Kazuto Nakamura

Persistent Impairment of Endothelial Vasomotor Function Has a Negative Impact on Outcome in Patients With Coronary Artery Disease

OBJECTIVESnWe assessed the hypothesis that changes in endothelial vasomotor function in response to optimized therapy for atherosclerotic coronary artery disease predict future cardiovascular events.nnnBACKGROUNDnAlthough endothelial vasomotor dysfunction is a predictor of cardiovascular events, it remains unclear whether reversibility of endothelial dysfunction in response to risk factor reduction provides prognostic information.nnnMETHODSnThis study included 251 patients with newly diagnosed coronary artery disease and an impaired flow-mediated dilation (FMD) of the brachial artery (FMD <5.5%). Measurement of FMD was repeated after 6 months for individualized and optimized therapy to reduce risk factors according to American College of Cardiology/American Heart Association guidelines. Patients were followed up for 36 months or until 1 of the following events occurred: cardiac death, nonfatal myocardial infarction, recurrent and refractory angina pectoris requiring coronary revascularization, or ischemic stroke.nnnRESULTSnFMD was persistently impaired (<5.5%) in 104 (41%) patients after 6 months of optimized therapy, whereas it improved (FMD > or =5.5%) in the remaining 147 (59%) patients. During 36 months of follow-up, events occurred in 27 (26%) patients with persistently impaired FMD and in 15 (10%) patients with improved FMD (p < 0.01 by chi-square test). Multivariate Cox hazards analysis showed that persistent impairment of FMD was an independent predictor of events (hazard ratio: 2.9, 95% confidence interval: 1.5 to 6.2, p < 0.01). Baseline FMD before the optimized therapy to reduce risk factor had no significant prognostic information.nnnCONCLUSIONSnPersistent impairment of endothelial vasomotor function despite optimized therapy to reduce risk factors has an adverse impact on outcome in coronary artery disease patients.

Candesartan Ameliorates Cardiac Dysfunction Observed in Angiotensin-Converting Enzyme 2-Deficient Mice

The renin-angiotensin (Ang) system plays a critical role in the regulation of blood pressure, body fluid, electrolyte homeostasis, and organ remodeling under physiological and pathological conditions. The carboxy-peptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). It has been reported that ACE2-deficient mice develop cardiac dysfunction with increased plasma levels of Ang II. However, the molecular mechanism by which genetic disruption of ACE2 results in heart dysfunction is not fully understood. Here, we generated mice with targeted disruption of the Ace2 gene and compared the cardiovascular function of ACE2–ly mice with that of their wild-type littermates. ACE2-deficient mice were viable and fertile and lacked any gross structural abnormalities. Echocardiographic study detected no functional difference between ACE2–ly and wild-type mice at 12 weeks of age. Twenty-four-week-old ACE2–ly mice displayed significantly enlarged hearts with impaired systolic and diastolic function. The Ang II level was elevated in the plasma and heart of ACE2–ly mice. Pharmacological blockade of Ang II type 1 receptor (AT1) with candesartan attenuated the development of cardiac dysfunction in ACE2–ly mice. These results suggest that enhanced stimulation of AT1 may play a role in the development of cardiac dysfunction observed in ACE2-deficient mice.

Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome

OBJECTIVEnThis study examined whether pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, may stabilize vulnerable plaque with use of ultrasound evaluation of carotid artery plaque echolucency in patients with acute coronary syndrome (ACS) and type 2 diabetes mellitus (DM).nnnMETHODS AND RESULTSnTreatment with pioglitazone (15 or 30mg/day, n=31) or placebo (n=30) was randomly assigned and initiated within 5 days after the onset of ACS in 61 patients with type 2 DM and echolucent carotid plaques. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, at 2 weeks, and 1 month and 6 months after initiation of treatment. An increase in IBS value reflects an increase in carotid plaque echogenicity. Calibrated IBS value (intima-media IBS value minus adventitia IBS value) of echolucent carotid plaques did not change at 2 weeks but was significantly increased at 1 month after treatment in the pioglitazone group but not in the placebo group. The increase in calibrated IBS value was not significantly correlated with the effect of pioglitazone on glycemia.nnnCONCLUSIONSnPioglitazone rapidly improved carotid plaque echolucency within 1 month of therapy initiation in patients with ACS and type 2 DM.

C-type lectin-like domain and fibronectin-like type II domain of phospholipase A2 receptor 1 modulate binding and migratory responses to collagen

Phospholipase A2 receptor 1 (PLA2R) mediates collagen‐dependent migration. The mechanisms by which PLA2R interacts with collagen remain unclear. We produced HEK293 cells expressing full‐length wild‐type PLA2R or a truncated PLA2R that lacks fibronectin‐like type II (FNII) domains or several regions of C‐type lectin‐like domain (CTLD). We show that the CTLD1–2 as well as the FNII domain of PLA2R are responsible for binding to collagen and for collagen‐dependent migration. Thus, multiple regions and domains of the extracellular portion of PLA2R participate in the responses to collagen. These data suggest a potentially new mechanism for PLA2R‐mediated biological response beyond that of a receptor for secretory PLA2.

Remnant lipoproteinemia predicts cardiovascular events in patients with type 2 diabetes and chronic kidney disease

BACKGROUNDnPatients having type 2 diabetes mellitus (DM) and chronic kidney disease (CKD) are at high risk of cardiovascular events. Triglyceride-rich lipoprotein levels are synergistically increased in patients with DM and CKD. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with DM and CKD.nnnMETHODSnThree hundred and sixty-five patients with type 2 DM and CKD were enrolled. Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. All patients were followed prospectively for a period of 45±23 months or until occurrence of one of the following events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or ischemic stroke.nnnRESULTSnDuring the follow-up period, 59 patients had cardiovascular events. Multivariate Cox analysis revealed that high levels of RLP-C (≥4.3mg/dL; median value) were a significant risk factor for cardiovascular events, independent of traditional risk factors (HR: 1.30; 95% CI: 1.04-1.63; p=0.02). The addition of high levels of RLP-C to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.36, p=0.01; and IDI 0.03, p=0.02).nnnCONCLUSIONSnRLP-C is useful for risk assessment of future cardiovascular events in patients having type 2 DM and CKD.

High levels of stromal cell-derived factor-1α predict secondary cardiac events in stable patients with a history of myocardial infarction

BACKGROUNDnWe recently showed that stromal cell-derived factor (SDF)-1α, a pro-inflammatory mediator, is produced in infarcted myocardium and is associated with left ventricular (LV) adverse remodeling and progressive dysfunction following acute myocardial infarction (AMI). The current study examined whether SDF-1α levels in the peripheral vein can provide prognostic information of outcomes in stable patients with a history of MI.nnnMETHODSnPlasma levels of SDF-1α in the peripheral vein were measured by enzyme-linked immunosorbent assay in 192 stable patients with a history of MI. All patients were followed prospectively for a period of 90 months or until occurrence of one of the following cardiac events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or worsening heart failure requiring hospital admission.nnnRESULTSnDuring the follow-up period (77±26 months), 30 patients had cardiac events. Multivariate Cox analysis revealed that high levels of SDF-1α (≥2162pg/mL; a cut-off value determined by receiver-operating characteristic analysis) were a significant predictor of cardiac events, independent of traditional risk factors (HR: 1.98; 95% CI: 1.38-2.85; p<0.001). The addition of high levels of SDF-1α to conventional risk factors including brain natriuretic peptide improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.90, p<0.0001; and IDI 0.05, p=0.002).nnnCONCLUSIONSnHigh levels of SDF-1α predicted secondary cardiac events in stable patients with a history of MI. SDF-1α levels may be a useful risk assessment tool in patients with a history of MI.

Phospholipase A2 Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery

Aims: Phospholipase A2 receptor 1 (PLA2R) has multiple biological functions other than functioning as a receptor for secretory PLA2s. Two nonsynonymous polymorphisms in the C-type lectin-like domains (CTLD) 1 of PLA2R gene have been associated with idiopathic membranous nephropathy. This study examined whether the same PLA2R polymorphisms may alter functions of PLA2R in cells expressing the variant PLA2R. In addition, the clinical relevance of the experiment was examined. Methods: Two nonsynonymous polymorphisms (T/C at rs3749117 and G/C at rs35771982) in CTLD1 of PLA2R gene were completely linked. HEK293 cells expressing human wild-type PLA2R (T at rs3749117 and G at rs35771982) or human mutant PLA2R that had double mutations (C at rs3749117 and C at rs35771982) were constructed. Results: HEK293 cells expressing mutant PLA2R had lower migratory and proliferative responses to collagen I compared with cells expressing wild-type PLA2R. In 580 male patients, PLA2R gene polymorphisms were associated with an increase in maximum intima-media thickness (maxIMT) of the carotid artery. The multivariate regression model showed that PLA2R gene polymorphisms were a risk factor of an increased maxIMT that was independent of conventional risk factors (OR = 1.93, 95% CI: 1.17–3.19, p < 0.01). Conclusions: The nonsynonymous common variants of PLA2R gene altered biological functions in cells expressing variant PLA2R. PLA2R gene polymorphisms present a genetic risk of an increased IMT of the carotid artery in male. The functional changes in the variant PLA2R may potentially be responsible for its association with an increased IMT of the carotid artery.

Echolucent Carotid Plaque is Associated with Future Renal Dysfunction in Patients with Stable Coronary Artery Disease

AIMnFunctional and structural abnormalities of the peripheral arteries are associated with renal dysfunction, independent of the presence of renal artery stenosis. This study investigated whether echolucent carotid plaque is associated with a future decline in the renal function in patients with coronary artery disease (CAD).nnnMETHODSnUltrasound assessments of carotid plaque echolucency with integrated backscatter (IBS) analyses were performed in 327 patients with stable CAD and carotid plaque who exhibited a normal renal function (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m(2)) at baseline. A lower IBS value reflects the presence of echolucent and lipid-rich unstable plaque. All patients were followed up for 36 months or until the occurrence of renal dysfunction, defined as an eGFR of ＜45 mL/min/1.73 m(2).nnnRESULTSnDuring the follow-up period, 39 patients developed renal dysfunction. A multivariate logistic regression analysis showed that the presence of carotid plaque with a low IBS value was significantly associated with progression to renal dysfunction (odds ratios 0.48; 95% CI 0.30-0.78, p= 0.003). In addition, carotid plaque with a low IBS value had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using c-statistics (AUC of the baseline risk model with and without IBS: 0.83 vs. 0.79, respectively, p=0.04), net reclassification improvement (index=0.549, p=0.001) and integrated discrimination improvement (index=0.068, p=0.002).nnnCONCLUSIONSnEcholucency of the carotid arteries is associated with future renal dysfunction in patients with stable CAD, indicating that the mechanisms related to plaque instability may be involved in the onset of renal dysfunction.

Echolucency of the carotid artery is associated with short-term plaque progression and positive remodeling in the culprit coronary artery in AMI survivors

BACKGROUNDnRapid plaque progression and positive remodeling are recognized as vulnerable coronary plaque characteristics. This study examined whether serial carotid ultrasonography might be of value for assessment of coronary plaque progression and positive remodeling, measured by serial intravascular ultrasound (IVUS), in survivors of acute myocardial infarction (AMI).nnnMETHODSnThirty-nine patients with AMI had repeated examinations by IVUS of culprit coronary arteries and echolucency of the coronary artery on admission (1st test) and 6 months later (2nd test). Plaque volume and external elastic membrane area of the native segment (15±9mm in length) beginning 5mm proximal to the stent edge in the culprit coronary artery were measured using volumetric IVUS. Echolucency of the carotid artery was assessed by integrated backscatter (IBS) analysis. Lower IBS reflects an echolucent and lipid-rich plaque.nnnRESULTSnIncrease in coronary plaque volume and positive remodeling over 6 months occurred in 17 and 12 patients, respectively. The % change in carotid IBS value over 6 months was correlated with the % change in the coronary plaque volume (r=-0.69, p<0.001). The aggravated change in the carotid IBS was significantly associated with increase in the coronary plaque volume and positive remodeling over 6 months (OR 0.94 and 0.95, respectively, 95% CI 0.90-0.99, both p<0.05).nnnCONCLUSIONSnSerial measurements of echolucency of the carotid artery may be of value for assessment of short-term progression and positive remodeling of coronary plaques in AMI survivors.

Effect of coronary artery spasm on long-term outcomes in survivors of acute myocardial infarction

BACKGROUNDnThe prevalence of coronary artery spasm (CAS) inducible by intracoronary injection of acetylcholine (ACh) is high in survivors of acute myocardial infarction (AMI). Although there is a potential risk of sudden cardiac death in patients with CAS, the prognostic value of CAS was not clear. Thus, this study examined the effect of CAS on long-term prognosis in survivors of AMI in a prospective manner.nnnMETHODSnThe study included a total of 437 patients with AMI who underwent a CAS provocation test using ACh. All patients were followed prospectively for 5years or until the occurrence of the primary composite endpoint that consisted of cardiac death and acute coronary syndrome (ACS).nnnRESULTSnCAS was induced in 195 (45%) of the study patients. During the follow-up period, 30 patients had a recurrent event (4 had cardiac death and 26 had ACS). Kaplan-Meier estimates in time-to-first-event analysis demonstrated a similar probability of the primary endpoint in patients with and without inducible CAS (p=0.13, log-rank test). The rate of each component of the composite endpoint was also comparable between the 2 patient groups. In Cox proportional hazards risk analysis, treatment with calcium channel blockers (CCBs) negatively predicted the primary endpoints in patients with inducible CAS (HR, 0.21; 95% CI, 0.08-0.55, p<0.01).nnnCONCLUSIONSnThe presence of inducible CAS did not increase the incidence of the cardiac events in AMI survivors. Treatment with CCBs may improve outcomes in AMI survivors with inducible CAS.nnnCLINICAL TRIAL REGISTRATIONnURL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021340, unique identifier: UMIN000018432.