Cardiovascular protection by ezetimibe and influence on oxidative stress in mice exposed to intermittent hypoxia.

Ezetimibe is as an inhibitor of NPC1L1 protein, which has a key role in cholesterol absorption. The aim of this study was to evaluate the influence of ezetimibe on the plasma lipid profile, atherosclerotic lesions, and cardiomyocyte ultrastructure in an animal model of atherosclerosis with intermittent hypoxia. Apolipoprotein E-knockout mice received a high-fat diet for 30 days. Then animals were exposed to intermittent hypoxia for 10 days or were maintained under normoxic conditions. In the ezetimibe group, ezetimibe (5 mg/kg/day) was added to the diet. Under normoxic conditions, the total cholesterol level was significantly lower in the ezetimibe group (63.6±6.6 mg/dl) than in the control group (116.3±16.9 mg/dl, P<0.001). Intermittent hypoxia accelerated atherosclerosis associated with increased superoxide production, which also caused degeneration of cardiomyocytes, mitochondrial abnormalities, and interstitial fibrosis. Compared with the control group, the ezetimibe group showed significantly less advanced atherosclerotic lesions and lower superoxide production in the thoracic aorta, as well as reduced oxidative stress, preservation of cardiomyocyte ultrastructure, and reduced interstitial fibrosis in the left ventricular myocardium. In conclusion, ezetimibe not only reduces total cholesterol, but also prevents the development of atherosclerosis and cardiovascular events due to intermittent hypoxia at least partly through suppression of oxidative stress.

Comparison of the acute effects of right ventricular apical pacing and biventricular pacing in patients with heart failure.

OBJECTIVE: Upgrading to biventricular (BiV) pacing benefits heart failure patients with right ventricular (RV) apical pacing. However, the impact of switching from RV apical pacing to BiV pacing on the left ventricular (LV) function accompanied by changes in the QRS duration remains unknown. We aimed to investigate the effects of BiV pacing in heart failure patients under RV apical pacing. METHODS: In 37 patients with heart failure (LV ejection fraction: 22±9%), the maximum rate of LV pressure rise (LV dP/dtmax) and time constant of LV relaxation (tau) were determined in order to assess LV contractility and diastolic relaxation, respectively, under RV apical pacing and BiV pacing. Switching from RV pacing to BiV pacing, the QRS duration was shortened from 209±42 to 162±28 ms (p<0.001) and the LV dP/dtmax values were increased in all patients (+18.4±11.3%, p<0.001), whereas the LV tau values varied (-1.5±13.0%, p=0.723). Shortening of the QRS duration correlated with the increase in LV dP/dtmax (r=-0.689, p<0.001); however, it was not closely associated with the changes in LV tau. CONCLUSION: Switching from RV apical pacing to BiV pacing improves the LV contractile function in proportion to the degree of QRS shortening. BiV pacing is recommended in patients with systolic heart failure and a prolonged RV-paced QRS duration.

Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade.

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar-Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 µg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 µg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher (P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher (P < 0.001) and average myocyte diameters greater (P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P < 0.01) and myocyte hypertrophy (P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.

Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Sarcoidosis does not belong to or overlap with immunoglobulin G4-related diseases based on an assessment of serum immunoglobulin G4 levels in cardiac and noncardiac sarcoidosis.

Although sarcoidosis may exhibit histopathologic features similar to those of a newly emerging clinical entity, immunoglobulin G4-related sclerosing disease, sarcoidosis is currently not considered to be associated with immunoglobulin G4-related immunoinflammation. Not many studies on this association have been reported. We investigated serum immunoglobulin G4 levels among patients with sarcoidosis with or without cardiac involvement (cardiac sarcoidosis and non-cardiac sarcoidosis patients). The mean serum immunoglobulin G4 level among the 65 patients with sarcoidosis was 56.8 ± 43.0 mg/dL, which did not significantly differ between patients with cardiac sarcoidosis (54 ± 48 mg/dL, n = 12) and patients without cardiac sarcoidosis (58 ± 42 mg/dL; n = 53). Serum level of soluble interleukin 2 receptor, a potent marker that may reflect sarcoidosis activity, was elevated in cardiac sarcoidosis (910 ± 683 U/L) and noncardiac sarcoidosis (689 ± 399 U/L) but did not significantly differ between the groups. Immunohistochemistry of cardiac or lymph node specimens from patients with cardiac sarcoidosis showed only sparse or no infiltration of immunoglobulin G4-positive lymphocytes, in contrast to the moderate to severe infiltration of CD68-positive macrophages and CD45-positive lymphocytes. Although the number of study subjects was small, these findings collectively suggest that regardless of the presence or absence of cardiac involvement, sarcoidosis does not belong to or overlap with immunoglobulin G4-related sclerosing disease.

Effect of efonidipine on TGF-ß1-induced cardiac fibrosis through Smad2-dependent pathway in rat cardiac fibroblasts.

Transforming growth factor beta-1 (TGF-ß1) plays a critical role in progression of cardiac fibrosis, which may involve intracellular calcium change. We examined effects of efonidipine, a dual T-type and L-type calcium channel blocker (CCB), on TGF-ß1-induced fibrotic changes in neonatal rat cardiac fibroblast. T-type and L-type calcium channel mRNAs were highly expressed in cultured cardiac fibroblasts. TGF-ß1 (5 ng/mL) significantly increased Smad2 phosphorylation and [(3)H]-leucine incorporation, which were attenuated by pretreatment with efonidipine (10 µM). Neither R(-)efonidipine (10 µM), selective T-type CCB, nor nifedipine (10 µM), selective L-type CCB, efficaciously inhibited both TGF-ß1-induced Smad2 phosphorylation and [(3)H]-leucine incorporation. However, both were markedly attenuated by combination of R(-)efonidipine and nifedipine, EDTA, or calcium-free medium. Pretreatment with Smad2 siRNA significantly attenuated [(3)H]-leucine incorporation induced by TGF-ß1. These data suggest that efonidipine elicits inhibitory effects on TGF-ß1- and Smad2-dependent protein synthesis through both T-type and L-type calcium channel-blocking actions in cardiac fibroblasts.

Impact of outdoor temperature on prewaking morning surge and nocturnal decline in blood pressure in a Japanese population.

Seasonal variations in blood pressure (BP) have often been attributed to meteorological factors, especially changes in outdoor temperature. We evaluated the direct association between meteorological factors and circadian BP variability. Twenty-four-hour ambulatory BP was monitored continuously for 7 days in 158 subjects. Mean awake, asleep, morning (first 2 h after waking) BP, prewaking morning BP surge (morning systolic BP (SBP)-mean SBP during the 2-h period before waking) and nocturnal BP decline were measured each day. We compared BP values for the lowest and highest days with regard to the daily mean outdoor temperature and mean atmospheric pressure. Morning BP and prewaking morning BP surge on the coldest day were significantly higher than those on the warmest day (morning SBP, 136.6 ± 1.6 vs. 133.1 ± 1.5 mm Hg, P = 0.002; morning diastolic BP, 84.4 ± 0.9 vs. 82.6 ± 0.9 mm Hg, P = 0.02; and prewaking morning BP surge, 20.8 ± 1.3 vs. 15.3 ± 1.3 mm Hg, P = 0.0004). The magnitude of nocturnal BP decline on the coldest day was significantly greater than that on the warmest day (15.8 ± 0.7 vs. 13.9 ± 0.7%, P = 0.01). Outdoor temperature is an important determinant of morning BP, prewaking morning BP surge and the magnitude of nocturnal BP decline. These findings may have important implications in management of hypertension and prevention of cardiovascular events.

Inhibitory effects of T/L-type calcium channel blockers on tubulointerstitial fibrosis in obstructed kidneys in rats.

OBJECTIVES: To examine the effect of L- and T/L-type calcium channel blockers on interstitial fibrosis in chronic unilateral ureteral obstruction (UUO). Tubulointerstitial fibrosis is a common outcome of several progressive renal diseases. Calcium channel blockers are widely used for the treatment of hypertension with renal diseases; however, the direct effect of calcium channel blockers on renal diseases independent of lowering blood pressure has not been fully elucidated. METHODS: Sprague-Dawley rats were divided into 3 treatment groups: (1) vehicle control; (2) nifedipine, an L-type calcium channel blockers; and (3) efonidipine, a T/L-type calcium channel blockers. Treatment was initiated 1 day before and continued until 6 days after creation of the UUO. RESULTS: Tubulointerstitial fibrosis in the obstructed kidney was significantly increased compared with that in the contralateral unobstructed kidney. Furthermore, the increased fibrosis was accompanied by increased fibrogenic signaling expressed by transforming growth factor ß1 and connective tissue growth factor mRNA levels, increased oxidative stress expressed by p22phox, p47phox and gp91phox mRNA level. Moreover, treatment with a nonhypotensive dose of efonidipine but not nifedipine in the obstructed kidney significantly suppressed the fibrogenic signaling and the oxidative stress, resulting in reduced tubulointerstitial fibrosis. The plasma aldosterone level in efonidipine-treated animals was increased compared with vehicle-treated animals, although not significantly. The increased plasma aldosterone level did not increase sgk-1 mRNA level in efonidipine but not in nifedipine treated animals. CONCLUSIONS: Treatment with efonidipine improved tubulointerstitial fibrosis more effectively than treatment with nifedipine in UUO. The antifibrogenic effect by efonidipine was obtained through suppression of fibrogenic signaling.

Survival and changes in physical ability after coronary revascularization for octa-nonagenerian patients with acute coronary syndrome.

Elderly populations are increasingly represented among patients with acute coronary syndrome (ACS), and advanced age has been identified as an important risk factor for death and adverse outcome in patients with ACS treated invasively. Although considerable data have demonstrated a prognostic benefit of early revascularization in ACS particularly in high-risk patients, elderly patients with ACS are treated invasively less often than younger patients because older age is thought to be an independent predictor of mortality after percutaneous coronary intervention (PCI) in ACS. Over the past 5 years, a total of 54 ACS patients over 85 years old were treated. The 6-month survival rate was around 50% in the non-PCI group (n = 12) and around 80% in the PCI group (n = 42) (P < 0.05). Cardiac death occurred in 6 patients in the PCI group and in 6 patients in the non-PCI group. The rates of both cardiac death and all-cause death were significantly lower in the PCI group. The change in ADL score before and 6 months after the procedure was from 1.57 to 1.59 in the PCI group and from 2.25 to 2.20 in the non-PCI group. PCI for elderly patients with ACS is safe and life saving, and does not reduce the ability to perform activities of daily living. PCI should be recommended even for octo-nonagenerians with ACS.

Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress.

The ubiquitin (Ub)-proteasome system (UPS) is an important proteolytic mechanism for selecting and digesting cytotoxic proteins. The aim of this study is to elucidate expression and in situ localization of the UPS in the myocardium from patients with dilated cardiomyopathy (DCM) with refractory heart failure. The expression profile of the oxidative stress-induced cytotoxic proteins was also examined. Myocardium was obtained from 26 patients with DCM at the left ventriculoplasty. Ten normal autopsied hearts served as controls. Myocardial expressions of Ub and proteasomes were studied immunohistochemically. Oxidative stresses were examined in point of localization of the oxidation-induced modifier molecules (OMM). The relationship between immunohistochemical results and clinical parameters was also evaluated. Both Ub and proteasomes were stained positive in granular structures accumulating between the myofibrils and adjacent to nuclei in cardiomyocytes. The OMMs were also positive in the same Ub-positive granular structures. The area fraction of Ub, proteasomes and OMM was significantly higher in DCM hearts than in normal controls. Significant positive correlation was observed between the area fractions of Ub and plasma levels of brain natriuretic peptide (p = 0.046) in DCM hearts. In conclusion, enhanced expression of the UPS colocalized with OMM in cardiomyocytes may be involved in the pathophysiology of DCM hearts.

Effects of acarbose on the acceleration of postprandial hyperglycemia-induced pathological changes induced by intermittent hypoxia in lean mice.

Postprandial hyperglycemia (PPH) and intermittent hypoxia related to the sleep apnea syndrome are important predictors of cardiovascular disease. We investigated the effects of intermittent hypoxia on pathological changes in the left ventricular (LV) myocardium caused by PPH in lean mice and evaluated the influence of acarbose, an α-glucosidase inhibitor. Male C57BL/6J mice aged 8 weeks were exposed to intermittent hypoxia (8 h/day during the daytime) or kept under normoxia. PPH was induced by restriction of feeding to 1-h periods twice a day, with the restricted diet (RD) mice receiving either standard chow or chow containing 0.02% acarbose. Another group of mice were fed standard chow ad libitum (AL). Plasma glucose levels after food intake were significantly elevated in RD but not in AL mice, and glucose levels were suppressed by acarbose. Intermittent hypoxia exacerbated cardiomyocyte hypertrophy and interstitial fibrosis in the LV myocardium of RD mice. Superoxide production and expression of 4-hydroxy-2-nonenal in the LV myocardium with intermittent hypoxia were increased in RD mice, but not AL mice. In addition, expression of tumor necrosis factor α (TNF-α) mRNA was increased in hypoxic RD mice. Treatment with acarbose inhibited oxidative stress and TNF-α mRNA expression and preserved the histological architecture of the LV myocardium.

Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown. METHODS AND RESULTS: We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. CONCLUSIONS: CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.

A sinus of Valsalva-right atrium fistula without aneurysm formation.

A 61-year-old man was admitted to the hospital because of orthopnea and was diagnosed with heart failure with a continuous heart murmur. A transthoracic echocardiogram revealed turbulent flow from the right coronary sinus of Valsalva to the right atrium throughout the cardiac cycle. Aortography confirmed the presence of a shunt jet from the right coronary sinus of Valsalva to the right atrium. Cardiac catheterization revealed a left-right shunt rate of 47% and a pulmonary to systemic blood flow ratio of 1.81. Transesophageal echocardiography confirmed the existence of the shunt jet and revealed no deformity of the sinus of Valsalva. We report a rare case of sinus of Valsalva-right atrium fistula without typical aneurysmal formation.

ATF6 is important under both pathological and physiological states in the heart.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response, including activating transcription factor 6 (ATF6), a key transcriptional activator to maintain cellular homeostasis. The ER stress has recently been reported to cause various diseases, but the role of ATF6 in the heart remains unknown. We clarified the role of ATF6 in the heart. The ATF6 activity was increased in the murine heart after myocardial infarction (MI). Treatment of mice with 4-(2-aminoethyl) benzenesulfonyl fluoride, an inhibitor of ATF6, further reduced cardiac function and increased the mortality rate at 14days after MI. Pharmacological inhibition of ATF6 induced dilatation of left ventricle and depression of cardiac function even in sham-operated murine hearts. The transgenic mice that expressed dominant negative mutant of ATF6 showed larger left ventricular dimension and reduced fractional shortening compared with wild-type littermates, resulting in death of heart failure at approximately 8weeks of age. In contrast, cardiac function after MI was better in transgenic mice that expressed constitutively active mutant of ATF6, compared with wild-type littermates. These results suggest that activation of the ER stress response factor ATF6 plays a critical role in not only protecting hearts under the pathological state but also maintaining cardiac function under the physiological state.

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice.

We have reported previously that intermittent hypoxia related to sleep apnea induces cardiovascular remodeling secondary to the oxidative stress. The aim of this study was to examine the effect of pitavastatin as an antioxidant to prevent intermittent hypoxia-induced left ventricular (LV) remodeling in mice without hypercholesterolemia. Eight-week-old male C57BL/6J mice (n=35) were exposed to intermittent hypoxia (30 s exposure to 5% oxygen, followed by 30 s exposure to 21% oxygen) for 8 h per day during the daytime or maintained under normoxic conditions; in addition, they were either treated with pitavastatin (3 mg kg(-1) per day) or vehicle for 10 days. After cardiac catheterization and blood sampling, the LV myocardium was examined. The systemic blood pressure and plasma level of total cholesterol were similar among the four groups. Intermittent hypoxia significantly increased the expression levels of 4-hydroxy-2-nonenal (4-HNE) proteins, TNF-alpha and TGF-beta mRNA, and also the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL)-positive myocardial cells in the LV myocardium. In addition, enhanced hypertrophy of the cardiomyocytes, perivascular fibrosis and histological degeneration were observed in the mice exposed to hypoxic stress. Treatment with pitavastatin significantly suppressed the expression levels of the 4-HNE proteins, cytokines, superoxide production and TUNEL-positive myocardial cells in the LV myocardium, consequently attenuating the hypoxia-induced histological changes. Pitavastatin preserved, at least partially, the morphological structure of the LV myocardium in lean mice exposed to intermittent hypoxia, through its antioxidant effect.

Enhanced expression of the S100A8/A9 complex in acute myocardial infarction patients.

BACKGROUND: S100A8/A9 complex (S100A8/A9) is expressed in activated human neutrophils and macrophages. Enhanced expression of S100A8/A9 in atherosclerotic plaque of patients with unstable angina pectoris (UAP) has been demonstrated, but its profile in acute myocardial infarction (AMI) has not been clarified. METHODS AND RESULTS: Serum S100A8/A9 levels were serially measured in patients with AMI (n=55) and UAP (n=16) during the acute period. The expression of S100A8/A9 was examined immunohistochemically in the infarcted myocardium of 7 autopsied patients with AMI. Serum S100A8/A9 levels on the 1st day were 1,118+/-115 (SE) ng/ml in AMI patients as compared with 787+/-147 ng/ml in UAP patients. On days 3-5, serum S100A8/A9 levels in AMI patients reached a peak value and were significantly higher than the values in UAP patients (1,690+/-144 ng/ml vs 844+/-100 ng/ml; P<0.0001). In AMI patients, peak S100A8/A9 levels positively correlated with peak white blood cell and neutrophil counts, and peak creatine kinase-MB and peak C-reactive protein levels. Double immunostaining revealed that S100A8/A9 was specifically expressed in neutrophils and macrophages infiltrating the infarcted myocardium. CONCLUSIONS: S100A8/A9 is implicated in the pathophysiology of AMI and may be an additional biomarker of the local inflammatory response following AMI.

Efficacy of olmesartan and nifedipine on recurrent hypoxia-induced left ventricular remodeling in diabetic mice.

AIMS: Recurrent hypoxia due to sleep apnea syndrome is implicated in cardiovascular events, especially in diabetic patients, but the underlying mechanisms remain controversial. We previously reported that angiotensin II receptor blockers can improve hypoxia-induced left ventricular remodeling. The aim of this study was to examine the effect on left ventricular remodeling of adding a calcium channel blocker to angiotensin II receptor blocker therapy in diabetic mice exposed to recurrent hypoxia. MAIN METHODS: Male db/db mice (8-week-old) and age-matched control db/+ mice were fed a Western diet and subjected to recurrent hypoxia (oxygen at 10+/-0.5% for 8h daily during the daytime) or normoxia for 3weeks. Hypoxic db/db mice were treated with the vehicle, olmesartan (3mg/kg/day), nifedipine (10mg/kg/day), or both drugs. KEY FINDINGS: Recurrent hypoxia caused hypertrophy of cardiomyocytes, interstitial fibrosis, and a significant increase in expression of the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in the left ventricular myocardium. Treatment with olmesartan, nifedipine, or both drugs had no effect on systolic blood pressure, and each treatment achieved similar suppression of 4-HNE expression. Olmesartan and the combination with olmesartan and nifedipine significantly prevented cardiomyocyte hypertrophy more than treatment with nifedipine alone. On the other hand, olmesartan combined with nifedipine significantly reduced cytokine expression, superoxide production and matrix metalloproteinase (MMP)-9 activity, and significantly suppressed interstitial fibrosis in the left ventricular myocardium. SIGNIFICANCE: The combination with olmesartan and nifedipine, as well as a monotherapy with olmesartan, exerts preferable cardioprotection in diabetic mice exposed to recurrent hypoxia.

Chronic total occlusion of the left main coronary artery with normal left ventricular motion: the occluded site confirmed by three-dimensional computed tomography.

Total occlusion of the left main trunk (LMT) frequently results in sudden cardiac death. As a result, it is rarely observed on coronary arteriogram. There are only a few reports on chronic total occlusion of the LMT. Most patients present with recent, severe angina, but it is not easy to distinguish chronic total occlusion of the LMT from other types of severe coronary heart diseases. Here, we report a very rare case of chronic total occlusion of the LMT. The patient is a 38-year-old female with a history of three normal deliveries. Chronic total occlusion of the LMT was suspected on coronary arteriogram 2 years previously in the other hospital; however, she continued working as a part-time employee at a supermarket. She was referred to our hospital because of slightly increased effort angina and shortness of breath. The final diagnosis and the site of occlusion were determined by three-dimensional computed tomography (3-D CT). The patient underwent coronary artery bypass graft (CABG) surgery, and ischemic symptoms completely disappeared.

Usefulness of carvedilol to abolish myocardial postsystolic shortening in patients with idiopathic dilated cardiomyopathy.

Postsystolic shortening (PSS), a positive myocardial velocity after aortic valve closure as assessed by Doppler tissue imaging, is a common pathologic finding in patients with myocardial disease. Beta-blocker therapy can improve global and regional myocardial function. The aim of the present study was to examine whether the beta-blocker carvedilol might reduce the incidence and magnitude of PSS in patients with idiopathic dilated cardiomyopathy. Before and 2 months after carvedilol therapy, 19 patients (7 men, 12 women; mean age 59 +/- 13 years) underwent conventional echocardiographic assessment and Doppler tissue imaging. Time-velocity curves were constructed at the 12 basal and mid myocardial segments of the left ventricular (LV) walls. PSS was defined if positive myocardial velocity after aortic valve closure was greater than the ejection peak. The number of segments showing PSS was assessed before and after carvedilol therapy. Carvedilol decreased LV end-diastolic dimension (from 66 +/- 5 to 62 +/- 7 mm, p <0.01), increased the LV ejection fraction (from 28 +/- 9% to 36 +/- 8%, p <0.01), and increased early diastolic mitral annular velocity (Ea) (from 5.0 +/- 1.6 to 5.5 +/- 1.7 cm/ms, p <0.01). This was associated with significant reductions in the number of segments showing PSS (from 2.8 +/- 3.0 to 0.8 +/- 1.4, p <0.01). There was a correlation between changes in the number of segments showing PSS and changes in Ea (r = -0.56, p = 0.01). In conclusion, PSS may reflect the severity of LV diastolic function during pharmacologic reverse remodeling in patients with idiopathic dilated cardiomyopathy. These data provide new insights into the mechanisms by which carvedilol improves cardiac function and symptoms in these patients.