Hajime Iwama

Usefulness of soluble Fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction.

Placental growth factor and vascular endothelial growth factor increase angiogenesis and promote healing after acute myocardial infarction (MI), but the significance of soluble Fms-like tyrosine kinase-1 (sFlt-1), an antagonist of placental growth factor and vascular endothelial growth factor, in the setting of acute MI has not been elucidated. The development of acute heart failure in the immediate period after MI is a dreaded complication, but there are no useful biomarkers that identify patients at risk of acute heart failure. We wished to investigate the clinical significance of circulating sFlt-1 during acute MI. We enrolled 174 patients with acute MI, and arterial blood sampling was performed. Plasma levels of sFlt-1 were measured by enzyme-linked immunosorbent assay and their relation to clinical parameters was analyzed. Circulating levels of sFlt-1 on admission were significantly increased in patients with acute MI compared to controls (528.1 +/- 290.9 vs 355.7 +/- 205.0 pg/ml, p <0.001). Circulating levels of sFlt-1 on admission were significantly higher in patients who developed severe acute heart failure requiring mechanical circulatory support devices compared to those with stable hemodynamics (611.4 +/- 373.6 vs 494.6 +/- 243.9 pg/ml, p = 0.016). Moreover, circulating levels of sFlt-1 on admission were directly related to duration of hospitalization. Multivariate logistic analysis showed that hemodynamic instability was predicted by sFlt-1 on admission and left ventricular systolic pressure. In conclusion, the circulating level of sFlt-1 is increased in patients with acute MI, and the sFlt-1 level on admission is a promising biomarker for the development of severe acute heart failure after MI.

Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis

Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)–nephrectomized apolipoprotein E–deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6–nephrectomized apolipoprotein E–deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. Conclusions— The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

Blocking T-type Ca2+ channels with efonidipine decreased plasma aldosterone concentration in healthy volunteers

Efonidipine can block both L- and T- type Ca2+ channels. In a previous in vitro study, we clarified that efonidipine dramatically suppresses aldosterone secretion from human adrenocortical tumor cells during angiotensin II (Ang II)− and K+-stimulation, whereas nifedipine, a dominant L-type Ca2+ channel antagonist, does not. This study was conducted to assess the in vivo effects of efonidipine and nilvadipine on the plasma aldosterone concentration. Placebo, 40 mg of efonidipine, or 2 mg of nilvadipine was administered to five healthy male volunteers. Hemodynamic parameters (pulse rate [PR] and blood pressure [BP]), plasma concentrations of neurohormonal factors (plasma renin activity, Ang II, aldosterone, and adrenocorticotropic hormone [ACTH]), and serum concentrations of Na+ and K+ were measured before and 6 h after administration of the agents. All three agents had little effect on PR and BP. Efonidipine and nilvadipine significantly increased plasma renin activity and Ang II. Both had little effect on ACTH, Na+, and K+. The plasma aldosterone concentration was significantly decreased after efonidipine treatment (88.3±21.3 to 81.6±24.9 pg/ml, p=0.0407), whereas it was significantly increased after nilvadipine treatment (66.5±12.2 to 82.17±16.6 pg/ml, p=0.0049). Placebo had little effect on neurohormonal factors. Efonidipine decreased plasma aldosterone concentration despite the increase in plasma renin activity and Ang II, suggesting that T-type Ca2+ channels may also play an essential role in the secretion of aldosterone in healthy human volunteers.

Acute myocardial infarction as a systemic prothrombotic condition evidenced by increased von Willebrand factor protein over ADAMTS13 activity in coronary and systemic circulation

The aim of the present study is to clarify the roles of circulating ADAMTS13 and von Willebrand factor (VWF) in the formation of coronary artery thrombi in acute myocardial infarction (AMI). Twenty-six AMI patients, 37 age-matched healthy controls, and 20 young controls were studied. Plasma ADAMTS13 activity and levels of VWF antigen (VWF: Ag) and unusually large VWF multimer (UL-VWFM) were measured in the femoral vein (FV), aortic root (Ao), and coronary sinus (Cs) immediately before percutaneous coronary intervention (PCI) during the acute phase of AMI, as well as 6 months later. During the acute phase of AMI, plasma levels of VWF: Ag were similar in FV, Ao, and Cs, and were higher than those of age-matched control. In contrast, ADAMTS13 activity in three sampling points in AMI patients was similar to that of age-matched controls. Thus, the ratio of VWF: Ag to ADAMTS13 activity in the acute phase of AMI was significantly higher in all three sampled sites than that of age-matched controls. In the chronic phase, plasma levels of VWF: Ag, ADAMTS13 activity, and the ratio of VWF: Ag to ADAMTS13 activity were similar to those of age-matched controls. UL-VWFM was detected in the acute phase of AMI but not in the chronic phase. The present study showed that the plasma VWF: Ag levels are increased and ADAMTS13 activity is relatively decreased in both systemic and coronary circulation during the acute phase of AMI, suggesting that an imbalance between the enzyme and its substrate may play a role in the formation of occlusive thrombi in a coronary artery.

Novel application of black-blood echo-planar imaging to the assessment of myocardial infarction

The purpose of this study was to clarify the characteristics of black-blood echo-planar imaging (BB-EPI) in the assessment of infarct-related myocardial edema (IRME), compared with T2-weighted imaging (T2WI). Thirteen acute myocardial infarction (MI) patients after reperfusion and 11 old MI patients underwent BB-EPI and T2WI, excluding those with posterior MI. In acute MI patients, signal intensity ratio (SI ratio) of edema to normal myocardium was measured. Black-blood echo-planar imaging revealed hyperintensity in the same region identified as IRME on T2WI in all acute MI patients, and SI ratio was significantly higher in BB-EPI (2.66 ± 1.58) than in T2WI (1.44 ± 0.22) (P < 0.05). However, BB-EPI showed hyperintensity in posterior wall, where there is no clinical evidence of acute MI, in 2 out of 13 acute MI patients. Both T2WI and BB-EPI detected no IRME in known old infarct area of all old MI patients, but BB-EPI showed hyperintensity in the posterior wall of 4 out of 11 old MI patients. Black-blood echo-planar imaging can depict IRME with sufficient suppression of background and blood flow signals, and with excellent edema-to-normal myocardium contrast resolution. However, BB-EPI sometimes shows an inconsistent signal area with T2WI specifically in posterior wall. The wide practical use of BB-EPI requires the solution to this serious problem.