Kunio Yufu

Pioglitazone attenuates inflammatory atrial fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats

BACKGROUND Inflammatory processes are involved in the pathogenesis of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to test the hypothesis that atrial fibrosis and enhanced vulnerability to AF evoked by pressure overload can be attenuated by pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, via suppression of inflammatory profibrotic signals. METHODS Male Sprague-Dawley rats were subjected to abdominal aortic constriction (AAC). Pioglitazone 3 mg/kg/day or vehicle was orally administered for 4 weeks. RESULTS Western blot analysis revealed that AAC enhanced expression of monocyte chemoattractant protein (MCP)-1, transforming growth factor-β1 and α-smooth muscle actin in the left atrium (LA), which was suppressed by pioglitazone. Messenger RNA expression of collagen type 1 and atrial natriuretic peptide in the LA was increased by AAC, which was suppressed by pioglitazone. Gelatin zymography demonstrated that activity of matrix metalloproteinase-9 was increased by AAC, which was suppressed by pioglitazone. Pioglitazone attenuated AAC-induced LA fibrosis. In isolated-perfused heart experiments, AAC did not alter the refractory period of the LA or the right atrium (RA), but it did prolong the interatrial conduction time. Programmed extrastimuli from the RA induced AF in all of the AAC-treated rats (8/8 [100%]). This was suppressed by pioglitazone (2/8 [25%], P <.05) with normalization to interatrial conduction time. CONCLUSION The results of this study suggest that inflammatory profibrotic mechanisms are involved in this pressure-overloaded AF model. The results also suggest that pioglitazone is effective at attenuating atrial fibrosis, possibly via suppression of MCP-1-mediated inflammatory profibrotic processes.

Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients.

OBJECTIVES The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.

Measurement of the Brachial-Ankle Pulse Wave Velocity and Flow-Mediated Dilatation in Young, Healthy Smokers

The brachial-ankle pulse wave velocity (PWV) is a quick test which adequately estimates arterial stiffness. Because flow-mediated dilatation (FMD) of the brachial artery assesses an essential endothelial function, we tested the hypothesis that the brachial-ankle PWV could reflect the early stages of endothelial dysfunction caused by smoking in young, healthy subjects. Fifty-seven healthy subjects (13 females and 44 males; mean 29.9±5.6 years) were enrolled. Twenty-six of the subjects (30.4±5.7 years) were active smokers, with a mean cumulative nicotine consumption of 10.0±8.6 pack/years, and thus were assigned to the smoking group. Thirty-one subjects without a history of smoking (29.5±5.5 years) were assigned to the non-smoking group. The brachial-ankle PWV and arterial blood pressure were simultaneously measured using a recently established, non-invasive automatic device (model BP-203RPE; Nihon Colin, Tokyo, Japan). Endothelium-dependent FMD was induced by reactive hyperemia, while endothelium-independent vasodilation of the brachial artery was induced by administration of sublingual nitroglycerin spray. The FMD was lower in the smoking group than in the non-smoking group (p<0.05). There was no significant difference between the two groups with respect to the brachial-ankle PWV. In the non-smoking group, multiple stepwise regression analysis revealed that FMD was predicted by the systolic blood pressure (F=16.351). In the smoking group, statistical analysis revealed that FMD was independently predicted by either the brachial-ankle PWV (F=8.108) or the subjects age (F=4.381). Our results suggest that a reduction in FMD is closely associated with the early stages of endothelial dysfunction caused by cigarette smoking in young, healthy subjects, which is at least partly reflected by the PWV value.

Early atorvastatin therapy improves cardiac function in patients with acute myocardial infarction.

BACKGROUND A number of experimental and clinical studies have demonstrated a cardioprotective effect of statins; however, the effect of atorvastatin on cardiac function in patients with an acute myocardial infarction (AMI) has not been established. METHODS AND RESULTS Thirty consecutive patients with an AMI (16 males and 14 females) were enrolled. All the patients underwent successful percutaneous coronary intervention in the early phase after the onset of an AMI. Patients with a total cholesterol level > 200mg/dL on admission (n = 14) were assigned to the atorvastatin group. They began taking 10 mg of atorvastatin daily within 48 h after the onset of the AMI, while the other patients (n = 16) did not receive atorvastatin and served as the control group. Echocardiography and blood sampling to measure brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels were repeated on the 2nd day (2D), 3 weeks (3W), 12 weeks (12W), and 24 weeks (24W) after the onset of the AMI. The percentage of patients with a high BNP level (BNP > 20 pg/mL) was significantly decreased from 2D to 24W in the atorvastatin group, but not in the control group (100 to 57% in the atorvastatin group, p < 0.05; 100 to 80% in the control group, n.s.). Similar results also occurred with respect to the ANP level (ANP > 40 pg/mL) (62 to 21% in the atorvastatin group, p < 0.05; 57 to 40% in the control group, n.s.). The left ventricular ejection fraction was significantly higher in the atorvastatin group than the control group at 3W (66.0 ± 7.8% vs. 56.5 ± 11.8%, p < 0.05) and 24W (67.5 ± 9.2% vs. 59.7 ± 9.8%, p < 0.05). In the atorvastatin group, the left ventricular systolic diameter was significantly decreased at 24W compared with that at 2D (37.1 ± 8.0 mm to 31.4 ± 6.5 mm, p < 0.05). CONCLUSIONS Initiation of atorvastatin in the early phase of an AMI has beneficial effects on cardiac function, probably by improving left ventricular remodeling.

New squatting test indices are useful for assessing baroreflex sensitivity in diabetes mellitus.

Aims  The heart rate (HR) responses after performance of the squatting and standing manoeuvre are thought to be a useful tool to assess autonomic neuropathy in diabetics. Our aim was to develop new simple squatting test indices and to analyse their applicability to the assessment of baroreflex sensitivity (BRS) in patients with diabetes.

Plasma norepinephrine is an independent predictor of adverse cerebral and cardiovascular events in type 2 diabetic patients without structural heart disease

BACKGROUND Resting plasma norepinephrine (NE) level was reportedly related to high mortality in patients with heart failure. The current study investigated whether resting NE could predict long-term major adverse cerebral and cardiovascular events (MACCEs) in Japanese type 2 diabetic patients without heart disease. METHODS AND SUBJECTS We evaluated resting NE in 95 patients with type 2 diabetes who did not have severe complications. Based on the ROC curves, high NE was defined as ≥333pg/ml. Accurate follow-up information during a mean of 3.6±1.9 years was obtained in 27 high NE patients (13 female, mean age 64±12 years) and 68 low NE patients (29 female, 60±12 years). ESSENTIAL RESULTS The Kaplan-Meier curves revealed that MACCE-free ratio was significantly lower in the high NE patients than in the low NE patients (log-rank 10.3, p=0.0013). Cox proportional hazards regression analysis revealed that female gender (hazard ratio 7.75), low baroreflex sensitivity (hazard ratio 6.66), and high NE (hazard ratio 5.40) were independently associated with the incidence of MACCE. PRINCIPAL CONCLUSIONS Our results suggest that resting NE is comparably useful to identify the high-risk patients for MACCE to baroreflex sensitivity in type 2 diabetic patients. The results also suggest that pathogenic sympathetic activation leading to MACCE may be identified by the assessment of resting NE, more easily and less expensively compared to cardiac iodine 123 metaiodobenzylguanidine scintigraphy in this population.

Electrocardiographic characteristics of patients with false tendon: Possible association of false tendon with J waves

BACKGROUND The false tendons (FTs) are fibromuscular bands that transverse the left ventricular cavity and often contain conduction tissue, suggesting that FTs may contribute to the occurrence of ventricular arrhythmias. The presence of J waves is associated with vulnerability to ventricular arrhythmias; however, the mechanisms underlying the manifestation of J waves remain to be elucidated. OBJECTIVE To investigate the electrocardiographic characteristics, including the presence of J waves, in patients with FTs. METHODS We studied 44 patients with distinct FTs detected by echocardiography (FT group) and 88 age- and sex-matched healthy subjects without FTs (control group). The PQ, QRS, JT, QT, corrected JT, and corrected QT intervals were automatically measured on surface 12-lead electrocardiograms, and the presence or absence of J waves was also determined. J waves were defined as terminal QRS notching or slurring. FTs were classified according to their points of attachment as type 1 (longitudinal, 52%), type 2 (diagonal, 25%), type 3 (transverse, 16%), and type 4 (weblike, 7%). RESULTS QRS and corrected QT intervals were significantly longer in the FT group than in the control group (P <.005 and P <.05, respectively). The incidence of J waves was significantly higher in the FT group (64%) than in the control group (19%) (P <.0001). J waves were more prevalent in type 1 (78%) and type 2 (73%) than in type 3 (14%) and 4 FTs (33%) (P <0.05) and in patients with thick FTs (≥ 2 mm) than with thinner FTs (<2 mm) (71% vs 33%; P <.05). The J-wave location differed according to the FT type. CONCLUSIONS Our results suggest that FTs may carry a certain role to the genesis of J waves.

High-glucose condition reduces cardioprotective effects of insulin against mechanical stress-induced cell injury

AIMS Mechanical stress induces cardiomyocyte injury and contributes to the progression of heart failure in patients with hypertension. In this study, we investigated whether insulin exerts cardioprotective effects against mechanical stretching-induced cell injury, and whether the protective effect is influenced by high-glucose condition. MAIN METHODS Cultured neonatal rat cardiomyocytes were plated on silicone chambers, and the cells were mechanically stretched by 15% to induce cell injury. KEY FINDINGS Mechanical stretching increased reactive oxygen species (ROS) and decreased mitochondrial inner membrane potential (DeltaPsi(m)), eventually leading to cell death by apoptosis and necrosis. Insulin activated the phosphoinositide 3 (PI3) kinase/Akt pathway and reduced apoptosis and necrosis by suppressing ROS increase and preserving DeltaPsi(m). However, high-glucose condition attenuated the insulin-induced Akt phosphorylation and cardioprotection. To investigate the mechanisms that attenuated the effects of insulin in high-glucose condition, we examined the expression of tensin homologue deleted on chromosome 10 (PTEN), which is a negative regulator of the PI3 kinase/Akt pathway. The expressions of PTEN and phosphorylated PTEN were significantly decreased by insulin, and those effects were attenuated in high-glucose condition. SIGNIFICANCE The present results suggest that insulin prevents mechanical stress-induced cell injury which otherwise lead to heart failure. Furthermore, we found that high-glucose condition prevented the decrease in PTEN expression and the cardioprotective effects induced by insulin.

Malignant neurocardiogenic vasovagal syncope associated with chronic exaggerated vagal tone.

NAKAGAWA, M., et al.: Malignant Neurocardiogenic Vasovagal Syncope Associated with Chronic Exaggerated Vagal Tone. A head‐up tilt test was performed in a 23‐year‐old woman with a history of two syncopal episodes. The patient developed abrupt syncope with 48 seconds of sinus arrest. Analysis of the high frequency (HF) power of heart rate variability over 24 hours before and after metoprolol therapy showed a significantly elevated HF power in this patient compared to age– and sex‐matched healthy subjects. It is suggested that an exaggerated resting vagal tone might be associated with the pathogenesis of prolonged asystole in our patient.

Cardiac Autonomic Dysfunction in Patients with Head-up Tilt Test-Induced Vasovagal Syncope

Vasovagal syncope (VVS) is the result of an autonomic reflex that has a final effect of reducing sympathetic drive and increasing vagal activity. However, whether syncopal symptoms are associated with pathological cardiac autonomic modulation is not fully known. We tested the hypothesis that cardiac autonomic function is impaired in patients with VVS.