Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina.

Aims: Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results: We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone. Conclusion: Rho-kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients.

A simple and rapid method for identification of lesions at high risk for the no-reflow phenomenon immediately before elective coronary stent implantation.

We aimed to design a rapid and reliable method to identify coronary lesions at high risk for the no-reflow phenomenon before elective coronary stent implantation using integrated backscatter intravascular ultrasound (IB-IVUS). The no-reflow phenomenon occurring during elective percutaneous coronary intervention (PCI) worsens patient prognosis, regardless of whether the phenomenon is transient or persistent. We retrospectively studied 353 coronary lesions to identify factors potentially promoting the no-reflow phenomenon, including lesion location and severity. We also performed component analysis by two- and three-dimensional IB-IVUS before elective stent implantation. The cutoff values of the true lipid volume and estimated lipid volume (lipid area at the minimal lumen diameter site × total stent length) for the no-reflow phenomenon were determined by receiver operating curve analysis. Type C lesions, regardless of location and a thrombolysis in myocardial flow grade of 0, were risk factors for the no-reflow phenomenon during PCI. The estimated lipid volume was significantly correlated with the true lipid volume (R 2 = 0.778, p < 0.0001). The cutoff value of the estimated lipid volume for the no-reflow phenomenon was 132.6 mm3 (area under the curve = 0.719), and the predictive value was equivalent to that of the true lipid volume. Lesions with an estimated lipid volume of ≥132.6 mm3 had a significantly higher risk of the no-reflow phenomenon during elective stent implantation (odds ratio, 4.35; 95 % confidence interval, 1.67-12.7; p = 0.0024). The simple and rapid measurement of the estimated lipid volume immediately before stenting during PCI constitutes a reliable predictor of lesions at high risk for the no-reflow phenomenon.

Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.

AIMS: Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA. METHODS AND RESULTS: A total of 1429 VSA patients (median 66 years; male/female, 1090/339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono- and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72-2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28-2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02-4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered. CONCLUSIONS: Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Clinical Characteristics of Patients With Acute Myocardial Infarction Who Did Not Undergo Primary Percutaneous Coronary Intervention- Report From the MIYAGI-AMI Registry Study.

BACKGROUND: In the current era of primary percutaneous coronary intervention (PCI), some patients with acute myocardial infarction (AMI) still do not undergo primary PCI. METHODS AND RESULTS: To examine the clinical characteristics of AMI patients who did not undergo primary PCI, we analyzed patients enrolled between 2002 and 2010 in the MIYAGI-AMI Registry Study, in which all AMI patients in the Miyagi prefecture have been prospectively registered. Among a total of 8,640 patients, 1,879 (21.7%) did not undergo primary PCI and their in-hospital mortality was significantly worse compared with those who did (21.4% vs. 6.4%, P<0.01). Multivariate analysis demonstrated that female sex was significantly associated with non-performance of primary PCI [odds ratio (95% confidence interval): 1.40 (1.22-1.61), P<0.001], along with age [1.01 (1.01-1.02), P<0.001] and heart failure on admission [2.69 (2.29-3.16), P<0.001]. When dividing by age, the non-performance rate of primary PCI in females showed a U-shaped prevalence, whereas it simply increased with aging in males. Importantly, female patients aged <80 years had a significantly higher non-performance rate of primary PCI compared with male patients, regardless of the severity of AMI. CONCLUSIONS: These results indicate that in the current PCI era, various factors, including aging, heart failure on admission and sex differences, are associated with non-performance of primary PCI, which remain to be resolved in order to further improve critical care of AMI.

Emergency care of acute myocardial infarction and the great East Japan earthquake disaster.

BACKGROUND: Although emergency care of acute myocardial infarction (AMI) could theoretically be improved through improved patient delay, this notion remains to be confirmed. Additionally, the influence of large earthquakes on the emergency care of AMI cases remains to be elucidated. The Great East Japan Earthquake (March 11, 2011) has enabled us to address these issues. METHODS AND RESULTS: We analyzed the data from 2008 to 2011 (n=3,937) in the Miyagi AMI Registry Study. In-hospital mortality was significantly lower in 2011 as compared with the previous 3 years (7.3% vs. 10.5%, P<0.05). This improvement was noted especially during the first 2 months after the Earthquake, associated with shorter elapsing time from onset to admission (120 vs. 240min, P<0.001) and higher performance rate of primary percutaneous coronary intervention (PCI) (86.8% vs. 76.2%, P<0.01). Importantly, after the Earthquake, patients with early admission (≤3h from onset) was significantly increased (59.1% vs. 47.0%, P<0.05) and their prognosis became better (7.9% vs. 11.4%, P=0.02), associated with a lower prevalence of heart failure on admission (6.9% vs. 16.2%, P=0.02) and higher performance rate of primary PCI (89.1% vs. 76.4%, P<0.01). CONCLUSIONS: Emergency care of AMI improved soon after the Great East Japan Earthquake compared with ordinary times by the contribution of earlier admission from onset and higher performance rate of primary PCI. (Circ J 2014; 78: 634-643).

Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina.

BACKGROUND: Vasospastic angina (VSA) is known to exhibit circadian variation with an early morning peak. We examined whether Rho-kinase activity in circulating leukocytes, which is a useful biomarker for disease activity assessment of VSA, exhibits circadian variation in patients with VSA. METHODS AND RESULTS: In consecutive 31 VSA patients (M/F 23/8, 57±13 [SD] years) and 18 non-VSA patients (M/F 8/10, 57±14 years), we measured Rho-kinase activity in circulating leukocytes at 6:00, 12:00 and 21:00. We also examined the relationship between the Rho-kinase activity and coronary vasomotor responses during provocation test. Rho-kinase activity was significantly higher in VSA patients than in non-VSA patients at 6:00 (1.17±0.17 vs. 0.92±0.22, P<0.001), and showed a significant circadian variation with a peak at 6:00 (1.00±0.15 at 21:00, 1.17±0.17 at 6:00 and 1.12±0.22 at 12:00, P<0.001) in VSA patients, whereas no such variation was noted in non-VSA patients. Importantly, Rho-kinase activity at spasm provocation test was significantly correlated with basal coronary tone defined by vasodilating responses to intracoronary nitrate (r=0.40, P<0.05) and coronary vasoconstricting responses to acetylcholine (r=0.44, P<0.05) in VSA patients. Furthermore, their Rho-kinase activity at 6:00 was positively correlated with nocturnal parasympathetic activity as evaluated by heart rate variability in Holter monitoring (r=0.48, P<0.05). CONCLUSIONS: Rho-kinase activity exhibits distinct circadian variation associated with alterations in coronary vasomotor responses and autonomic activity in VSA patients.

Rho-kinase activation in patients with heart failure.

BACKGROUND: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. METHODS AND RESULTS: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19 ± 0.06 vs. 0.97 ± 0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14 ± 0.02 vs. 0.77 ± 0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. CONCLUSIONS: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder.

Enhanced Rho-kinase activity in patients with vasospastic angina after the Great East Japan Earthquake.

BACKGROUND: It remains unclear whether disease activity of vasospastic angina (VSA) is altered during a disaster. METHODS AND RESULTS: Before and after the Great East Japan Earthquake, we examined Rho-kinase activity in circulating neutrophils of 11 VSA patients and their mental stress with the post-traumatic stress disorder (PTSD) questionnaire. Rho-kinase activity was significantly increased at 6 months after the Earthquake, and was returned to baseline level at 12 months. Importantly, percent change in Rho-kinase activity was significantly correlated with the PTSD score. CONCLUSIONS: These results indicate that the Rho-kinase activity of VSA patients was transiently enhanced associated with disaster-related mental stress.

Impact of the Intracoronary Rendezvous technique on coronary angioplasty for chronic total occlusion.

The Rendezvous technique, which requires bidirectional wiring, is one of the useful methods for improving the success rate of recanalization for chronic total occlusion (CTO) in the field of peripheral intervention. Recently, advanced new devices for percutaneous coronary intervention have enabled us to perform the Rendezvous technique for peripheral as well as for coronary CTO lesions. We used the Intracoronary Rendezvous technique to perform angioplasty for coronary CTO. "Intracoronary Rendezvous" means that Rendezvous was achieved within the CTO lesion. From March 2009 to November 2015, 189 patients underwent CTO angioplasty at our institute, and we treated 10 patients with the Intracoronary Rendezvous technique. This technique involves crossing the Gaia series guidewire to the contralateral Corsair microcatheter located inside the plaque of CTO lesions. The majority of the CTO sites examined were in the proximal RCA (60 %). Lesion length of the occlusion was relatively long (64.4 ± 12.2 mm). Using the biplane imaging system, we were able to control the Gaia guidewires in a specific direction. Furthermore, if the antegrade and retrograde wires can be advanced into contiguous space inside the CTO lesion, we intentionally entered either wire into the contralateral Corsair microcatheter, followed by successful CTO crossing. CTO recanalization was completed for all patients without controlled antegrade retrograde subintimal tracking (CART) or reverse CART. No major complications occurred during hospitalization. These results indicate that the Rendezvous technique, assisted by new devices and a biplane imaging system, represents one of the primary options to achieve successful coronary CTO recanalization.

Usefulness of Testing for Coronary Artery Spasm and Programmed Ventricular Stimulation in Survivors of Out-of-Hospital Cardiac Arrest.

BACKGROUND: Optimal therapy for patients resuscitated from out-of-hospital cardiac arrest (OHCA) who are not found to have structural heart disease remains to be established, especially regarding the use of implantable cardioverter-defibrillators. Coronary artery spasm (CAS) and lethal ventricular arrhythmias are important causes of OHCA. METHODS AND RESULTS: In 47 consecutive OHCA survivors without structural heart disease who had fully recovered (M/F 44/3, 43±13 years.), we performed dual induction tests, including acetylcholine provocation test first followed by programmed ventricular stimulation after 1 to 2 weeks. Patients with CAS were treated with calcium channel blocker-based antianginal medications; implantable cardioverter-defibrillators were implanted in all patients. The results of the dual induction tests defined 4 groups: CAS alone (n=7), inducible ventricular arrhythmias alone (n=13), both positive (n=24), and both negative (n=3). During a median follow-up period of 38 months, ventricular fibrillation recurred in all groups except the both-negative group. Of the 16 patients with a type I Brugada ECG, 2 had CAS alone, 8 had ventricular arrhythmias alone, and 6 had both positive. No ventricular fibrillation episodes were observed in the CAS-alone patients who did not also have Brugada syndrome. Kaplan-Meier analysis showed that the CAS-alone group was at lower risk for OHCA recurrence as compared with the Brugada syndrome group (log-rank test; P=0.036). CONCLUSIONS: Among OHCA survivors without structural heart disease, provokable CAS and ventricular arrhythmias are common and can be seen in Brugada syndrome. CAS alone without Brugada syndrome who are treated for CAS may be a lower-risk group.