Evaluation of Need for Implantable Cardioverter-Defibrillator by Thallium-201 Scintigraphy Among Japanese Patients With Prior Myocardial Infarction.

BACKGROUND: Identifying who among current Japanese patients with prior myocardial infarction (MI) would benefit from an implantable cardioverter-defibrillator (ICD) is imperative. Accordingly, this study seeks to determine whether single-photon emission computed tomography (SPECT) can help identify such patients. Methods and Results: This retrospective study enrolled 60 consecutive patients with prior MI who underwent stress thallium-201 SPECT and ICD implantation from February 2000 to October 2014. Occurrence of arrhythmic death and/or or appropriate ICD therapy, defined as shock or antitachycardia pacing for ventricular fibrillation or tachycardia, was identified until November 2016. During the median follow-up interval of 6.6 years, 18 (30%) patients experienced arrhythmic death and/or appropriate ICD therapy. Multivariate Cox proportional hazard regression analysis revealed that the summed stress score (SSS) [hazard ratio (HR)=1.14; P=0.005] and left ventricular ejection fraction (LVEF) at rest (HR=0.92; P=0.038) were significantly associated with the occurrence of arrhythmic events. Patients with SSS ≥21 and LVEF ≤30%, which were determined to be the best cutoff points, had significantly higher incidence of the arrhythmic events than the other patients (64% vs. 11%; HR=7.18; log-rank P=0.001). CONCLUSIONS: SSS using stress thallium-201 SPECT in combination with LVEF can help determine the need for ICD therapy among current Japanese patients with prior MI.

Atherosclerotic change at one year after implantation of Endeavor zotarolimus-eluting stent vs. everolimus-eluting stent.

BACKGROUND: Atherosclerosis progression is thought to be one of the mechanisms of late stent failure. Atherosclerosis progression is detected as yellow plaque formation on angioscopy. Cypher sirolimus-eluting stent has been reported to accelerate atherosclerosis progression, but the influence of Endeavor zotarolimus-eluting stent (Endeavor-ZES) or Xience everolimus-eluting stent (Xience-EES) on atherosclerosis has not been clarified. Therefore, we examined the serial changes in extent of atherosclerosis after the implantation of Endeavor-ZES or Xience-EES. METHODS AND RESULTS: Consecutive patients who received implantation of Endeavor-ZES (n=25) or Xience-EES (n=30) at de novo lesion of native coronary artery and who had successful angioscopy immediately after stent implantation (baseline) and at 1-year follow-up were included in the study. Change in the maximum yellow color grade (grade 0-3) of the stented segment from baseline to follow-up was examined and was compared between Endeavor-ZES and Xience-EES. The maximum yellow color grade decreased significantly from baseline to follow-up in Endeavor-ZES (1.6±1.1 vs. 0.4±0.8, P<0.001), but it did not change in Xience-EES (1.7±1.0 vs. 1.4±0.7, P=0.23). Although the maximum yellow color grade was not different between Endeavor-ZES and Xience-EES at baseline (P=0.72), it was significantly lower in Endeavor-ZES than in Xience-EES at follow-up (P<0.001). CONCLUSIONS: Atherosclerosis evaluated by yellow color of the plaque was significantly reduced at 1 year after Endeavor-ZES implantation, but was not changed after Xience-EES implantation.

Association of target lesion characteristics evaluated by coronary computed tomography angiography and plaque debris distal embolization during percutaneous coronary intervention.

BACKGROUND: The slow-flow or no re-flow phenomenon has been associated with distal embolization, especially of plaque debris, and with unfavorable clinical outcomes. Therefore, we examined the association between the coronary computed tomography angiography (CCTA) findings of the target lesion and distal embolization during percutaneous coronary intervention (PCI). METHODS AND RESULTS: Consecutive patients (n=55: 18 unstable angina, 19 stable effort angina, 18 silent ischemia) who underwent PCI with a filter-type distal protection device after evaluation of the target lesion by CCTA were analyzed. CCTA examined low-attenuation plaque (LAP), positive remodeling (PR), and ring-like enhancement of the target lesion. Distal embolization of thrombus and plaque debris was evaluated by pathological examination of material collected in the filter.Any distal embolization and distal embolization of plaque debris were respectively detected in 75% and 0% of patients with LAP or PR alone, in 95% and 17% of patients with both LAP and PR, and in 100% and 27% of patients with all of LAP, PR and ring-like enhancement. The sensitivity and specificity to predict plaque debris embolization by having both findings of LAP and PR was 100% and 46%, respectively. CONCLUSIONS: The CCTA findings of the target lesion were associated with distal embolization and were very sensitive for predicting plaque debris embolization.

Exposure to volatile ferroptosis inhibitor, TEMPO, reduced cutaneous ischemia-reperfusion injury progression to pressure ulcer formation in a mouse model.

BACKGROUND: Ischemia- reperfusion (I/R) injury-induced oxidative stress is a key factor in the pathogenesis of pressure ulcer formation. Ferroptosis is an iron-dependent programmed cell death that connects oxidative stress and inflammation in various diseases. Recent studies revealed the protective effect of inhibition of ferroptosis in I/R injury. However, the role of ferroptosis in cutaneous I/R injury remains elusive. OBJECTIVE: To assess the role of ferroptosis in the progression of cutaneous I/R injury. METHODS: Cutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro. RESULTS: Inhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3+ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro, ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis. CONCLUSION: Cutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury.

Regression of luminal stenosis at the site of silent plaque disruption in the era of optimal medical therapy. Low high-density lipoprotein cholesterol level isa potential risk of stenosis progression.

BACKGROUND: Plaque disruption and its healing is thought to be the major mechanism of atherosclerosis, but the contribution of silent plaque disruption to luminal stenosis progression has not been fully clarified. The aim of this study was therefore to examine the change in luminal stenosis at the site of silent plaque disruption. METHODS AND RESULTS: Consecutive patients (n=36) who received coronary angiography and angioscopy that identified silent plaque disruption (baseline) and had repeated coronary angiography later (follow-up) were included for analysis. Silent plaque disruption was defined as plaque with thrombus detected in non-culprit segments. Diameter stenosis of the site was angiographically measured at baseline and at follow-up, and their difference was defined as stenosis change. Statin was used in 89% of study patients, and serum low-density lipoprotein cholesterol level was 91 ± 21 mg/dl. The diameter stenosis decreased significantly from baseline to follow-up at 12 ± 4 months (32 ± 14% vs. 27 ± 14%, P<0.001), and the stenosis change was -5.6 ± 7.9%. High-density lipoprotein cholesterol (HDL-C) was significantly associated with stenosis change (r=-0.51, P=0.001) and was the only factor significantly associated with stenosis change. CONCLUSIONS: In the era of optimal medical therapy with statin, the site of silent plaque disruption showed significant regression of luminal stenosis. Nevertheless, serum HDL-C was inversely associated with stenosis change, and its low level remained as a potential risk of luminal stenosis progression at the site of silent plaque disruption.

Recurrent pericardial effusion caused by pacemaker lead perforation and warfarin therapy at seven years after implantation.

A 66-year-old man was implanted with a pacemaker. Seven years after implantation he was admitted due to cardiogenic cerebral embolism and warfarin therapy was introduced. After that, he suffered recurrent pericardial effusion for unexplained reasons. An exploratory thoracotomy revealed that the screw of the atrial lead had penetrated through the right auricular appendage wall.

Microthrombosis as a cause of fulminant myocarditis-like presentation with COVID-19 proven by endomyocardial biopsy.

Myocardial injury has been reported as a complication of COVID-19. Although several mechanisms have been proposed as its cause, they are mostly based on autopsy studies, We report a 49-year-old male with COVID-19-associated myocardial injury presented like fulminant myocarditis. We performed endomyocardial biopsy on day 2 and we confirmed the presence of microthrombosis histologically. He died on day 5 due to cardiogenic shock.

Anti-polymyositis/Scl antibody-positive overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, systemic lupus erythematosus, and antiphospholipid syndrome.

A 37-year-old Japanese man with a 3-year history of diffuse cutaneous systemic sclerosis was admitted to our hospital with high fever, arthralgia, myalgia, and muscle weakness. A physical examination revealed facial erythema, Gottron's sign, and mechanic's hands in addition to skin sclerosis. Laboratory data revealed significantly elevated levels of creatine kinase and decreased complement. Anti-RNP, anti-Smith, anti-DNA, anti-ß2 -glycoprotein 1, anti-polymyositis (PM)/Scl75, and anti-PM/Scl100 antibodies were detected. He also had urinary protein, interstitial lung disease, pericarditis, multifocal cerebral infarctions, and leukoencephalopathy. Thus, a diagnosis of overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, and systemic lupus erythematosus with antiphospholipid syndrome was made. Because of the intractable course, he was treated with multiple immunosuppressive and immunomodulatory drugs, including three rounds of 1000 mg methylprednisolone pulse therapy. This is the first case report of anti-PM/Scl antibody-positive overlap syndrome of three major connective tissue diseases.

Relationship between coronary plaque vulnerability and serum n-3/n-6 polyunsaturated fatty acid ratio.

BACKGROUND: A low ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) has been associated with cardiovascular events. Higher-grade yellow color coronary plaques are associated with higher plaque vulnerability and higher thrombogenic potential. Therefore, the association between EPA/AA ratio and yellow color grade of coronary plaques was examined. METHODS AND RESULTS: Consecutive patients (n=54) who underwent percutaneous coronary intervention were enrolled in this study. The serum EPA/AA ratio was examined on admission. All patients underwent an angioscopic examination of the culprit vessel to examine the color grade of yellow plaques (0, white; 1, slight yellow; 2, yellow; and 3, intense yellow) and the presence of thrombus. Excluding 16 patients with acute coronary syndrome (ACS), 38 patients with stable angina were divided into 2 groups according to their EPA/AA ratio: the low EPA/AA group (n=19, EPA/AA ratio <0.37 [median]) and the high EPA/AA group (n=19, EPA/AA ratio ≥0.37). The maximum color grade (2.5 ± 0.5 vs. 1.9 ± 0.9; P=0.01) of yellow plaques was significantly higher and the number of non-culprit yellow plaques with thrombus (1.7 ± 0.8 vs. 1.2 ± 1.1; P=0.06) tended to be higher in low EPA/AA than in high EPA/AA stable angina patients. Multivariate analysis revealed that the serum EPA level (odds ratio=0.98, 95% confidence interval=0.96-0.99, P=0.03) was associated with the presence of grade-3 yellow plaques. CONCLUSIONS: A low serum EPA level and a low EPA/AA ratio was associated with high vulnerability of coronary plaques.

Frequency and location of yellow and disrupted coronary plaques in patients as detected by angioscopy.

BACKGROUND: Clarification of frequency and distribution of yellow plaques and disrupted plaques will increase understanding of acute coronary syndrome (ACS) onset. METHODS AND RESULTS: Consecutive patients with ACS (n=75) or without ACS (n=90) who received coronary angioscopic examination were studied. Distance from ostium to yellow plaques, diameter stenosis and vessel wall irregularity at the site of yellow plaques, their yellow color grade (grade 13) and if they had thrombus were analyzed. Yellow plaques with thrombus were regarded as disrupted. Average number of yellow plaques, grade-3 yellow plaques and disrupted yellow plaques per vessel was 4.0, 0.87 and 1.0, respectively. The number of grade-3 yellow plaques and disrupted yellow plaques per vessel were larger in ACS than in non-ACS patients. Yellow plaques were distributed diffusely in the right coronary artery but more in mid-segments in the left anterior descending coronary artery and left circumflex coronary artery. Diameter stenosis in the non-culprit segments was severer at disrupted than at non-disrupted yellow plaques. Vessel wall irregularity was detected more frequently at disrupted than at non-disrupted yellow plaques. CONCLUSIONS: Approximately 4 yellow plaques, 1 grade-3 yellow plaque and 1 disrupted yellow plaque were detected per vessel. About 25% of detected yellow plaques were disrupted. More grade-3 yellow plaques and disrupted yellow plaques were detected in ACS than in non-ACS patients. These findings strengthen the association between yellow plaques detected by angioscopy and ACS events.

Acute coronary syndrome: insight from angioscopy.

Although the concept of vulnerable plaque has become common, it is still impossible to predict effectively the onset of acute coronary syndrome (ACS). Thin-cap fibroatheroma (TCFA) is regarded as vulnerable from pathological studies and various diagnostic tools have tried to detect TCFA clinically but failed to predict ACS. Because there are so many silent plaque ruptures detected, it is supposed that many vulnerable plaques might have ruptured but not caused ACS. Some factor(s) other than the rupture of vulnerable plaque is required for the onset of ACS. "Vulnerable blood" may be one of them. The thrombogenic potential of blood (ie, vulnerable blood) may play an important and determinant role in the onset of ACS, the process of which will be discussed from the angioscopic point of view.

Takotsubo syndrome triggered by coronary artery embolism in a patient with chronic atrial fibrillation.

Although takotsubo syndrome is defined as a reversible heart failure syndrome with the absence of obstructive coronary artery disease, some cases of concomitant takotsubo syndrome and acute myocardial infarction have been reported. We herein describe the case of a patient with chronic nonvalvular atrial fibrillation who was not receiving anticoagulant therapy, who developed takotsubo syndrome triggered by acute myocardial infarction probably due to coronary artery thromboembolism. .

Noninvasive assessment of wall distensibility with the evaluation of diastolic epicardial movement.

BACKGROUND: Left ventricular (LV) wall stiffening plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Based on the linear elastic theory, we hypothesized that the evaluation of epicardial movement during diastole is helpful for the noninvasive assessment of LV wall distensibility. METHODS AND RESULTS: Based on the linear elastic theory, the epicardial movement index (EMI) was calculated on the echocardiogram as: [see text.] We calculated diastolic wall strain (DWS) as follows to examine whether DWS substitutes for EMI: [see text.] The animal study using hypertensive Dahl salt-sensitive rats, HFpEF model, and normotensive Dahl rats showed the significant and inverse correlation of EMI or DWS with myocardial stiffness constant. Preload alteration did not affect EMI or DWS. In the clinical study, the HFpEF patients had lower EMI and DWS than the normal volunteers and the asymptomatic patients with LV hypertrophy. CONCLUSIONS: The evaluation of epicardial movement may be useful in noninvasively assessing wall distensibility in the absence of LV systolic dysfunction.

Noninvasive assessment of diastolic function in subjects with preserved left ventricular ejection fraction: usefulness of color kinetic imaging.

BACKGROUND: Noninvasive assessment of left ventricular (LV) diastolic function is not established in patients with preserved ejection fraction. We investigated a relation between diastolic function and diastolic wall dynamics. METHODS AND RESULTS: In the animal study, data were collected in hypertensive Dahl salt-sensitive rats, a diastolic heart failure (DHF) model (n = 35), and normotensive Dahl rats (n = 26). In the clinical study, echocardiography was conducted in 26 diabetic patients with normal ejection fraction and 10 age-matched controls. The diastolic index of color-encoded images (color kinesis diastolic index [CK-DI]) was calculated as the ratio of LV cavity area expansion during the first 30% of diastolic filling time to that during the whole diastolic filling period. In the DHF model, the E/A ratio of the transmitral flow velocity curves was pseudonormalized with the development of heart failure, but CK-DI was not. CK-DI, not E/A, was significantly and inversely correlated with the time constant of LV relaxation. Angiotensin receptor blocker improved LV relaxation in the DHF model and increased CK-DI, but not E/A. The diabetic patients showed lower CK-DI than the controls, although E/A was not different. CONCLUSION: Color-encoded imaging is useful in evaluating LV diastolic function. The prevalence of LV diastolic dysfunction may have been clinically underestimated by the transmitral flow velocity curves.

Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats.

BACKGROUND: beta-blocker therapy is an established therapeutic strategy for systolic heart failure. However, its benefits in diastolic heart failure (DHF) are controversial. AIMS: This study was designed to investigate the effects of bisoprolol on DHF. METHODS AND RESULTS: Dahl salt-sensitive rats fed on 8% NaCl diet from age 6 weeks, DHF model rats, were divided into three groups at age 13 weeks. One group was treated with bisoprolol 12.5 mg/kg/day (Low dose group, n=18), one group was treated with bisoprolol 250 mg/kg/day (High dose group, n=18), and there was also an untreated group (Untreated group, n=18). The survival rate was best in the High dose group. Left ventricular hypertrophy and the expression of proinflammatory cytokines in the myocardium were significantly attenuated in the High dose group, but not in the Low dose group, and oxidative stress was most suppressed in the High dose group. Measurement with electron spin resonance revealed that bisoprolol had a potent scavenging ability, and bisoprolol attenuated the down-regulation of peroxisome proliferation-activated receptor coactivator-1alpha, an important element in the mitochondrial reactive oxygen species detoxification system. CONCLUSION: beta-blocker administration, particularly at high dose, improved the survival rate of the DHF model, at least partly through the attenuation of inflammatory changes and oxidative stress.

Difference of clinical characteristics between hypertensive patients with and without diastolic heart failure: the roles of diastolic dysfunction and renal insufficiency.

Clinical characteristics were compared between hypertensive patients with and without heart failure in the absence of reduced ejection fraction (EF) to gain insights into the effects of renal insufficiency on the prevalence of diastolic heart failure. Study subjects consisted of 691 hypertensive patients with an EF>40%. Patients with serum creatinine >2.5 mg/dL were excluded from the study. The Framingham heart failure criteria were met by 198 patients, and competing risks of the prevalence of heart failure were analyzed. The multiple logistic regression analysis revealed that obesity, female gender, creatinine clearance (CCr), and a ratio of transmitral E velocity to early diastolic mitral annular velocity (E/ E')>15 were independently associated with the prevalence of heart failure with preserved EF. Patients with 60< or =CCr<90 mL/min represented higher E/E' ratio and lower E' velocity than the patients with CCr> or =90 mL/min, although there was no difference in the prevalence of heart failure between the two groups. These indices were not different between the patients with 60< or =CCr<90 mL/min and CCr<60 mL/min, although the prevalence of heart failure was higher in the patients with CCr<60 mL/min. The hemoglobin concentration was significantly decreased and the brachial-ankle pulse wave velocity was significantly elevated in patients with CCr<60 mL/min. Thus, progressive left ventricular diastolic dysfunction and renal insufficiency are competing risks of the prevalence of diastolic heart failure in hypertensive patients. Renal insufficiency may exert its effects through the modulation of extracardiac factors such as anemia and arterial stiffening rather than through the promotion of diastolic dysfunction.

Therapeutic effects of angiotensin II type 1 receptor blocker at an advanced stage of hypertensive diastolic heart failure.

OBJECTIVE: Angiotensin II type 1 receptor blocker (ARB) is increasingly prescribed for the treatment of systolic heart failure with a growing body of clinical evidence. The roles of ARB, however, remain to be clarified in the treatment of diastolic heart failure (DHF), particularly at its advanced stage. This experimental study investigated the effects of ARB administered at an advanced stage of hypertensive DHF. METHODS: Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks represent overt DHF at age 20 weeks, as noted in previous studies (hypertensive DHF model). The DHF model rats were randomly divided into two groups at age 17 weeks when left ventricular diastolic dysfunction, hypertrophy, fibrosis, macrophage infiltration and reactive oxygen species generation were already augmented; six rats treated for 3 weeks with a subdepressor dose of ARB (olmesartan 0.6 mg/kg per day), and six untreated rats. RESULTS: The 3-week administration of ARB significantly decreased the left ventricular end-diastolic pressure in association with attenuation of left ventricular hypertrophy, fibrosis and diastolic dysfunction. Macrophage infiltration was attenuated with decreased gene expression of transforming growth factor-beta1 and monocyte chemoattractant protein-1 in the left ventricular myocardium of the ARB-treated rats. The production of reactive oxygen species also decreased with NADPH oxidase activity. CONCLUSIONS: ARB provides beneficial effects in hypertensive DHF independent of its antihypertensive effects even if initiated at an advanced stage. The beneficial effects are at least partly attributed to the attenuation of inflammatory changes and oxidative stress through the suppression of cytokine and chemokine production and of NADPH oxidase activity.