Masashi Ikushima

Association between hyperglycemia and the no-reflow phenomenon inpatients with acute myocardial infarction

OBJECTIVES We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). BACKGROUND Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. METHODS A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom onset. Two-dimensional echocardiography was recorded on day 1 and three months later to determine the change in the wall motion score (DeltaWMS; sum of 16 segmental scores; dyskinesia = 4 to normokinesia = 0). RESULTS The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose level on hospital admission was significantly higher than that of patients who did not exhibit this phenomenon (209 +/- 79 vs. 159 +/- 56 mg/dl; p < 0.0001). There was no difference in glycosylated hemoglobin or in the incidence of diabetes mellitus between the two subsets. The no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia (>/=160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2,497 +/- 1,603 vs. 1,804 +/- 1,300 IU/l; p = 0.005) and a lower DeltaWMS (3.7 +/- 4.8 vs. 5.7 +/- 4.3; p = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the culprit lesion, and anterior AMI. CONCLUSIONS Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.

Deletion of Angiotensin-Converting Enzyme 2 Accelerates Pressure Overload-Induced Cardiac Dysfunction by Increasing Local Angiotensin II

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2−/y mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin–angiotensin system, we used ACE2−/y mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2−/y mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2−/y mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2−/y mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2−/y mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2−/y mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2−/y mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2−/y mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.

Predictive Factors for Development of the No-Reflow Phenomenon in Patients With Reperfused Anterior Wall Acute Myocardial Infarction

OBJECTIVES We sought to elucidate the clinical factors related to the development of no-reflow phenomenon after successful coronary reperfusion in patients with an acute myocardial infarction (AMI). BACKGROUND Myocardial contrast echocardiography revealed that the no-reflow phenomenon is observed in some patients with a reperfused AMI, and those patients usually have poor functional and clinical outcomes. It is still unknown what clinical factors are related to the development of the no-reflow phenomenon. METHODS Myocardial contrast echocardiography was performed 15 min after successful coronary reperfusion therapy in 199 patients with an anterior wall AMI who underwent successful coronary reperfusion with primary coronary angioplasty within 24 h after the onset of AMI. Multiple logistic regression analysis was used to identify independent predictors of the no-reflow phenomenon. RESULTS Seventy-nine patients showed the no-reflow phenomenon. Univariate analysis indicated that pre-infarction angina within 48 h before symptom onset, Killip class, Thrombolysis in Myocardial Infarction flow grade 0 on the initial coronary angiogram, the number of abnormal Q-waves and the wall motion score (WMS) on the echocardiogram obtained at hospital admission are related to the no-reflow phenomenon. Multivariate logistic regression analysis revealed that all of these factors, except for Killip class, are independent predictive factors of the no-reflow phenomenon. CONCLUSIONS Development of the no-reflow phenomenon is related to the severity of myocardial damage (number of Q-waves), the size of the risk area (WMS) and the occlusion status of infarct-related artery. In addition, ischemic preconditioning (pre-infarction angina) seems to be the factor that attenuates the no-reflow phenomenon.

Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.

Aim:  Mice that carry the Klotho mutation (KL‐/‐) manifest diverse age‐related disorders similar to those observed in humans. Thus, the Klotho protein might function as an anti‐aging hormone in mammals. Recently, we reported that Klotho recombinant protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal‐regulated kinase and mitogen‐activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence.

Two different coronary blood flow velocity patterns in thrombolysis in myocardial infarction flow grade 2 in acute myocardial infarction: Insight into mechanisms of microvascular dysfunction

OBJECTIVES We sought to determine which of the two main potential mechanisms underlying Thrombolysis In Myocardial Infarction flow grade 2 (TIMI-2 flow) operate in an individual patient who has had an acute myocardial infarction (AMI). BACKGROUND Systolic flow reversal (SFR) is a specific finding of capillary damage, the no-reflow phenomenon. The coronary blood flow velocity (CBFV) pattern of thromboemboli, however, remains unknown. METHODS Data on 105 patients with AMI (57 with anterior and 48 with nonanterior cases) who underwent a coronary intervention were analyzed. The CBFV was recorded by a Doppler guide wire, and tissue perfusion was assessed with myocardial contrast echocardiography (MCE). RESULTS Study patients were classified into three groups according to TIMI grade and the presence or absence of SFR: 1) TIMI-3 flow (n = 80); 2) TIMI-2 flow with SFR (SFR[+], n = 14); and 3) TIMI-2 flow without SFR (SFR[-], n = 11). Diastolic CBFV was the lowest in SFR(-) (TIMI-3 vs. SFR[+] vs. SFR[-]: 34 vs. 31 vs. 9 cm/s), and the systolic to diastolic CBFV ratio was also the highest in SFR(-) (0.43 vs. -0.18 vs. 0.66). The no-reflow phenomenon documented by MCE was found in all patients in the SFR(+) group, but in only one patient (10%) in the SFR(-) group. Intracoronary thrombus was more frequently found in SFR(-) than in SFR(+) (91% vs. 14%, p < 0.05). CONCLUSIONS At least two different CBFV patterns are noted in patients with reperfused AMI who have TIMI-2 flow. Capillary damage is mostly responsible for SFR(+), and SFR(-) is seen in thromboemboli possibly due to increased coronary arterial resistance.

Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1α-hydroxylase gene expression

Homozygous Klotho mutant (kl−/−) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl−/− mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D3 1α-hydroxylase in the kidney. We studied 25-hydroxyvitamin D3 1α-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho protein production. It was found that Klotho protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D3 1α-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1α-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D3 1α-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.

Klotho gene delivery suppresses oxidative stress in vivo

Objective:  Mice deficient in the klotho gene exhibit a syndrome resembling premature human aging. A recent report also suggested that klotho transgenic mice exhibited a long lifespan, which shows that klotho is an antisenescence gene. Previously, klotho has been reported to improve endothelial dysfunction, and also to have a preventive effect against oxidative stress. In the present study, we investigated the effect of klotho gene delivery on blood pressure and oxidative stress in vivo.

ANG II inhibits insulin-mediated production of PI 3,4,5-trisphosphates via a Ca2+-dependent but PKC-independent pathway in the cardiomyocytes

Insulin resistance (IR) is a condition where different organs are refractory to insulin stimulation of glucose uptake. ANG II has been suggested to be involved in the development of IR in the heart. The precise mechanism by which this occurs is still unknown. Here we have used dynamic fluorescent imaging techniques to show that ANG II inhibits insulin production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)] in cardiac myocytes. Fluorophore (Venus)-conjugated cAMP-dependent protein kinase-pleckstrin homology domain, which specifically binds to PI(3,4,5)P(3), was transfected in neonatal rat cardiac myocytes. Insulin induced a robust increase in the fluorescence intensity at the cell surface, which was diminished by application of ANG II. The inhibitory action of ANG II was antagonized by RNH-6270 (an angiotensin type 1 receptor antagonist) but not by PD-122370 (an angiotensin type 2 receptor antagonist). BAPTA-AM (Ca(2+) chelator) largely attenuated the ANG II effect, whereas K-252b (PKC inhibitor) did not. Furthermore, an elevation of intracellular Ca(2+) induced by ionomycin mimicked the ANG II effect. Therefore, it is suggested that ANG II antagonizes insulin-mediated production of PI(3,4,5)P(3) via a Ca(2+)-dependent but PKC-independent pathway in cardiac myocytes.

Association between senescence‐related uncoupling protein 2 gene polymorphisms and abdominal obesity in Japanese subjects: The Tanno and Sobetsu study

Background:  Uncoupling protein 2 (UCP2) plays an important role in regulating body weight, energy expenditure and insulin secretion. UCP2 is upregulated in white fat in response to fat feeding, and negatively controls insulin secretion. UCP2 also has a function that protects cells from apoptosis and oxidative stress, which shows UCP2 might be a senescence‐related gene. Previously, UCP2‐866G/A polymorphism in the promoter region has been reported to alter adipose tissue mRNA expression and is associated with obesity in Caucasians.