Association between Right Ventricular Function and Exercise Capacity in Patients with Chronic Heart Failure.

BACKGROUND: The association between right ventricular function and exercise capacity in patients with chronic heart failure remains uncertain. Several studies very recently mentioned the association between right ventricular reserve and exercise capacity, whereas the implication of tricuspid annular plane systolic excursion (TAPSE) remains uninvestigated. We aimed to assess the impact of TAPSE on exercise capacity in cardiac rehabilitation candidates. METHODS: Data from patients with chronic heart failure who received cardiopulmonary exercise tests and transthoracic echocardiography prior to cardiac rehabilitation were retrospectively collected, and their association was investigated. RESULTS: A total of 169 patients with chronic heart failure (70.3 ± 11.7 years old, 74.6% men) were included. Tertiled tricuspid annular plane systolic excursion significantly stratified anaerobic threshold (10.2 ± 2.2, 11.4 ± 2.2, and 12.2 ± 2.8 mm; p < 0.01) and peak oxygen consumption (15.9 ± 4.5, 18.3 ± 5.3, and 19.8 ± 5.6 mm; p < 0.01). In the multivariate logistic regression analyses, TAPSE was an independent factor associated with anaerobic threshold and peak oxygen consumption (p < 0.05 for both). CONCLUSIONS: Right ventricular impairment was associated with reduced exercise capacity in patients with chronic heart failure. Such knowledge would be useful to estimate patients' exercise capacity and prescribe cardiac rehabilitation. Its longitudinal association and clinical implication need further studies.

Enhanced expression of hemoglobin scavenger receptor CD163 in accumulated macrophages within filtered debris between acute coronary syndromes and stable angina pectoris.

Coronary intraplaque hemorrhage up-regulates hemoglobin scavenger receptor CD163 expression on macrophages, and has an association with vulnerable plaque development. During percutaneous coronary intervention, mechanical plaque disruption exposes potentially embolic atheromatous contents from culprit plaque.In 37 patients with stable angina pectoris (SAP, n = 20) or acute coronary syndrome (ACS, n = 17), atherothrombotic debris was collected using a filter-based distal embolic protection device. We immunohistochemically determined CD14-positive macrophages and CD163-positive macrophages in filtered debris. We also examined the relation of CD14- and CD163-positive macrophages with culprit plaque volume and components evaluated with ultrasonic tissue characterization (VH-IVUS).The only significant difference in clinical characteristics between the two groups was in hs-CRP. In ACS, the percentage of CD14- and CD163-positive macrophages to the whole cells (%CD14 and %CD163, respectively) was significantly higher than that in SAP (20.1 ± 8.2 versus 8.8 ± 6.8%, P < 0.001 and 32.6 ± 18.9 versus 9.0 ± 3.8%, P < 0.001, respectively). In IVUS indices of culprit plaque, the remodeling index was significantly higher in ACS than in SAP. However, necrotic core component (%NC) in ACS was significantly higher than that in SAP. Furthermore, fibrotic component (%Fibrous) in ACS was significantly lower than that in SAP (56.1 ± 4.7 versus 60.1 ± 3.3%, P = 0.03). %CD14 and %CD163 had a significant positive correlation with %NC (%CD14: r = 0.40, P = 0.01 and %CD163: r = 0.45, P = 0.01), but only %CD163 was negatively correlated with %Fibrous (%CD163: r = -0.48, P = 0.01).These findings suggest that the presence of CD14- and CD163-positive macrophages may reflect plaque inflammation, NC expansion, and plaque vulnerability in patients with coronary heart disease.

Association between virtual histology intravascular ultrasound findings and subsequent coronary events in patients with acute coronary syndrome.

Virtual histology intravascular ultrasound (VH-IVUS) was employed to compare coronary plaque characteristics between acute coronary syndrome (ACS) patients with and without subsequent coronary events.It is critical to predict subsequent coronary events in patients treated for ACS. Coronary artery events sometimes occur in lesions that do not receive intervention.VH-IVUS was performed in 57 patients with ACS to analyze 83 non-culprit lesions. Characteristics of plaques in the non-culprit lesions were determined. Patients were followed-up for 4.8 ± 1.8 years.During the follow-up period, ACS and stable angina pectoris occurred in 7 patients in whom 13 non-culprit lesions had been analyzed. Seventy non-culprit lesions in 50 patients who did not experience subsequent coronary events were also analyzed. Plaque area was greater in 7 patients who had subsequent coronary events than in those who did not (11.5 ± 3.1 versus 9.1 ± 3.6 mm(3)/mm, P = 0.03). However, there was no significant difference in plaque burden between the two groups (57.1 ± 8.9 versus 55.6 ± 8.7%, P = 0.18). Areas of dense calcium (DC) and necrotic core (NC) were greater in patients who had subsequent coronary events than in those who did not (0.6 ± 0.5 versus 0.2 ± 0.3 mm(3)/mm, P < 0.001, and 1.8 ± 1.0 versus 1.0 ± 0.8 mm(3)/mm, P < 0.01, respectively). When DC area was larger (≥ 3.4% of the plaque area), the cumulative coronary event rate increased significantly (28.6 versus 6.5%, P < 0.01). This was also true for NC area (≥ 20.9%, 31.4 versus 5.1%, P < 0.01).Area size of DC or NC in non-culprit plaques may be associated with subsequent coronary events in patients with ACS.

Effects of eicosapentaenoic acid treatment on epicardial and abdominal visceral adipose tissue volumes in patients with coronary artery disease.

AIM: Epicardial adipose tissue (EAT) is a pathogenic fat depot that may be associated with coronary atherosclerosis and cardiovascular events. Because eicosapentaenoic acid (EPA) has been reported to exert cardiovascular protective effects, we aimed to assess the effects of EPA on the volume of visceral adipose tissue, including EAT and abdominal visceral adipose tissue (AVAT), using multislice computed tomography (CT). METHODS: In 30 patients with coronary artery diseases (9 women; mean age, 67.2 ± 5.4 years), EAT and AVAT volumes were compared between the control group (n=15, conventional therapy) and the EPA group (n=15, conventional therapy plus purified EPA 1800 mg/day) during a six-month period. EAT was defined as any pixel that had CT attenuation of -150 to -30 Hounsfield units (HU) within the pericardial sac. RESULTS: After the six-month follow-up, the serum EPA level increased from 59.9 ± 18.8 to 177.2 ± 3.3 µg/mL in the EPA group (p<0.01), but no increase was noted in the control group. Similarly, the EPA/arachidonic acid (AA) ratio increased from 0.39 ± 0.12 to 1.22 ± 0.28 in the EPA group (p<0.01), with no significant increase in the control group. The AVAT and EAT volumes decreased in the EPA group but were unchanged in the control group (AVAT, -11.6 ± 17.0 vs. +8.8 ± 13.6 cm(2), p<0.01; EAT, -7.3 ± 8.3 vs. +8.7 ± 8.8 cm(3), p<0.01). Moreover, the change in the AVAT volume negatively correlated with the change in EPA (r=-0.58, p<0.01) and EPA/AA levels (r=-0.53, p<0.01). A similar negative correlation in these parameters was also observed for the EAT volume. CONCLUSIONS: Oral intake of purified EPA appears to be associated with reductions in EAT and AVAT volumes.

Intravascular ultrasound predictors of CD163 positive macrophage infiltration.

OBJECTIVES: The present study aimed to determine characteristics of macrophage accumulation and predictors of CD163 positive macrophages by ultrasonic tissue characterization. BACKGROUND: Intraplaque hemorrhage is associated with plaque instability and induces macrophage accumulation with a scavenger receptor, CD163. These CD163 positive macrophages have anti-atherogenic property. METHODS: In 50 patients with acute coronary syndrome, lumen, vessel and plaque area, and plaque components (% fibrous, % fibro fatty, % dense calcium, and % necrotic core) of the culprit lesion were determined by virtual histology (VH) intravascular ultrasound (IVUS). Remodeling index (RI) was also determined. Atherothrombotic debris of the culprit lesion was collected during percutaneous coronary intervention using a distal protection device. CD163 positive macrophages and glycophorin A (a protein specific to erythrocytes) were determined immunohistochemically. RESULTS: Percentage of CD163 positive macrophages to the whole cells (% CD163) correlated positively with lumen, vessel and plaque area, and RI. Further, % CD163 had significant positive correlation with % necrotic core and negative correlation with % dense calcium. Immunopositive areas of glycophorin A (% glycophorin A), expressed as the ratio of positively stained areas per total tissue, had a significant positive correlation with % CD163. On multivariate analysis, % necrotic core, % dense calcium, and RI were independent determinants of % CD163. CONCLUSION: Positive remodeling and large necrotic core without calcification on VH-IVUS were likely to indicate coronary intraplaque hemorrhage with CD163 positive macrophages infiltration.

Association of reduced levels of serum 1,5-Anhydro-d-glucitol with carotid atherosclerosis in patients with type 2 diabetes.

BACKGROUND: HbA1c level represents mean blood glycemic control. 1,5-Anhydro-d-glucitol (1,5-AG) level reflects glycemic fluctuations, a strong risk factor for the development of macroangiopathy. The present study investigated the relationship between serum 1,5-AG levels and macroangiopathy in patients with type 2 diabetes. METHODS: A total of 115 consecutive patients with type 2 diabetes, aged 45-79 years, were included. HbA1c, 1,5-AG, and lipid profile were measured. Carotid maximum intima-media thickness (IMT) and plaque score (PS) were determined by carotid sonography. An 1,5-AG level < 14.2 µg/mL was used as a predictor of a post-challenge 2-h blood glucose level > 200 mg/dL. Patients were divided into four groups: A (n=32), HbA1c ≥ 6.5% and 1,5-AG<14.2 µg/mL; B (n=23), HbA1c ≥ 6.5% and 1,5-AG ≥ 14.2 µg/mL; C (n=24), HbA1c < 6.5% and 1,5-AG <14.2 µg/mL; and D (n=36), HbA1c < 6.5% and 1,5-AG ≥ 14.2 µg/mL. RESULTS: HbA1c level had significant positive correlation with IMT and PS. 1,5-AG level had a significant negative correlation with PS. PS was significantly higher in group C than in group D, but similar to that in group B. In multivariate analysis, HbA1c (ß=0.27, p=0.03) and 1,5-AG (ß=-0.24, P=0.04) were independent determinants of PS. CONCLUSIONS: 1,5-AG level might provide additional information to identify macroangiopathy of patients with type 2 diabetes, especially in those with excellent HbA1c levels.

Impaired macrophage production of anti-atherosclerotic interleukin-10 induced by coronary intraplaque hemorrhage in patients with acute coronary syndrome and hyperglycemia.

BACKGROUND: Coronary intraplaque hemorrhage (IPH) accelerates atherosclerosis. Extracellular hemoglobin (Hb) released by IPH is cleared by macrophages with CD163 receptors. This process provokes secretion of the anti-atherosclerotic cytokine interleukin (IL)-10. The present study aimed to investigate the relationship between macrophage accumulation and IL-10 production provoked by IPH in plaques obtained from acute coronary syndrome (ACS) patients with hyperglycemia. METHODS: In 50 ACS patients, atherothrombotic debris was retrieved during percutaneous coronary intervention (PCI). The debris was stained with antibodies to CD163, glycophorin A (GPA, a marker of IPH) and IL-10. %CD163 was defined as the ratios of CD163-positive cells to all cells. %IL-10 and %GPA were defined as the ratio of positively stained areas per total tissue area. Based on glycosylated Hb [HbA1c (NGSP)] ≥ 6.5%, fasting blood sugar (FBS) ≥ 126 mg/dL, and insulin resistance (HOMA-IR>2.5), patients were divided into a diabetes mellitus (DM) group (N = 18, HbA1c ≥ 6.5% or FBS ≥ 126 mg/dL), an insulin resistance (IR) group (N = 15, HOMA-IR>2.5, HbA1c<6.5%, and FBS< 126 mg/dL), and a normal (NR) group (N = 17). RESULTS: Compared to the NR group, %GPA and %CD163 were increased in the DM and IR groups. %IL-10 was similar among the three groups. However, %IL-10/%CD163 ratios were decreased in the DM (2.5 ± 0.6, P = 0.01) and IR (2.7 ± 0.8, P = 0.02) groups compared to the NR group (5.8 ± 4.7). Only in the NR group was there a significant correlation between %IL-10 and %CD163. CONCLUSIONS: Impairment of the anti-inflammatory effect provoked by IPH contributes to premature atherosclerosis even in the IR group.

The impact of anti-inflammatory cytokines provoked by CD163 positive macrophages on ventricular functional recovery after myocardial infarction.

Present study aimed to investigate the impact of anti-inflammatory cytokines provoked by the hemoglobin scavenger receptor, CD163, on left ventricular (LV) functional recovery after successful reperfusion in patients with acute myocardial infarction (AMI). Intraplaque hemorrhage accelerates plaque destabilization. Extracellular hemoglobin is cleared by CD163, a macrophage scavenger receptor. This process provokes secretion of anti-inflammatory atheroprotective cytokine, interleukin (IL)-10. In 40 patients with the first AMI, coronary atherothrombotic debris was retrieved during percutaneous coronary intervention (PCI), stained with antibodies to CD163 and IL-10. LV function was determined by echocardiography before PCI and 6 months after PCI. %CD163 was defined as ratio of CD163 (+)-cells to whole cells. %IL-10 was expressed as the ratio of positively stained areas per total tissue. Patients were divided into two groups depending on the amount of CD163 (+)-cells: CD163 > 10 % (CD163high, n = 20) and CD163 ≤ 10 % (CD163low, n = 20). CD163high group had significantly higher %IL-10. Final thrombolysis in myocardial infarction (TIMI) flow grade was significantly lower in CD163high group. In subgroups with the final TIMI-3 flow (CD163high-Reflow, n = 15 and CD163low-Reflow, n = 20), the time to reperfusion, infarct size, LV dimensions and fractional shortening (%FS) before PCI were similar. Significant correlation was observed between %IL10 and changes in LV dimensions (diastole, r = -0.49, P = 0.01; systole, r = -0.65, P < 0.01) or %FS (r = 0.51, P < 0.01) at 6 months after PCI. Plaque with CD163(+)-macrophages could impair distal flow after primary PCI. However, CD163(+)-macrophages enhance the anti-inflammatory cytokine expression that aids in ventricular functional recovery if distal flow can be achieved by successful reperfusion.

Impact of preinterventional plaque composition and eccentricity on late-acquired incomplete stent apposition after sirolimus-eluting stent implantation: an intravascular ultrasound radiofrequency analysis.

OBJECTIVES: The present study aimed to investigate differences in plaque morphology and components in between the target coronary artery lesion with and without late-acquired incomplete stent apposition (LISA) using radiofrequency analysis (virtual histology) of intravascular ultrasound data. BACKGROUND: Incomplete stent apposition is frequently observed in patients with very late stent thrombosis after sirolimus-eluting stent implantation. METHODS: The study group consisted of 70 coronary artery lesions in 43 patients who underwent elective coronary stenting for stable angina pectoris. Virtual histology intravascular ultrasound was performed at the implantation of stent and 12-month follow-up. LISA was defined as a separation of stent struts from the intimal surface of the arterial wall that had not been present at the time of stent implantation. The plaque eccentricity index (EI) was calculated as (lumen radius+maximal plaque thickness)/(lumen radius+minimal plaque thickness). RESULTS: At 12-month follow-up, LISA occurred in 15 plaques (LISA group). Compared with the non-LISA group, the LISA group had significantly longer stents, a higher EI, smaller amount of fibro-fatty component (7.7±4.2 vs. 12.5±7.0%, P=0.01) and larger amount of necrotic core component (16.6±9.8 vs. 11.1±6.4%, P=0.06). Multivariate logistic regression analysis revealed that amount of necrotic core and plaque EI were independent positive predictors for LISA (odds ratio=1.4, 95% confidence interval=1.1-1.6, P=0.04 and 11.2, 1.9-64.9, P<0.01, respectively). CONCLUSION: Plaques with increased amounts of necrotic core and higher eccentricity are associated with subsequent LISA after sirolimus-eluting stent implantation.

Combination therapy of candesartan with statin inhibits progression of atherosclerosis more than statin alone in patients with coronary artery disease.

OBJECTIVES: Both statins and renin-angiotensin system (RAS) inhibitors inhibit atherosclerotic progression and reduce cardiovascular events. However, it remains unclear whether combination therapy of RAS inhibitor with statin could inhibit plaque progression more than statin alone. METHODS: Using 64 multislice computed tomography, vessel wall areas (VWAs) and total vascular areas of the left main trunk (LMT) and proximal right coronary artery (RCA) and the thoracic descending aorta (TDA) were determined in patients with coronary artery disease before and after 2.0-year treatment with atorvastatin and candesartan (n=20) or with atorvastatin alone (n=16), although these patients had been treated with the combination therapy or statin alone at the study enrollment. Plasma levels of high sensitive C-reactive protein, matrix metalloproteinase-9, and urinary 8-iso-prostaglandin F2α were determined at the baseline. RESULTS: There were no significant differences in low-density lipoprotein and high-density lipoprotein cholesterol, C-reactive protein, matrix metalloproteinase-9, or urinary 8-iso-prostaglandin F2α levels between the two groups. Two years later, total vascular areas of TDA and RCA increased significantly in the atorvastatin group but not in the combination group. Moreover, increases in VWAs were less in the combination group than in the atorvastatin group in TDA (3.6 ± 23.1 vs. 28.6 ± 25.5 mm, P=0.004), RCA (-1.6 ±1.6 vs. 0.6 ± 2.5 mm, P=0.005), and left main trunk (-0.9 ± 3.5 vs. 1.3 ± 2.4 mm, P=0.095). Biomarker levels at the baseline did not affect the progression of VWA. CONCLUSION: Combination therapy of RAS inhibitor with statin is more effective than statin alone in inhibiting atherosclerotic progression of coronary arteries and the aorta in patients with coronary artery disease.

Plaque regression in one artery is not necessarily associated with parallel changes in other vascular beds.

It remains unclear whether atherosclerosis in one vascular bed progresses in parallel with that in other vascular beds. We investigated serial changes in vessel wall areas (VWAs) in various vessels over 2 years of follow-up. Vessel wall areas in the thoracic descending aorta (TDA), common carotid artery (CCA), right (RCA), and left main trunk (LMT) of coronary artery were determined in 52 patients with coronary artery disease (CAD) using 64-slice multidetector computed tomography. Plasma levels of high-sensitivity CRP (hs-CRP) and matrix metalloproteinase (MMP)-9, as well as urinary 8-iso-prostaglandin F2α (PGF2α) were determined at the baseline. After the follow-up period, plaque progression in a specific vessel did not parallel that of other vessels, although changes in TDA-VWAs were weakly correlated with those of LMT-VWAs. Basal levels of hs-CRP, MMP-9, and PGF2α did not predict progression or regression of VWAs in any vessels. Multivariate analyses showed that LDL-cholesterol < 100 mg/dl and use of statin emerged as predictors of regressing VWAs in TDA (p < 0.05 and p < 0.05, respectively) and LMT (p < 0.05 and p = 0.13, respectively). Changes in soft plaques over 2 years paralleled those of VWAs in both coronary arteries. In conclusion, the progression or regression of atherosclerotic plaques is inhomogeneous among the vascular beds of patients with CAD.

Circadian changes in autonomic function in conscious rats with heart failure: effects of amiodarone on sympathetic surge.

Cardiovascular events are characterized by circadian periodicity with a peak prevalence during the awakening period, which suggests a morning surge in sympathetic activity. We developed an experimental system to determine circadian changes in heart rate (HR), blood pressure (BP), locomotor activity (Loc), respiratory rate and autonomic function in conscious, unrestrained rats. The effects of amiodarone on circadian variation of these variables were determined in rats with myocardial infarction and subsequent congestive heart failure (CHF). We continuously recorded BP, HR and Loc for 24h in rats with CHF (n=16) or after a sham operation (Sham; n=7). To determine circadian changes in sympathovagal balance, digitized BP and HR data throughout 24h were analyzed based on maximum entropy. The study was repeated after 3 weeks of oral amiodarone (50mg/kg/day) or saline administration. Baseline HR, mean BP, and Loc were higher in the dark period than in the light period (all p<0.05) in both CHF and Sham rats, which is consistent with the circadian periodicity of nocturnal animals. Low-frequency components of diastolic BP variability (LFdp), an index of sympathetic tone, were significantly higher during the awakening period (16:00-20:00) than during the sleeping period (08:00-14:00), a finding analogous to the sympathetic morning surge in men. Amiodarone suppressed this transient increase in LFdp power during the awakening period. Our experimental system could detect sympathetic surge in conscious rats. Amiodarone suppressed the sympathetic surge, which could explain, at least in part, beneficial effects of amiodarone in patients with CHF.

Central sympathetic inhibition augments sleep-related ultradian rhythm of parasympathetic tone in patients with chronic heart failure.

BACKGROUND: Abnormal sleep dynamics in patients with heart failure is one of the mechanisms for the relative predominance of central sympathetic outflow over parasympathetic tone. This study was designed to examine whether central sympathoinhibition could improve the sympathovagal imbalance related to rapid-eye-movement (REM)/non-REM ultradian sleep rhythm in these patients. METHODS AND RESULTS: Beat-by-beat RR intervals of overnight electrocardiogram were serially subject to power spectral analysis in 14 patients with chronic heart failure and 13 age-matched subjects with normal cardiac function. To assess autonomic sleep dynamics, the ultradian rhythm was extracted from all-night consecutive high-frequency (HF) components of heart rate variability (HRV) before and after administration of an (alpha2)-adrenergic agonist, guanfacine. Night-time HRV in heart failure was characterized by an attenuated ultradian rhythm of HF-components with a concomitant reduction in averaged HF power. Guanfacine reduced blood pressure, heart rate, and plasma norepinephrine concentrations by 7%, 8%, and 34% (p < 0.01), respectively. After guanfacine, HF power rose by 154% (p < 0.01) with a prominent augmentation of the all-night ultradian rhythm (+361%, p < 0.01). CONCLUSIONS: Central sympathoinhibition augments a sleep-related ultradian rhythm of parasympathetic tone, suggesting a potential benefit to autonomic balancing and sleep quality in patients with chronic heart failure.

Circadian dynamics of heart rate and physical activity in patients with heart failure.

The present study was designed to develop a method to continuously measure Holter electrocardiogram (ECG) and physical activity in terms of metabolic costs to examine circadian dynamics of RR intervals and physical activity in patients with heart failure. A total of 7 healthy subjects and 3 heart failure patients performed cardiopulmonary exercise test using four-stage graded treadmill walking at 0% grade to examine whether the acceleration signals in the vertical direction could reflect actual body energy expenditure during physical activity. Then, using this new method, 24-hr monitorings of ECG and physical activity were performed in 24 inpatients with heart failure while they were allowed to walk around freely. Our results showed the integral of rectified acceleration signals was closely correlated with actual metabolic cost in all subjects. Instantaneous changes in heart rate were quite concordant with physical activity. As compared with the asymptomatic patients (n = 12), the symptomatic patients (n = 12) had lower energy expenditure during 8-hr daytime periods but higher mean heart rate. Furthermore, a more prominent ultradian rhythm of circadian changes in heart rate and physical activity was found in 50% of all subjects studied. The simultaneous analysis of Holter ECG and physical activity as the same time series revealed that in patients with heart failure, sympathovagal balance shifted toward sympathotonic conditions and their physical activity could become subject to intrinsic ultradian dynamics of body's homeostasis.

Prolonged activation of hemostatic markers following conversion of atrial flutter to sinus rhythm.

BACKGROUND: It remains controversial whether prophylactic anticoagulation for embolism is required in patients with atrial flutter (AFL) prior to and following cardioversion as in patients with atrial fibrillation. To evaluate the potential prothrombotic state following cardioversion of AFL, concentrations of hemostatic markers were determined before and after conversion to sinus rhythm (SR). METHODS AND RESULTS: In 12 patients (mean age 68 years) with AFL who underwent transesophageal echocardiography in the plasma concentrations of markers for platelet activity (platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG)), thrombotic status (thrombin-antithrombin III complex (TAT) and prothrombin fragments 1 and 2 (F1+2)) and fibrinolytic status (D-dimer and plasmin-alpha(2)-plasmin inhibitor complex (PIC)) were determined during AFL, and 3 days and 7 days after restoration of SR. Left atrial appendage (LAA) blood flow velocity was lower immediately after than before restoration of SR (29+/-11 vs 41+/-23 cm/s, p<0.05). Three patients developed left atrial spontaneous echo contrast immediately after restoration of SR. Although the concentrations of the markers of platelet activity did not change after restoration of SR, those of TAT and PIC increased 7 days after restoration of SR as compared with during AFL (p<0.05). CONCLUSIONS: AFL patients have a potential risk for thromboembolism after restoration of SR and therefore anticoagulation might be required in selected patients.

Pulse-synchronous sympathetic burst power as a new index of sympathoexcitation in patients with heart failure.

The upper limit of incidence of muscle sympathetic neural bursts can lead to underestimation of sympathetic activity in patients with severe heart failure. This study aimed to evaluate the pulse-synchronous burst power of muscle sympathetic nerve activity (MSNA) as a more specific indicator that could discriminate sympathetic activity in patients with heart failure. In 54 patients with heart failure, the pulse-synchronous burst power at the mean heart rate was quantified by spectral analysis of MSNA. Thirteen patients received a central sympatholytic agent (guanfacine) for 5 days to validate the feasibility of this new index. Both burst incidence and plasma norepinephrine level showed no significant difference between patients in New York Heart Association functional class III (94 +/- 6 per 100 heartbeats and 477 +/- 219 pg/ml, respectively) and class II (79 +/- 14 per 100 heartbeats and 424 +/- 268 pg/ml, respectively). In contrast, the burst power was useful for discriminating patients in class III from those in class II (61 +/- 8% vs. 39 +/- 10%; P < 0.05). Inhibition of sympathetic nerve activity by guanfacine was more sensitively reflected by the change of burst power (-36 +/- 25%) than by that of burst incidence (-12 +/- 14%; P < 0.001). The sympathetic burst power reflects both burst frequency and amplitude independently of the absolute values and provides a sensitive new index for interindividual comparisons of sympathetic activity in patients with heart failure.

Attenuated respiratory modulation of chemoreflex-mediated sympathoexcitation in patients with chronic heart failure.

BACKGROUND: Enhanced hypercapnic chemoreflex in chronic heart failure could modulate sympathetic nerve activity in a different manner depending on the severity of heart failure. This study was designed to evaluate the dynamic aspects of sympathoexcitation caused by central hypercapnic chemoreflex in patients with chronic heart failure. METHODS AND RESULTS: In 21 patients with chronic heart failure, wavelet analysis was applied to elucidate the spectral components of muscle sympathetic nerve activity (MSNA) and instantaneous ventilation during hypercapnic chemoreceptor stimulation. Hypercapnia increased MSNA (83+/-8 versus 29+/-9 %, P<.01) and ventilation (209+/-27 versus 190+/-21%, P<.05) more in 12 symptomatic patients than in 9 asymptomatic patients. This hypercapnic chemoreflex exerted a greater influence on the sympathetic limb than on the ventilatory limb in the symptomatic patients. The wavelet analysis revealed that the within-breath sympathoinhibition in the symptomatic patients was attenuated as compared with that in the asymptomatic patients (0.33+/-0.03 vs. 0.44+/-0.04, P<.05). CONCLUSIONS: The enhanced chemoreflex sympathetic drive and relative attenuation of ventilatory sympathoinhibition could contribute to exaggerated sympathoexcitation in patients with heart failure when they are exposed to carbon dioxide during exercise or sleep apnea.

Role of central sympathoexcitation in enhanced hypercapnic chemosensitivity in patients with heart failure.

BACKGROUND: Enhanced central hypercapnic chemosensitivity is known to mediate excessive exercise ventilation and to indicate a poor prognosis in patients with chronic heart failure. The present study was designed to elucidate the role of central sympathetic activity in the enhancement of hypercapnic chemosensitivity. METHODS: Central hypercapnic chemosensitivity and plasma norepinephrine were measured in 99 patients with chronic heart failure. In 40 patients, the alpha index was derived from simultaneous analysis of R-R interval and systolic blood pressure variability. The effects of a central sympatholytic agent, guanfacine (0.25 mg/day), on hypercapnic chemosensitivity and exercise ventilatory response were studied in 20 of these patients. RESULTS: Hypercapnic chemosensitivity was enhanced in 76% of the patients and correlated significantly with plasma norepinephrine levels (r = 0.49, P < .01) at rest. There was a significant inverse relationship between central chemosensitivity and the alpha index (r = -0.41, P < .01). Guanfacine significantly reduced plasma norepinephrine levels by 29% (P < .01) and chemosensitivity by 31% (P < .01). The beneficial effect of central sympathoinhibition with guanfacine was observed specifically in patients who had enhanced chemosensitivity prior to drug administration. Similarly, the patients with excessive exercise ventilation showed a greater reduction in exercise ventilation with this agent. CONCLUSIONS: The present findings suggest that central sympathoexcitation could play an important role in the pathogenesis of enhanced hypercapnic chemosensitivity and a resultant increase in exercise ventilation in chronic heart failure.

Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.

STUDY OBJECTIVES: The prevalence of thromboembolism might be higher than previously recognized in patients with atrial flutter (AFL) based on findings of transesophageal echocardiography (TEE). To evaluate the potential prothrombotic state in patients with AFL, TEE findings and hemostatic markers were compared among patient groups with AFL, normal sinus rhythm (NSR) and chronic nonvalvular atrial fibrillation (AF). DESIGN AND SETTINGS: Cross-sectional study at a university hospital. METHODS: In 28 patients (mean age, 63 years) with AFL, 58 patients (mean age, 66 years) with AF, and 27 patients (mean age, 61 years) with NSR who underwent TEE, plasma levels of markers for platelet activity (platelet factor 4 and beta-thromboglobulin [beta-TG]), thrombotic status (thrombin-antithrombin III complex and prothrombin fragments 1 and 2) and fibrinolytic status (d-dimer and plasmin-alpha(2)-plasmin inhibitor complex) were determined. RESULTS: Left atrial appendage (LAA) blood flow velocity in patients with AFL was higher (p < 0.05) than that in patients with AF, but was lower (p < 0.05) than that in patients with NSR (AF, 25 +/- 2; AFL, 44 +/- 4; NSR, 60 +/- 4 cm/s). Dense left atrial spontaneous echo contrast (SEC) was found in 4 patients (14%) with AFL and 16 patients (28%) with AF. There was no significant difference in plasma levels of hemostatic markers between the AFL group and the NSR group. AFL patients with impaired LAA function (LAA flow < 30cm/s, dense SEC, or both), however, showed higher level of d-dimer and beta-TG than those without impaired LAA function (d-dimer, 1.9 +/- 0.6 microg/mL vs 0.4 +/- 0.1 microg/mL; beta-TG, 73 +/- 17 ng/mL vs 33 +/- 5 ng/mL, p < 0.05). CONCLUSIONS: Patients with AFL as a whole are not in the prothrombotic state as compared with those with AF. However, patients with AFL and impaired LAA function are at potentially high risk for thromboembolism and might require anticoagulation.