left ventricular (LV) systolic and diastolic function. We comprehensively evaluated LV function using 2-dimensional echocardiography (2DE), tissue Doppler imaging (TDI), and 3-dimensional echocardiography (3DE) in subjects moderate-severe OSA, who were compared with disease (patients with hypertension, no OSA) and healthy control subjects. Methods and Results—A total of 120 subjects (n=40 each of matched OSA, hypertension and healthy cohorts) underwent echocardiographic examination for the assessment of septal and posterior wall thickness, LV mass index, LV volumes and ejection fraction, mitral valve inflow indices (E, A), mitral annular velocity (S, E′), and left atrial volume index (LAVI). OSA subjects were treated with continuous positive airway pressure (mean duration of 26 weeks), after which the echocardiographic parameters were reassessed. Posterior wall thickness and LV mass index were significantly higher in OSA and hypertensive groups compared with healthy. Systolic S velocity was reduced in OSA and hypertensive compared with healthy control subjects (P<0.05). Diastolic function (E/A, IVRT, and E/E′) was impaired in both OSA and hypertensive groups. On 3DE, mean LAVI was significantly greater in OSA and hypertensive compared with healthy. In OSA patients, continuous positive airway pressure therapy resulted in reduction of the posterior wall thickness (P=0.02) and improvement in LV ejection fraction (P<0.05), systolic S velocity (P<0.05), and diastolic LV impairment parameters. Conclusions—Moderate to severe OSA causes structural and functional changes in LV function and are comparable to that seen in hypertension. These abnormalities significantly improve after CPAP therapy.

Myocardial Perfusion by Myocardial Contrast Echocardiography and Endothelial Dysfunction in Obstructive Sleep Apnea

Obstructive sleep apnea is associated with increased cardiovascular morbidity and mortality. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial dysfunction in normotensive subjects with moderate-to-severe obstructive sleep apnea, who were compared with hypertensive and healthy subjects, as well as the impact of continuous positive airway pressure treatment on obstructive sleep apnea subjects. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), cutaneous perfusion responses to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, and circulating endothelial and endothelial progenitor cells in a total of 108 subjects (n=36 each of matched obstructive sleep apnea, hypertension, and healthy cohorts). Subjects with obstructive sleep apnea and hypertension demonstrated abnormal myocardial perfusion (P<0.001 for both comparisons), attenuated brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) compared with healthy individuals. Both hypertensive and obstructive sleep apnea patients showed significant improvements in myocardial perfusion (P<0.01), brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) after 26 weeks of continuous positive airway pressure therapy. There were no significant differences in pulse wave velocity and endothelial cells across the 3 groups. Concomitant endothelial dysfunction and impaired myocardial perfusion are present in otherwise normal subjects with moderate-to-severe obstructive sleep apnea, and effective continuous positive airway pressure treatment reverses many of these macrovascular/microvascular abnormalities.

Persistent Macrovascular and Microvascular Dysfunction in Patients With Malignant Hypertension

Endothelial dysfunction is characteristic of patients with essential hypertension, but only limited data are available on different aspects of endothelial function in patients with malignant-phase hypertension. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial damage/dysfunction in patients with previous malignant hypertension (but now in stable phase), who were compared with patients with treated “high-risk” hypertension (hypertension) and healthy controls. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), microvascular (forearm) response to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, circulating endothelial and endothelial progenitor cells in 15 patients with malignant hypertension, 40 matched patients with hypertension, and 40 healthy controls. Patients with malignant hypertension had impaired endothelial-dependant response to acetylcholine (P<0.001, but not to sodium nitroprusside) compared with hypertension and impaired reaction to both stimuli compared with healthy subjects (P<0.001). Patients with malignant hypertension had increased circulating endothelial cells (P=0.001), endothelial progenitors (P=0.008), and stiffness (P=0.003). Both hypertensive groups had impaired response to hyperemia and glyceryl trinitrate when compared with healthy controls (P<0.05). Both hypertensive groups had similar myocardial perfusion, which was significantly lower than in healthy controls. There were no significant differences in hyperemia and endothelium-independent stimuli between the 2 hypertensive groups. In conclusion, despite fairly well-controlled blood pressure, malignant hypertension patients had more pronounced abnormalities of macrovascular and microvascular function (which seem to be both endothelium dependent and endothelium independent) compared with patients with hypertension and healthy controls.

Microparticles and Arterial Disease

Microparticles (MPs) are small (diameter <1 microm) fragments that seem likely to represent some form of physiology and/or pathophysiology of the originating cell, be it endothelial, platelet, or leukocyte. Increased numbers of MPs are found in various disease states, including cardiovascular disease, and a considerable weight of literature suggests a value in dissecting the various aspects of cell biology. A role in coagulation has been proposed because there is evidence that some MPs expose tissue factor. This article reviews the definitions, mechanisms of production, and links with pathophysiology of MPs in arterial disease, and thus whether or not they can contribute to improved patient care.

Muscle metaboreflex and autonomic regulation of heart rate in humans

•  Heart rate increases during exercise due to withdrawal of cardiac parasympathetic tone and increased cardiac sympathetic nerve activity. •  We investigated the autonomic mechanisms whereby heart rate is regulated by the activation of metabolically sensitive skeletal muscle afferents (muscle metaboreflex). •  Heart rate responses elicited by partial flow restriction during leg cycling (enhanced metaboreflex activation) and post‐exercise muscle ischemia following leg cycling and handgrip (isolated metaboreflex activation) were evaluated under control (no drug), β‐adrenergic blockade and parasympathetic blockade conditions. •  We show that the muscle metaboreflex principally elevates heart rate by increasing cardiac sympathetic activity, and only following dynamic exercise with a large muscle mass (post‐exercise muscle ischemia following leg cycling) does the partial withdrawal of cardiac parasympathetic tone make a contribution to this heart rate response. •  These findings may have implications for patient populations in which alterations in skeletal muscle afferent sensitivity have been identified.

Rivaroxaban Versus Dabigatran or Warfarin in Real-World Studies of Stroke Prevention in Atrial Fibrillation: Systematic Review and Meta-Analysis

Background and Purpose— This study was designed to evaluate the effectiveness and safety of rivaroxaban in real-world practice compared with effectiveness and safety of dabigatran or warfarin for stroke prevention in atrial fibrillation through meta-analyzing observational studies. Methods— Seventeen studies were included after searching in PubMed for studies reporting the comparative effectiveness and safety of rivaroxaban versus dabigatran (n=3), rivaroxaban versus Warfarin (n=11), or both (n=3) for stroke prevention in atrial fibrillation. Results— Overall, the risks of stroke/systematic thromboembolism with rivaroxaban were similar when compared with those with dabigatran (stroke/thromboembolism: hazard ratio, 1.02; 95% confidence interval, 0.91–1.13; I2=70.2%, N=5), but were significantly reduced when compared with those with warfarin (hazard ratio, 0.75; 95% confidence interval, 0.64–0.85; I2=45.1%, N=9). Major bleeding risk was significantly higher with rivaroxaban than with dabigatran (hazard ratio, 1.38; 95% confidence interval, 1.27–1.49; I2=26.1%, N=5), but similar to that with warfarin (hazard ratio, 0.99; 95% confidence interval, 0.91–1.07; I2=0.0%, N=6). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding, but similar risk of acute myocardial infarction and intracranial hemorrhage when compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute myocardial infarction, but a higher risk of gastrointestinal bleeding and lower risk of intracranial hemorrhage. Conclusions— In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran, but was more effective than warfarin for the prevention of stroke/thromboembolism in atrial fibrillation patients. Major bleeding risk was significantly higher with rivaroxaban than with dabigatran, as was all-cause mortality and gastrointestinal bleeding. Rivaroxaban was comparable to warfarin for major bleeding, with an increased risk in gastrointestinal bleeding and decreased risk of intracranial hemorrhage.

Expression of monocyte subsets and angiogenic markers in relation to carotid plaque neovascularization in patients with pre-existing coronary artery disease and carotid stenosis.

Abstract Aim. To characterize blood monocyte subsets in patients with different degrees of carotid atherosclerosis and pathological carotid plaque neovascularization. Methods. Assessment of carotid plaque neovascularization using contrast ultrasonography and flow cytometric quantification of monocyte subsets and their receptors involved in inflammation, angiogenesis, and tissue repair was done in 40 patients with carotid stenosis ≥ 50% and CAD (CS > 50), 40 patients with carotid stenosis < 50% and documented CAD (CS < 50), 40 hypercholesterolaemic controls (HC group), and 40 normocholesterolaemic controls (NC). Results. CS > 50 and CS < 50 groups had increased counts of Mon1 (‘classical’ CD14++ CD16-CCR2 + cells) compared to HCs (P = 0.03, and P = 0.009). Mon3 (‘non-classical’ CD14 + CD16++ CCR2- cells) were only increased in CS < 50 compared with HCs (P < 0.01). Both CS>50 and CS < 50 groups showed increased expression of proinflammatory interleukin-6 receptor on Mon1 and Mon2 (‘intermediate’ CD14++ CD16 + CCR2+ cells); TLR4, proangiogenic Tie2 on all subsets (P < 0.01 for all). In multivariate regression analysis only high Mon1 count was a significant predictor of carotid stenosis (P = 0.04) and intima-media thickness (P = 0.02). In multivariate regression analysis only the Mon1 subset was significantly associated with severe, grade 2 neovascularization (P = 0.034). Conclusion. In this pilot study classical monocytes (Mon1) represent the only monocyte subset predictive of the severity of carotid and systemic atherosclerosis, such as carotid intima-media thickness, degree of carotid stenosis, and presence of carotid intraplaque neovascularization.

The Global Burden of Atrial Fibrillation and Stroke: A Systematic Review of the Clinical Epidemiology of Atrial Fibrillation in Asia

BACKGROUND: Our previous review reported great variability in the incidence and prevalence of atrial fibrillation (AF) in non‐Western cohorts, especially from Asian countries; in recent years, epidemiologic studies on AF have been increasingly reported from Asia. METHODS: The goal of this updated systematic review was to present the current knowledge base of AF epidemiology in Asian countries since our previous review. We also explored AF incidence and the risk of stroke in AF by using a meta‐analysis, with I2 testing the heterogeneity. Third, “real‐world” antithrombotic drug use for ischemic stroke (IS) prevention associated with AF was studied. RESULTS: A total of 58 articles from eight countries in Asia were included in the analysis. The summary annual incidence of AF was 5.38 (95% CI, 4.53–6.24; I2 = 99.5%; n = 10) per 1,000 person‐years, and the IS annual risk in AF was 3.0% (1.60%‐4.95%; I2 = 99.8%; n = 8) when meta‐analysis was performed on hospital‐ and community‐based studies. Hospital‐ and community‐based AF prevalence ranged from 0.37% to 3.56% and 2.8% to 15.8%, respectively. IS prevalence in AF ranged from 1.9% to 6.0% and 0.36% to 28.3% in community‐ and hospital‐based studies. Warfarin use in Chinese subjects is relatively low (1.0%‐4.1%) compared with Japanese subjects (49.1%‐70.0%) in community‐based studies. The rate of warfarin use was < 50% in hospital‐based studies. CONCLUSIONS: The incidence and prevalence of AF have increased in recent years, although great variability still exists in Asian countries. Variability in annual IS risk in patients with AF was apparent between hospital‐ and community‐based studies. However, the rate of warfarin use was < 50% in hospital studies from Asian countries.

Ethnic Differences in Macrovascular and Microvascular Function in Systolic Heart Failure

Background— Endothelial dysfunction is implicated in the pathophysiological features of heart failure (HF), and ethnic differences in the presentation of cardiovascular disease are evident, with an excess seen among South Asians (SAs). However, data on ethnic differences in endothelial function in HF are limited. Methods and Results— In a cross-sectional study, we recruited 128 subjects with systolic HF: 50 SAs, 50 whites, and 28 African Caribbeans (ACs). In addition, SAs with systolic HF were compared with 40 SAs with coronary artery disease without HF (“disease controls”) and 40 SA healthy controls. Macrovascular endothelial function was assessed by measurement of flow-mediated dilation (FMD) in response to hyperemia, arterial stiffness was assessed by the pulse-wave velocity, and microvascular endothelial function was assessed by forearm laser Doppler flowmetry. CD144-expressing endothelial microparticles were measured by flow cytometry. When compared with disease controls and healthy controls, SAs with HF had an impaired microvascular response to acetylcholine (P=0.001) and reduced FMD (P<0.001). In comparing ethnic groups, SAs with HF had an impaired response to acetylcholine (123±95.5%) compared with whites (258±156%) and ACs (286±173%, P<0.001 for both). Whites had a higher FMD (8.49±4.63%) than SAs (4.76±4.78%, P<0.001) and ACs (4.55±3.56%, P=0.01). No difference in endothelial-independent response was observed between study groups or in pulse-wave velocity. Ethnicity remained associated with microvascular endothelial function even after adjustment for age, presence of hypertension and diabetes mellitus, blood pressure, and glucose levels (P=0.003). There were no differences in numbers of endothelial microparticles. Conclusions— The SAs with HF have impaired microvascular and macrovascular endothelial function but preserved arterial elastic properties. Significant ethnic differences in endothelial function are evident in subjects with HF, with ethnicity being associated with microvascular endothelial dysfunction in this disorder.

Prediction of very late arrhythmia recurrence after radiofrequency catheter ablation of atrial fibrillation: The MB-LATER clinical score

Reliable prediction of very late recurrence of atrial fibrillation (VLRAF) occuring >12 months after catheter ablation (CA) in apparently “cured” patients could optimize long-term follow-up and modify decision-making regarding the discontinuation of oral anticoagulant therapy. In a single-centre cohort of consecutive patients post radiofrequency AFCA, we retrospectively derived a novel score for VLRAF prediction. Of 133 consecutive post AFCA patients (mean age 56.9 ± 11.8 years, 63.9% male, 69.2% with paroxysmal AF) who were arrhythmia-free at 12 months (excluding 3-month “blanking period”), 20 patients expirienced a VLRAF during a 29.1 ± 10.1-month follow-up, with a 3-year cumulative VLRAF rate of 31.1%. The MB-LATER score (Male, Bundle brunch block, Left atrium ≥47 mm, Type of AF [paroxysmal, persistent or long-standing persistent], and ER-AF = early recurrent AF), had better predictive ability for VLRAF (AUC 0.782) than the APPLE, ALARMc, BASE-AF2, CHADS2, CHA2DS2VASc or HATCH score (AUC 0.716, 0.671, 0.648, 0.552, 0.519 and 0.583, respectively), resulted in an improved net reclassification index (NRI) of 48.6–95.1% and better identified patients with subsequent VLRAF using decision-curve analysis (DCA). The MB-LATER score provides a readily available VLRAF risk assessment, and performs better than other scores. Validation of the MB-LATER score in other cohorts is underway.