Sudden cardiac death after myocardial infarction in patients with type 2 diabetes

Junttila, M. Juhani; Barthel, Petra; Myerburg, Robert J.; Mäkikallio, Timo H.; Bauer, Axel; Ulm, Kurt; Kiviniemi, Antti M.; Tulppo, Mikko P.; Perkiömäki, Juha S.; Schmidt, Georg

doi:10.1016/j.hrthm.2010.07.031

Cited by 85 publications

(70 citation statements)

References 29 publications

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“…One of the early and most consistent observations in the heart of diabetics is the prolongation of QTc interval (23). Disrupted I CaL inactivation may cause a long QTc interval, a precursor for sudden cardiac arrest that occurred in patients with type 1 and type 2 diabetes (14,21), under obese conditions. Prolongation of QTc interval has also been demonstrated as an independent risk factor in type 1 and type 2 diabetes (34,37,38), as well as a significant predictor of cardiac death (31,34).…”

Section: Discussionmentioning

confidence: 99%

Defective calcium inactivation causes long QT in obese insulin-resistant rat

Lin

Huang

Kan

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16 -17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I CaL) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca 2ϩ influx. The current density of I CaL was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I CaL were not significantly altered. L-type Ba 2ϩ current (IBaL) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I BaL in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cav␤2 subunit was not altered in OZR. Together, these results suggested that the 16-to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of ICaL and IBaL, 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of insulin resistance, enhancing our understanding of long QT associated with obese type 2 diabetic patients. obesity; insulin resistance; long QT; action potential; L-type calcium current; calmodulin OBESITY IS DIRECTLY LINKED to type 2 diabetes, which has become an increasingly public health problem. In 2004, heart disease was noted on 65-68% of diabetes-related death among people aged 65 years and older

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Section: Discussionmentioning

confidence: 99%

Defective calcium inactivation causes long QT in obese insulin-resistant rat

Lin

Huang

Kan

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…These patients may also have an increased storage of triglycerides during acute ischemia because they overproduce triglyceride-rich lipoproteins (36), which are ligands of the VLDLR. The increased VLDLR-mediated lipid accumulation may partly explain why patients with type 2 diabetes have an increased risk of sudden cardiac death after myocardial infarction (37).…”

Section: Discussionmentioning

confidence: 99%

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Perman¹,

Boström²,

Lindbom³

et al. 2011

J. Clin. Invest.

137

132

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Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr -/-mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr -/-mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.

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“…There is evidence to suggest that obesity, diabetes, and heart failure are all associated with decreased NOS1 activity (16)(17)(18)(19)(20). Junttila et al (21) recently reported a markedly increased incidence of sudden arrhythmic death in diabetic patients after MI compared with nondiabetic controls. Diabetic patients with left ventricle ejection fractions (LVEF) >35% had a sudden death rate equal to nondiabetic patients with LVEF <35%.…”

Section: Combination Of Decreased Nos1 Activity and Oxidative Stress mentioning

confidence: 99%

Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart

Cutler

Plummer

Wan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO) derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca 2+ handling proteins. Deficient S-nitrosylation of the cardiac ryanodine receptor (RyR2) has a variable effect on SR Ca 2+ leak/sparks in isolated myocytes, likely dependent on the underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis in the intact heart. Here we show in the intact heart, reduced NOS1 activity increased Ca 2+ -mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca 2+ ] i . These arrhythmias arose from increased spontaneous SR Ca 2+ release, resulting from a combination of decreased RyR2 S-nitrosylation (RyR2-SNO) and increased RyR2 oxidation (RyR-SOx) (i.e., increased reactive oxygen species (ROS) from xanthine oxidoreductase activity) and could be suppressed with xanthine oxidoreductase (XOR) inhibition (i.e., allopurinol) or nitric oxide donors (i.e., S-nitrosoglutathione, GSNO). Surprisingly, we found evidence of NOS1 down-regulation of RyR2 phosphorylation at the Ca 2+ /calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between nitrosylation and phosphorylation of RyR2. Finally, we show that nitroso-redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype by oxidative stress. Our findings suggest that nitroso-redox imbalance is an important mechanism of ventricular arrhythmias in the intact heart under disease conditions (i.e., elevated [Ca 2+ ] i and oxidative stress), and that therapies restoring nitroso-redox balance in the heart could prevent sudden arrhythmic death. N itric oxide (NO) is an important regulator of cardiac function via both the activation of cyclic guanosine monophosphatedependent signaling pathways and direct posttranslational modification of protein thiols (S-nitrosylation) (1). NO derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca 2+ handling proteins (2). In particular, nitrosylation of both skeletal and cardiac muscle ryanodine receptors (RyR1 and RyR2, respectively) alters their release properties, favoring activation (3, 4). Notably, an increase in RyR2 open probability can cause spontaneous SR Ca 2+ release, which may cause arrhythmias. Recently, it was shown that decreased RyR2 S-nitrosylation (RyR2-SNO) through loss of NOS1, was associated with increased spontaneous SR Ca 2+ release events in isolated cardiomyocytes, following rapid pacing (5). In a separate study, NOS1 deficiency was shown to decrease spontaneous SR Ca 2+ sparks and the open probability of RyR2 under resting conditions in cardiomyocytes and lipid bilayers, respectively (6). These studies suggest that NOS1 deficiency has a variable effect on RyR2 function, likely dependent on the underlying physiological state (i.e., rapid heart rate versus quiescence). It remains unk...

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Sudden cardiac death after myocardial infarction in patients with type 2 diabetes

Cited by 85 publications

References 29 publications

Defective calcium inactivation causes long QT in obese insulin-resistant rat

Defective calcium inactivation causes long QT in obese insulin-resistant rat

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart

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