Alteration of myocardial characteristics and function in patients with obstructive sleep apnea.

The aim of the present study was to examine subclinical effect of the severity of obstructive sleep apnea (OSA) on myocardial structural changes and function using echocardiographic integrated backscatter and tissue Doppler imaging. Fifty patients with suspected OSA underwent overnight polysomnography and echocardiographic assessment. The myocardial reflectivity and mitral annular velocity were obtained as measures of subclinical myocardial disease. The OSA patients had lower annular velocity and higher myocardial reflectivity compared with non-OSA subjects, although global systolic function was similar. In conclusion, OSA can affect myocardial integrity as well as myocardial diastolic function.

Depressed myocardial contractile reserve in patients with obstructive sleep apnea assessed by tissue Doppler imaging with dobutamine stress echocardiography.

BACKGROUND: Hypoxia has been suggested to affect myocardial contractile function in patients with obstructive sleep apnea (OSA). We sought to determine whether myocardial contractile reserve (MCR), as evaluated by echocardiographic tissue Doppler imaging with dobutamine stress (TDDS), might be depressed in OSA patients. METHODS: Thirty patients with suspected OSA (25 men and 5 women; mean age, 51 +/- 11 years [+/- SD]) underwent overnight polysomnography and TDDS. Peak myocardial systolic velocity (Sm) and peak myocardial early diastolic velocity (Em) in the 12 myocardial segments of the left ventricular (LV) walls were averaged, and the mean Sm and Em during TDDS were compared between patients with apnea-hypopnea index (AHI) <15/h (group 1, n = 13) and those with AHI >/= 15/h (group 2, n = 17). MCR was calculated as the difference between the resting and peak Sm during TDDS. RESULTS: In both groups, Sm increased dose dependently during TDDS. However, the relative increase in Sm was significantly lower in group 2, resulting in a lower value of MCR (5.5 +/- 1.2 cm/s vs 7.4 +/- 1.3 cm/s, p < 0.001). The Em was lower in group 2 compared with group 1 throughout TDDS. MCR was correlated significantly with AHI (r = - 0.67, p < 0.0001), resting Em (r = 0.53, p < 0.005), and body mass index (r = - 0.46, p < 0.05) independent of the LV mass index. CONCLUSIONS: OSA can affect MCR, implying an etiologic contribution from repetitive hypoxic events. TDDS could identify subtle abnormalities of OSA-related cardiac involvement.

Regional postsystolic shortening in patients with hypertrophic cardiomyopathy: its incidence and characteristics assessed by strain imaging.

BACKGROUND: Postsystolic shortening (PSS) is considered myocardial shortening after the point of aortic valve closure and can be observed physiologically in healthy individuals. However, the incidence and magnitude of PSS in myocardial disorders have not been investigated. OBJECTIVES: We performed strain imaging to characterize PSS in patients with hypertrophic cardiomyopathy (HCM) versus healthy individuals. METHODS: Thirty patients with HCM (22 men and 8 women; mean age 62+/-6 years) and 30 control subjects (20 men and 10 women; mean age 61 +/- 9 years) were studied. For both groups, patterns of myocardial strain curves were assessed by the 18-segment model using apical 2-chamber, 4-chamber, and long-axis views. PSS was defined if the peak strain existed beyond aortic valve closure. The severity of PSS was assessed as postsystolic index (strain amplitude beyond aortic closure divided by whole strain amplitude) for each segment. RESULTS: As compared with control subjects, patients with HCM had a greater isovolumic relaxation time (105 +/- 31 vs 74 +/- 28 milliseconds, P < .001), despite the comparable value of left ventricular ejection fraction (65 +/- 6% vs 65 +/- 4%, P = not significant). The number of segments having PSS was greater in patients with HCM than in control subjects (12.6 +/- 3.0 vs 8.4 +/- 3.7, P < .001). This was associated with greater values of postsystolic index in all segments for patients with HCM. In patients with HCM, the number of segments having PSS correlated significantly with the isovolumic relaxation time (r = 0.36, P < .05). CONCLUSIONS: Patients with HCM have more pathologic PSS, which may have etiologic contribution to the functional heterogeneity of this disease entity, especially diastolic dysfunction.

Angiotensin-II receptor blocker exerts cardioprotection in diabetic rats exposed to hypoxia.

BACKGROUND: Hypoxia caused by sleep apnea might be associated with an increased risk of cardiovascular events in subjects with metabolic syndrome. The aim of this study was to examine the effect of hypoxia on the left ventricular (LV) myocardium and evaluate the cardioprotective effect of an angiotensin-II receptor blocker (ARB) in diabetic rats. METHODS AND RESULTS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 30 weeks of age (n=30) were divided into 2 groups that were treated with vehicle or candesartan 0.2 mg x kg(-1) x day (-1). The animals were housed in a hypoxic gas chamber (oxygen, 10.0+/-0.5%, mean +/- standard deviation) for 2 weeks. Hypoxia increased right ventricular (RV) systolic pressure (hypoxia; 78+/-14 mmHg vs control; 22+/-5, p<0.05), but did not increase LV systolic pressure (131+/-23 mmHg vs 121+/-10). Hypoxia exacerbated the degeneration of cardiomyocytes, and accelerated the expression of hypoxia inducible factor-1alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) in the myocardium. Treatment with ARB decreased RV and LV pressures (46+/-7 and 100+/-18 mmHg, respectively), suppressed the expression of HIF-1alpha and VEGF, and preserved the fine structure of the LV myocardium. CONCLUSIONS: ARB exhibited cardioprotection under hypoxia, in part through the reduction of blood pressure and cytokine expression, in OLETF rats. Thus, ARB might be a potent agent for the treatment of diabetic patients with the complication of sleep apnea.

Nifedipine enhances the cardioprotective effect of an angiotensin-II receptor blocker in an experimental animal model of heart failure.

This study was designed to examine the hypothesis that a calcium channel blocker nifedipine (CCB) could enhance the cardioprotective effect of an angiotensin-ll receptor blocker candesartan (ARB) in the treatment for heart failure. Isoproterenol (ISP) was injected into male rats at 300 mg/kg to produce progressive heart failure. Three months later, the rats were divided into 4 groups and treated for 4 weeks with 1) vehicle (n = 20), 2) ARB at 0.2 mg/kg/day (n = 6), 3) CCB at 10 mg/kg/day (n = 6), or 4) both drugs (n = 8). Rats injected with saline served as controls (n = 13). ISP caused severe myocardial degeneration and decreased the capillary density (D(cap)) of the left ventricular (LV) myocardium (mean +/- SD: 2,197 +/- 627 vs. 2,847 +/- 298 N/mm2 for normal controls), while increasing plasma thiobarbituric acid-reactive substances (TBARS; 3.6 +/- 1.1 vs. 1.9 +/- 0.5 nmol/ml). Although ARB therapy preserved cardiac morphology, it had little effect on D(cap) or oxidative stress. On the other hand, CCB decreased plasma TBARS and 4-hydroxy-2-nonenal protein expression in LV myocardium. Furthermore, the combination of CCB and ARB increased D(cap) and preserved the ultrastructure of LV myocardium, so this combination may be a useful option for the treatment of heart failure.

Mechanisms of combined treatment with celiprolol and candesartan for ventricular remodeling in experimental heart failure.

BACKGROUND: Both beta-adrenergic blockers and angiotensin-II receptor blockers were reported to improve the prognosis of patients with heart failure, but the efficacy of combination therapy with these agents has not been fully elucidated. Also the efficacy of celiprolol, a beta1-selective adrenoceptor antagonist with partial beta2-agonist properties, for heart failure treatment is still controversial. We examined the cardioprotective effects and mechanisms of the therapy with celiprolol or candesartan, an angiotensin-II receptor blockers and their combination in heart failure induced by isoproterenol (ISO). METHODS AND RESULTS: ISO 300 mg/kg was injected in rats to produce heart failure. Two months after the injection, the ISO-injected rats were divided into 4 groups (8 rats each) and treated for 4 weeks as follows: (a) vehicle; (b) celiprolol 10 mg/kg per day (BB); (c) candesartan 0.2 mg/kg per day (ARB); and (d) their combination BB+ARB. ISO significantly elevated left ventricular (LV) end-diastolic pressure, decreased peak-negative dP/dt and LV ejection fraction. BB and ARB similarly ameliorated cardiac dysfunction due to ISO, but BB+ARB were more potent than the individual therapies. Separately, ARB preserved the histological structure in LV myocardium. In contrast, BB ameliorated calcium handling, as shown by the increased ratio of SERCA2 to phospholamban protein, despite having little effect on the histology. CONCLUSION: Both celiprolol and candesartan showed cardioprotective effects in this heart failure model. The potential use of the combination treatment in heart failure might result in a synergistic effect through the different cardioprotective mechanisms of celiprolol and candesartan.

Effects of postischemic regional left ventricular diastolic wall motion abnormalities or delayed relaxation following coronary vasospasm on global diastolic function.

BACKGROUND: Regional left ventricular (LV) diastolic wall motion abnormalities detected by color kinesis (CK), an echocardiographic technique, may be a more sensitive measure to postischemic damage following coronary spasm than parameters of global diastolic function. METHODS AND RESULTS: Regional LV diastolic wall motion was evaluated by using CK in 18 patients with variant angina on the day following coronary spasm, which was induced by intracoronary acetylcholine. Fractional regional LV cavity area expansion in the short-axis view during the first 30% of the LV filling time, was used to identify postischemic asynchronous diastolic wall motion. Regional delayed relaxation was observed in any of the LV regions in all the patients, who were divided into 2 groups (Group S: 7 patients with single-vessel spasm with regional delayed relaxation in one area. Group M: 11 patients with multivessel spasm or spasm of the proximal left anterior descending branch with regional delayed relaxation in multiple areas). In Group S, no abnormality (0%) was noted in any of the indexes of global diastolic function including the isovolumic relaxation time, the ratio of peak rapid filling to peak atrial filling velocities and the deceleration time. In contrast, in 5 (45%) of the Group M patients, abnormalities were noted in all of those indexes. CONCLUSIONS: Postischemic regional LV-delayed relaxation following coronary vasospasm was detected sensitively by analysis of CK images. The indexes of global LV diastolic function are insensitive to postischemic damage following single vessel spasm, although they are somewhat sensitive following multivessel spasm.

Serum thioredoxin and alpha-tocopherol concentrations in patients with major risk factors.

BACKGROUND: Oxidative stress, which is thought to be increased in subjects with various coronary risk factors, induces thioredoxin (TRX), a redox-active protein. METHODS AND RESULTS: To determine whether oxidative stress is increased, serum concentrations of both TRX and alpha-tocopherol (vitamin E) were determined in 12 control subjects without any coronary risk factors (CONTROL), 6 current smokers (SMOKING), 19 hypertensive patients (HT), 7 hypercholesterolemic patients (HC) and 14 subjects with multiple risk factors (MULTIPLE). Patients with diabetes mellitus were not included. The serum TRX concentrations (mean +/- SD ng/ml) were significantly higher in SMOKING (41+/-10), HT (41+/-17), HC (48+/-15) and MULTIPLE (46+/-15) than in CONTROL (24+/-11). The serum alpha-tocopherol concentrations (mg/g lipids) were not significantly different among CONTROL (4.0+/-0.7), SMOKING (4.0+/-0.8), HT (4.1+/-0.6) and HC (4.2+/-0.6), although the concentration was significantly lower in MULTIPLE (3.3+/-0.7) than in any of the other study groups. CONCLUSIONS: SMOKING, HT, HC and MULTIPLE had significantly higher serum TRX concentrations than CONTROL, suggesting increased oxidative stress. MULTIPLE had a lower serum concentration of antioxidant alpha-tocopherol than any of the other study groups, suggesting impaired or exhausted defense against chronic oxidative stress in the presence of the multiple risk factors.

Chronic hypoxia accelerates the progression of atherosclerosis in apolipoprotein E-knockout mice.

The aim of this study was to investigate the effect of chronic hypoxia on the development and progression of atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. Male and female apoE-KO mice (6 weeks old) and age- and sex-matched wild-type mice were kept under hypoxic conditions (10.0 +/- 0.5% O2) in a gas chamber or in room air for 3 weeks. Aortic atherosclerotic plaque was not observed in wild-type mice under normoxic or hypoxic conditions. In the apoE-KO mice, however, hypoxia induced proliferation of smooth muscle cells and plaque formation in the aorta, which were not observed under normoxic conditions. Although sexual dimorphism of the response to hypoxia was not observed, these hypoxia-induced atherogenic changes were accompanied by a significant increase of plasma low density lipoprotein (LDL) cholesterol and NADPH-dependent vascular superoxide (O2-) production. Furthermore, matrix metalloproteinase (MMP)-9 was activated in the aorta of apoE-KO mice. In conclusion, chronic hypoxia accelerated the development of atherosclerosis in apoE-KO mice, along with increased O2- production and activated MMP-9 in the aorta.

High remnant lipoprotein levels in patients with variant angina.

BACKGROUND: Dyslipidemia with increased oxidative stress but without elevation of low-density lipoprotein cholesterol has been recently implicated in the pathogenesis of coronary vasospasm. HYPOTHESIS: Disordered triglyceride-rich lipoprotein metabolism may be linked to the genesis of coronary artery spasm. METHODS: Both serum remnant lipoprotein (RLP) and alpha-tocopherol levels were determined in 18 patients with the active stage of variant angina (VA), in 16 patients with the inactive stage of variant angina (IVA), and in 19 control subjects (CONTROL). RESULTS: The RLP levels were significantly (p < 0.05) higher in VA (6.4 +/- 2.7 mg/dl) than in IVA (4.4 +/- 1.5 mg/dl). In contrast, alpha-tocopherol levels were significantly lower in VA than that in CONTROL. Serum trigyceride levels were not significantly different among the study groups, although serum high-density lipoprotein cholesterol levels were significantly lower in VA than in CONTROL. Smoking was significantly (p < 0.05) more prevalent in VA (72%) than in IVA (25%) and CONTROL (37%). Serum RLP levels correlated positively with triglyceride levels (R = 0.73) and correlated inversely with alpha-tocopherol levels (R = -0.31) significantly in all study subjects. CONCLUSIONS: Patients with active stage of variant angina had higher RLP levels than inactive patients with variant angina and lower alpha-tocopherol levels than control subjects. Disordered triglyceride-rich lipoprotein metabolism with increased oxidative stress appears to be linked to the activity of coronary vasospasm, suggesting a possible role in its pathogenesis.

Diagnosis of multivessel coronary vasospasm by detecting postischemic regional left ventricular delayed relaxation on echocardiography using color kinesis.

BACKGROUND: It is not known whether multivessel coronary spasm occurs spontaneously in patients who have variant angina (VA) with demonstrated multivessel spasm induced by intracoronary injection of acetylcholine (ACh). Regional left ventricular (LV) diastolic dysfunction or wall motion abnormality may persist after an episode of coronary vasospasm. Color kinesis (CK) is a recent development that facilitates the echocardiographic evaluation of regional diastolic wall motion. METHODS AND RESULTS: Regional diastolic wall motion was evaluated using CK in 26 patients with VA within 1 week of the last episode of angina. The LV segmental filling fraction in the short-axis view during the first 30% of the diastolic filling time, expressed as a percentage, was used to objectively identify postischemic diastolic endocardial motion asynchrony. Diastolic asynchrony or regional LV delayed relaxation was noted in all 26 (100%) patients and in 14 (54%) it was detected in multiple vascular territories, suggesting multivessel spasm. Multivessel spasm was induced by ACh in 11 (79%) of the patients with suspected multivessel spasm by CK. In 11 (92%) of the 12 patients with multivessel spasm induced by ACh multiple regions of delayed relaxation had been noted by CK. The regions of delayed relaxation were largely consistent with the territories perfused by the arteries reacting to ACh (sensitivity: 96%, specificity: 91%). CONCLUSION: ACh induced spasm in the same coronary arteries as those perfusing the regions with delayed diastolic wall motion detected by CK in most of the patients with VA, suggesting that multivessel spasm does occur spontaneously in patients with susceptible arteries.

Diagnosis of coronary vasospasm by detection of postischemic regional left ventricular delayed relaxation using echocardiographic evaluation with color kinesis.

BACKGROUND: Coronary vasospasm has been diagnosed by invasive provocative procedures during coronary arteriography. It would be useful to have a reliable, noninvasive, and safe diagnostic method for coronary vasospasm. Regional left ventricular (LV) diastolic dysfunction may persist without systolic dysfunction after an episode of coronary vasospasm. Color kinesis (CK) has been recently developed to facilitate the echocardiographic evaluation of regional wall motion. HYPOTHESIS: Color kinesis may be useful for diagnosis of coronary vasospasm by detection of postischemic regional LV diastolic wall motion abnormality. METHODS: Fifty-one consecutive patients with the last chest symptom within 2 weeks (4 +/- 3 days) were studied echocardiographically. Regional fractional area change during the first 30% of LV filling time in percentage of the segmental end-diastolic area change (CK diastolic index) was used to identify diastolic endocardial motion asynchrony. RESULTS: After diagnostic coronary arteriography with spasm provocation, 26 patients were diagnosed with coronary spastic angina (CSA) and the other 25 with chest pain syndrome (CPS). Regional delayed relaxation (CK-diastolic index < or = 50%) or diastolic asynchrony had been observed in at least one region in 25 (96%) patients with CSA, whereas it had been noted in 2 (8%) patients with CPS. In 17 (65%) patients with CSA, it had been detected in multiple vascular territories, suggesting multivessel spasm. The diastolic asynchrony disappeared in CSA after a month of angina-free period. CONCLUSION: Analysis of CK images allows identification of regional LV delayed relaxation or diastolic asynchrony in patients with coronary vasospasm, differentiating them from patients with chest pain syndrome (sensitivity 96%, specificity 92%).

Efficacy of edaravone, a free radical scavenger, on left ventricular function and structure in diabetes mellitus.

This study was designed to assess the efficacy of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger that possesses anti-oxidant effects, on cardiac function and fine structure of the left ventricular myocardium in diabetes mellitus. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous development of type II diabetes (30 weeks; n = 15) were divided into two groups and treated with edaravone 30 mg/kg/d or vehicle for 2 weeks. OLETF rats showed hyperglycemia (352 +/- 71 mg/dl vs normal control; 128 +/- 52 mg/dl), increased thiobarbituric acid-reactive substances (TBARS; 6.9 +/- 2.5 nM/ml vs 2.8 +/- 0.6 nM/ml), and decreased superoxide dismutase activity (21.5 +/- 0.9 U/ml vs 25.8 +/- 0.7 U/ml). Increased left ventricular end-diastolic pressure (12 +/- 3 mm Hg vs 6 +/- 2 mm Hg) and hypertrophied cardiocytes (23.1 +/- 1.4 vs 17.6 +/- 1.0 microm) were also observed (P < 0.05, respectively). Edaravone could not improve plasma glucose level and hemodynamic parameters but significantly decreased TBARS values (3.8 +/- 0.5) and increased superoxide dismutase activity (24.5 +/- 0.8) (vs OLETF, P < 0.05, respectively). Moreover, edaravone effectively preserved cardiocyte diameter (18.2 +/- 0.9 microm) and the fine structure of mitochondria. Thus, edaravone exhibits modest cardiac protection in diabetes mellitus independent of blood sugar level.

Increased oxidative stress with elevated serum thioredoxin level in patients with coronary spastic angina.

BACKGROUND: Increased oxidative stress has been implicated in the pathogenesis of coronary vasospasm. Thioredoxin (TRX) is a redox-active protein that is known to be induced by oxidative stress. HYPOTHESIS: The serum TRX level may be high in patients with coronary vasospasm. METHODS: The serum TRX level was determined using an enzyme-linked immunosorbent assay in 21 patients with the active stage of coronary spastic angina (CSA), in 18 patients with the inactive stage of CSA (iCSA), in 24 control subjects without coronary artery disease (Control), and in 20 patients with stable effort angina (SEA). RESULTS: Serum TRX levels (mean +/- standard deviation ng/ml) were significantly higher in CSA (64 +/- 44) than in iCSA (28 +/- 26), in Control (34 +/- 15), and in SEA (36 +/- 16). In contrast, serum alpha-tocopherol levels (mg/g lipids) were significantly lower in CSA (2.8 +/- 0.7) than in Control (4.0 +/- 1.2) and in SEA (3.2 +/- 0.4). Current smoking was significantly more prevalent in CSA (76%) than in any of the other groups. No significant correlation was found between the serum level of TRX and alpha-tocopherol in the study subjects. In nine patients with CSA, the serum TRX level decreased (93 +/- 41 --> 41 +/- 35 ng/ml) and the alpha-tocopherol level increased (2.7 +/- 0.6 --> 3.2 +/- 0.7 mg/g lipids) significantly under medication with calcium entry blockers after an at least 3-month angina-free period. CONCLUSIONS: Patients with coronary spastic angina had a higher serum TRX level associated with a lower serum level of antioxidant vitamin E, with redox equilibrium appearing to be related to the disease activity of coronary vasospasm in these patients. Oxidative stress may be related to the genesis of coronary vasospasm.