Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is characterized by transient left ventricular apical wall motion abnormalities, chest pain with electrocardiographic changes, and modest myocardial enzymatic release mimicking acute coronary syndrome, but without significant coronary artery disease. TC is an increasingly recognized type of acquired cardiomyopathy occurring commonly after a recent stressful event, in particular emotional stress, and is relatively common in middle-aged and older women. The pathogenetic mechanism remains unknown. Catecholamine surge related to emotional distress seems to play a major role in the pathogenesis of this cardiomyopathy, rendering TC a type of neurocardiological disorder that manifests as acute but reversible heart failure. Clinicians should consider this syndrome in the differential diagnosis of patients presenting with clinical findings suggestive of acute coronary syndrome, especially in postmenopausal women with a recent history of acute emotional or physical stress.

Caseous calcification of mitral annulus evaluated by multi-modality imaging including cardiac magnetic resonance parametric mapping.

We report an 85-year-old woman with caseous calcification of mitral annulus (CCMA), a rare variant of mitral annular calcification with caseous degeneration, in which imaging findings were useful for elucidating the pathogenesis and diagnosis. Since the CCMA is considered to be benign, it is important for clinicians to differentiate CCMA from other cardiac masses using multi-modality imaging in order to avoid unnecessary surgery. To the best of our knowledge, there is a paucity of literature regarding cardiac magnetic resonance (CMR) parametric mapping, an emerging technique, for evaluating CCMA. In the present case, by using multi-modality imaging including CMR parametric mapping, we were able to characterize the abnormal structure at mitral annulus non-invasively, and diagnosed the structure as CCMA. CMR with parametric mapping may have a role in the identification and definition of cardiac masses including CCMA. Learning objective: Caseous calcification of mitral annulus (CCMA) is a rare variant of mitral annular calcification, but is not infrequently encountered in daily practice. Multi-modality imaging including cardiac magnetic resonance is useful for the diagnosis of CCMA. Differential diagnosis of cardiac masses at the mitral annulus including CCMA is important, and clinicians need to know the multi-modality imaging findings related to CCMA.

Thiamine ameliorates diabetes-induced inhibition of pyruvate dehydrogenase (PDH) in rat heart mitochondria: investigating the discrepancy between PDH activity and PDH E1alpha phosphorylation in cardiac fibroblasts exposed to high glucose.

The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1alpha subunit by PDH kinase contributes to the suppression of PDH activity. PDH requires thiamine as a coenzyme. We investigated the exact mechanism of diabetes-induced PDH inhibition, and the effect of thiamine in both in vivo and in vitro experiments. Treatment of rats with thiamine significantly, although partially, recovered streptozotocin (STZ)-induced reductions in mitochondrial PDH activity. Nevertheless, we found that PDH E1alpha phosphorylation in the thiamine-treated STZ group was perfectly diminished to the same level as that in the control group. STZ treatment significantly caused enhancements of the expression of O-glycosylated protein in the rat hearts, which was decreased by thiamine repletion. Next, the rat cardiac fibroblasts (RCFs) were cultured in the presence of high glucose levels. Thiamine dramatically recovered high glucose-induced PDH inhibition. High glucose loads did not alter the phosphorylated PDH E1alpha. PDH inhibition in RCFs was not accompanied by an increase in the PDH E1alpha phosphorylation. The O-glycosylated protein was markedly increased in RCFs exposed to high glucose, which was inhibited by thiamine. These results suggest that thiamine ameliorates diabetes-induced PDH inhibition by suppressing the increased expression of the O-glycosylated protein. The O-glycosylation of PDH E1alpha may be involved in the regulation of the PDH activity.

Suppression of inflammation in rat autoimmune myocarditis by S100A8/A9 through modulation of the proinflammatory cytokine network.

AIMS: S100A8/A9 is expressed in activated monocytes/macrophages and assumed to be heavily involved in the pathogenesis of acute inflammation. Although several studies have asserted that S100A8/A9 has a proinflammatory function, the exact biological function of S100A8/A9 is yet to be described. We examined the anti-inflammatory effects of S100A8/A9 on experimental autoimmune myocarditis (EAM) in rats. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The recombinant (R-) S100A8/A9 was injected intraperitoneally into EAM rats. R-S100A8/A9 attenuated the severity of myocarditis, as evidenced by echocardiographic and histological findings. In addition, we found that not only the mRNA expression of proinflammatory cytokines [interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF)-alpha] in the myocardium, but also their serum concentrations were suppressed in EAM rats treated with R-S100A8/A9. Nuclear factor-kappa B expression in inflammatory cells was also suppressed in the treated rats. To elucidate the mechanistic function of S100A8/A9 on proinflammatory cytokines in vivo, we used an ELISA on the supernatant of homogenized heart tissue treated with R-S100A8/A9. The findings revealed high-affinity binding of R-S100A8/A9 with IL-1beta, IL-6, and TNF-alpha in the myocardium, suggesting the trapping of proinflammatory cytokines by R-S100A8/A9. CONCLUSION: S100A8/A9 attenuates EAM through modulation of the proinflammatory cytokine network.

Protein O-glycosylation induces collagen expression and contributes to diabetic cardiomyopathy in rat cardiac fibroblasts.

Diabetic cardiomyopathy may be accompanied by myocardial fibrosis. We have previously reported that cardiac fibrosis and protein O-glycosylation are elevated in diabetes. In this study, we examined if the hexosamine biosynthesis pathway (HBP) was involved with collagen expression in rat cardiac fibroblasts (RCFs). Long-term glucose load significantly increased type III collagen expression in RCFs, but did not affect the protein O-glycosylation. In addition, glucosamine treatment not only induced expressions of collagen types I and III, but also increased the O-glycosylated protein. These results suggest that O-glycosylation of protein induced by HBP activation modifies collagen expression and contributes to diabetic cardiomyopathy.

Repeated ambulatory monitoring reveals an evening rise in blood pressure in a Japanese population.

Recent studies have revealed 2 peaks in the onset of cardiovascular events, 1 in the morning and another in the evening. We evaluated whether blood pressure (BP) also rises in the morning/evening and identified the determinants of evening BP rise using 24-hour ambulatory BP monitoring for 7 consecutive days. We identified 2 BP peaks, 1 in the morning (0-3 hours after waking) and 1 in the evening (9-12 hours after waking). Subjects were subclassified according to the extent of evening BP rise: those in the top quartile (≥6.45 mm Hg, n = 34; ER group) vs all others. After adjustment for age, sex, and 24-hour systolic BP, evening BP rise was associated with the use of antihypertensive medications [odds ratio (OR), 3.57; 95% confidence interval (CI), 1.46-8.74; P = .01] and estimated glomerular filtration rate (OR, 0.96; 95% CI, 0.93-0.99; P = .04), confirming its association with antihypertensive medication use and renal dysfunction.

Retroperitoneal fibrosis in a patient with gastric cancer manifested by lower extremity edema and hydrocele.

Herein we report a 57-year-old man with lower extremity edema and swelling in the scrotum who was found to have a periaortic soft tissue mass and hydronephrosis by computed tomography. With the most plausible diagnosis of retroperitoneal fibrosis, corticosteroid therapy was initiated; however, it did not improve his symptoms. Upper gastroscopy performed on day 20 post admission showed ulcerative regions with an irregular border and fusion of thickened rugae at the gastric angle; the diagnosis of gastric adenocarcinoma was confirmed histologically. It is important to always be aware of unrecognized malignancies that are accompanied by retroperitoneal fibrosis.

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.

Thiamine prevents obesity and obesity-associated metabolic disorders in OLETF rats.

We previously found that thiamine mitigates metabolic disorders in spontaneously hypertensive rats, harboring defects in glucose and fatty acid metabolism. Mutation of thiamine transporter gene SLC19A2 is linked to type 2 diabetes mellitus. The current study extends our hypothesis that thiamine intervention may impact metabolic abnormalities in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, exhibiting obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4 wk old) were given free access to water containing either 0.2% or 0% of thiamine for 21 and 51 wk. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, organs weights, histological findings, and hepatic pyruvate dehydrogenase (PDH) activity in the liver were evaluated. Thiamine intervention averted obesity and prevented metabolic disorders in OLETF rats which accompanied mitigation of reduced lipid oxidation and increased hepatic PDH activity. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, sinusoidal fibrosis with formation of basement membranes (called pseudocapillarization) which accompanied significantly reduced expression of laminin ß1 and nidogen-1 mRNA, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of the vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Thiamine has a potential to prevent obesity and metabolic disorders in OLETF rats.

Prevention of incipient diabetic cardiomyopathy by high-dose thiamine.

Diabetic cardiomyopathy can progress toward overt heart failure with increased mortality. The hexosamine biosynthesis pathway has been implicated in signaling for fibrosis by the kidney. Thiamine (vitamin B(1)) is an indispensable coenzyme and required at intracellular glucose metabolism. In this study, we assessed if decrease of flux through the hexosamine biosynthesis pathway induced by high-dose thiamine therapy counteracts diabetes-induced cardiac fibrosis. The diabetes model used was the streptozotocin-induced diabetic rat. Normal control and diabetic rats were studied for 2 weeks with and without thiamine, and followings were analyzed; plasma biochemicals (total cholesterol and triglycerides), morphological changes, mRNA abundance relevant to cardiac failure (brain natriuretic peptide) and fibrosis (transforming growth factor-beta1, thrombospondine, fibronectin, plasminogen activator-I and connective tissue growth factor) as well as and matrix metalloproteinase activity were investigated. Thiamine repletion prevented diabetes-induced cardiac fibrosis without changes in plasma glucose concentration. This was achieved by prevention of thiamine depletion, increased pro-fibrotic mRNA abundance and decreased metalloproteinase activity in the heart of diabetic rats. O-glycosylated protein was significantly higher in the left ventricular of diabetic rats compared to control rats, which was decreased by thiamine administration. Thiamine repletion prevented diabetes-induced cardiac fibrosis in experimental diabetes, probably by suppression of hexosamine biosynthesis pathway.

Postoperative outcome in aortic stenosis with diastolic heart failure compared to one with depressed systolic function.

BACKGROUND: In patients with aortic stenosis (AS), the clinical outcome worsens after the development of angina, syncope, and heart failure. This study was performed to elucidate whether the outcome with AS was also poor in patients with diastolic heart failure. METHODS AND RESULTS: Fifty-two patients who had undergone aortic valve replacement (AVR) for AS were retrospectively classified into 3 groups (G) on the basis of LV ejection fraction (EF) and pulmonary wedge pressure (PWP): G-1) normal LVEF, low PWP (EF > or = 45% and PWP < 16 mmHg; n = 35), G-2) normal LVEF, high PWP (EF > or = 45% and PWP > or = 16 mmHg; n = 8), and G-3) low LVEF (EF < 45%; n = 9). Among these 3 groups, we compared the outcome after AVR. None of the patients died after the operation in AS with preserved LVEF irrespective of the PWP, whereas there were 3 cardiac deaths in AS with low EF irrespective of the PWP. CONCLUSIONS: In patients with AS, diastolic heart failure developed in addition to systolic heart failure. The development of LV systolic dysfunction in AS was regarded as poor during the postoperative course, but diastolic heart failure did not affect the outcome. The occurrence of heart failure with preserved systolic function may have a slightly better prognosis and may still be suitable for AVR.

Thiamine attenuates the hypertension and metabolic abnormalities in CD36-defective SHR: uncoupling of glucose oxidation from cellular entry accompanied with enhanced protein O-GlcNAcylation in CD36 deficiency.

BACKGROUND AND OBJECTIVES: The spontaneous hypertensive rat (SHR) is a widely studied model of hypertension that exhibits metabolic abnormalities, which share features with the human metabolic syndrome. Genetic linkage studies have revealed a defective CD36 gene, encoding a membrane fatty acid (FA) transporter, in hyperinsulinemia of the SHR. However, there is no unifying mechanism that can explain these phenotypes as a consequence of a defective CD36 gene. Impaired fatty acid uptake is compensated by increased glucose uptake. We hypothesized that (1) the abundant intracellular glucose is not oxidized proportionally and (2) the correction of the uncoupling of glucose oxidation to its cellular entry might be effective against the pathophysiology of CD36-defective SHR. Therefore, we attempted to activate glucose oxidation with the repletion of thiamine, a coenzyme for multiple steps of glucose metabolism. METHODS AND RESULTS: In one series of experiments, intracellular glucose fate was assessed by the ratio of [(14)C]glucose/[(3)H]deoxyglucose radioactivity, which suggested that glucose oxidation was uncoupled from its cellular entry in SHR. Protein O-GlcNAcylation was intense in the hearts of CD36-defective SHR compared with that of wild-type CD36 rats [Wister Kyoto rats (WKY)], indicating the shunt of glucose through the hexosamine biosynthetic pathway (HBP). In another series of studies, 4-week-old SHR were maintained with water containing 0.2% thiamine for 10 weeks. Systolic blood pressure, plasma insulin and norepinephrine levels were significantly lower in the thiamine-group, as compared with the untreated-group. In epididymal adipose tissue, thiamine repletion down-regulated the expression levels of mRNA transcripts for UDP-N-acetylglucosamine:peptide glycosyltransferase, angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1 and plasminogen activator inhibitor-1. CONCLUSIONS: The hearts of CD36-defective SHR exhibited uncoupling of glucose oxidation from its cellular entry, accompanied with the enhanced protein O-GlcNAcylation, suggesting increased glucose shunt through the HBP. Thiamine repletion in CD36-defective SHR resulted in (1) the correction of the uncoupling of glucose oxidation to its cellular entry, concomitant with reduced protein O-GlcNAcylation, (2) the down-regulation of the expression of mRNAs involved in HBP, the renin-angiotensin system and adipokines in epididymal adipose tissue, and (3) the attenuation of the hypertension and hyperinsulinemia. We propose that interventions targeting glucose oxidation with thiamine repletion may provide a novel adjunctive approach to attenuate metabolic abnormalities and related hypertension.

Intraventricular dyssynchrony may play a role in the development of mitral regurgitation in dilated cardiomyopathy.

BACKGROUND: The development of functional mitral regurgitation (MR) in dilated cardiomyopathy (DCM) has been attributed to altered left ventricular (LV) geometry and annular dilatation. We propose the hypothesis that intraventricular dyssynchrony may play a role in the development of MR in DCM. METHODS AND RESULTS: Tissue Doppler echocardiography was performed in 32 DCM patients to assess the time from the onset of the QRS complex to the peak systolic myocardial strain (Ts) at 2 segments adjacent to the anterolateral and posteromedial papillary muscles from a short axis view. The time difference corrected by the RR interval (DeltaTs/ radicalRR) was used to evaluate dyssynchrony of these segments. There was no difference in the QRS duration (103 +/- 29 ms versus 95 +/- 22 ms, P = .38) or the presence of left bundle branch block (39% versus 14 %, P = .25) between 18 patients with MR and 14 patients without MR. However, DeltaTs/ radicalRR was significantly increased in the patients with MR, compared with those without MR (104 +/- 67 ms versus 5 +/- 16 ms, P < .0001). Stepwise multiple regression analysis showed that DeltaTs/ radicalRR was independent contributing factor of MR. CONCLUSION: Dyssynchrony of myocardial segments adjacent to the papillary muscles may disturb synchronized closure of the mitral leaflets and cause MR in DCM.

Gene-environment interactions in wet beriberi: effects of thiamine depletion in CD36-defect rats.

Selective vulnerability to thiamine deficiency is known to occur between individuals and within different tissues. However, no comprehensive explanation for this has been found, and there are no reports that reproduce the cardiovascular manifestations of human wet beriberi in animals. We hypothesized that the distinction of substrate reliance, namely, the primary dependency on glucose as substrate, could be an underlying factor in the selective vulnerability of thiamine deficiency. In the setting of impaired fatty acid entry, which occurs in CD36-defect rats, substrate reliance shifts from fatty acid to glucose, which would be expected to lead to a susceptibility to thiamine deficiency. Genomic DNA was analyzed for CD36 defects in three cognate strains of rats [spontaneously hypertensive rats (SHR)/NCrj, SHR/Izm, and Wistar-Kyoto (WKY)/NCrj], which identified the presence of a CD36 defect in SHR/NCrj rats but not in SHR/Izm and WKY/NCrj rats. Treatment with 2 wk of thiamine-depleted chow on 4-wk-old rats of each of these strains resulted in increased body and lung weight in the SHR/NCrj rats but not in the SHR/Izm and WKY/NCrj rats. The increased lung weight in the SHR/NCrj rats was accompanied with histological changes of congestive vasculopathy, which were not observed in either the SHR/Izm or the WKY/NCrj rats. Thiamine-deficient 12-wk-old SHR/NCrj rats demonstrated increased body weight (305.6 +/- 6.2 g in thiamine-deficient rats vs. 280.8 +/- 9.1 g in control; P < 0.0001), lactic acidemia (pH, 7.322 +/- 0.026 in thiamine-deficient rats vs. 7.443 +/- 0.016 in control; P < 0.0001; lactate, 2.42 +/- 0.28 mM in thiamine-deficient rats vs. 1.20 +/- 0.11 mM in control; P < 0.0001) and reduced systemic vascular resistance (4.61 +/- 0.42 x 104 dyn.s.cm-5 in thiamine-deficient rats vs. 6.55 +/- 1.36 x 104 dyn.s.cm-5 in control; P < 0.0001) with high cardiac output (186.0 +/- 24.7 ml in thiamine-deficient rats vs. 135.4 +/- 27.2 ml in control; P < 0.0019). In conclusion, SHR/NCrj rats harboring a genetic defect of long-chain fatty acid uptake present the relevant clinical cardiovascular signs of human wet beriberi, strongly indicating a close gene-environment interaction in wet beriberi.

Gitelman's syndrome with exercise-induced ventricular tachycardia.

A 62-year-old female with palpitations was admitted to hospital where she recorded 12,299 monofocal ventricular premature contractions (VPCs) in 24 h and nonsustained ventricular tachycardia (VT) on exertion. She had hypokalemia with renal potassium wasting, a chloride-resistant metabolic alkalosis, elevated plasma renin, elevated plasma aldosterone (relative to the serum K concentration), hypomagnesemia with renal magnesium wasting, decreased urine calcium excretion, and normal blood pressure. The hypokalemia and hypomagnesemia were thought to have precipitated the VT. The coronary angiogram showed normal coronary arteries; however, the left ventriculogram revealed akinesis of the posterolateral wall. Because the VT could not be induced by programmed electrical stimulation either before or during intravenous administration of isoproterenol, the VPC with the same QRS morphology as the VT became the target of radiofrequency catheter ablation (RF-CA). Intracardiac mapping showed that the earliest activation site was situated in the asynergic area of the left ventricle (LV) and radiofrequency catheter ablation directed at the LV asynergy area completely eliminated the VPCs without any complications. During the follow-up period (6 months), she was free from palpitation and VT was not clinically documented.