Impact of combined lipid lowering and blood pressure control on coronary plaque: myocardial ischemia treated by percutaneous coronary intervention and plaque regression by lipid lowering and blood pressure controlling assessed by intravascular ultrasonography (MILLION) study.

The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.0 ± 9.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18-24 months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100 mg/dL and 140/90 mmHg vs. 70 mg/dL and 120/70 mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.9 ± 14.7 vs. 63.7 ± 11.9 mg/dL (NS) and 124.1 ± 9.4/75.8 ± 7.7 vs. 113.6 ± 9.6/65.8 ± 9.4 mmHg (systolic BP; NS, diastolic BP; p < 0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of -9.4 ± 10.7% and -8.7 ± 8.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.

Impact of thin-cap fibroatheroma on predicting deteriorated coronary flow during interventional procedures in acute as well as stable coronary syndromes: insights from optical coherence tomography analysis.

The occurrence of deteriorated coronary flow associated with distal embolization during percutaneous coronary intervention results in impaired myocardial perfusion and worsens the clinical prognosis. This study aimed to examine the impact of optical coherence tomography (OCT)-determined coronary plaque morphology on the prediction of deteriorated coronary flow after stent implantation in acute as well as stable coronary syndromes (ACS and SAP, respectively). We studied 126 patients who underwent OCT during stenting for ACS (n = 44) and SAP (n = 82) with a de novo lesion. Angiographic deteriorated coronary flow was defined as the deterioration of TIMI flow grade after mechanical dilatation in the absence of a mechanical obstruction on angiograms. Patients could be divided into the deteriorated flow group (n = 21) and the reflow group (n = 105). Under these conditions, the presence of thin-cap fibroatheroma (TCFA) was more frequently observed in the deteriorated flow group than in the reflow group in both ACS and SAP. A multivariable logistic regression model revealed that TCFA was an independent predictor of deteriorated coronary flow (hazard ratio: 12.32; 95 % confidence interval: 3.02-50.31; p = 0.0005). These results demonstrate that TCFA detected by OCT could be a strong predictor of the occurrence of deteriorated coronary flow during stent implantation in ACS as well as SAP.

Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study.

A line of epidemiological studies suggests that the accumulation of coronary risk factors promotes the progression of coronary atherosclerosis. Recent clinical studies showed that aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy using statins could regress coronary atheroma and reduce major cardiovascular events. Additionally, therapy that controlled amlodipine-based blood pressure reduced major cardiovascular events in patients with hypertension compared with an atenolol-based regimen. An open-label randomized multicenter study is primarily planned to evaluate the changes in coronary atheroma volume using intravascular ultrasonography 18-24 months after intensive lowering of LDL-cholesterol and blood pressure compared with a standard therapy indicated by current guidelines in Japanese patients with coronary artery disease (CAD). The secondary endpoints include changes in serum lipid levels, inflammatory markers, glucose markers and blood pressure. In total, 100 subjects with CAD who are undergoing percutaneous coronary intervention will be tested. The MILLION study will provide new evidence and therapeutic standards for the prevention of CAD in Japanese patients by controlling both LDL-C levels and blood pressure.

Intravascular ultrasound appearance of scattered necrotic core as an index for deterioration of coronary flow during intervention in acute coronary syndrome.

In acute coronary syndrome (ACS) patients with deterioration of coronary flow during percutaneous coronary intervention (PCI), a scattered necrotic core pattern (SNC) is observed by intravascular ultrasound virtual histology (VH-IVUS). The purpose of this study was to evaluate the impact of SNC on deterioration of coronary flow during PCI in ACS. A total of 38 ACS patients were imaged using VH-IVUS before PCI. In addition to conventional definitions of thin-cap fibroatheroma by VH-IVUS (ID-TCFA), the SNC was defined as necrotic core foci with a maximum diameter of <14 pixels on a 400 × 400 VH-IVUS image in the presence of >50% plaque burden except in the ID-TCFA frame. Patients were divided into deterioration of coronary flow group (n = 15) and normal-reflow group (n = 23). The incidence of residual thrombus and plaque rupture, the external elastic membrane, plaque and fibrous volumes, the incidence of ID-TCFA and the average number of SNC per frame was significantly greater in deterioration of coronary flow group than in normal-reflow group (all parameters P < 0.05). Multivariate analysis revealed that the average number of SNC per frame was independently associated with deterioration of coronary flow in ACS patients (odds ratio 1.18, P < 0.05). In conclusion, an increased number of SNC is associated with deterioration of coronary flow during PCI in ACS patients.

Coronary intervention for severe stenosis in the ostial right coronary artery with cardiac angiosarcoma: a case report.

BACKGROUND: Although rare, angiosarcoma is the most common type of cardiac primary malignancy. This disease can cause life-threatening complications and the prognosis remains poor. There is no standard approach to care, and clinical judgement is exercised on a case-by-case basis. Tumour progression causes serious complications, such as heart failure and vascular disruption. CASE SUMMARY: A 64-year-old Japanese woman presenting with a right atrial tumour was referred to our department. Tumour biopsy revealed that the patient suffered from angiosarcoma. We performed a lumpectomy to excise the tumour, but due to tissue adhesions in and around the right atrium, the malignancy could not be completely removed. After 3 years of chemotherapy, the patient was admitted to our hospital with increased chest pain. Emergency coronary angiogram revealed severe stenosis of the ostial right coronary artery. Intravascular ultrasound (IVUS) and computed tomography suggested coronary compression due to cardiac angiosarcoma. In this study, we report a unique case of advanced cardiac angiosarcoma, presenting as unstable angina, which was successfully treated with percutaneous coronary intervention using stent implantation. DISCUSSION: Due to the rarity of cardiac primary angiosarcoma, many symptoms are misdiagnosed until mechanical complications arise, such as coronary compression. The clinical course and various imaging modalities are useful for differentiating angiosarcomas from coronary stenosis.

A case of torsades de pointes due to takotsubo cardiomyopathy after common atrial flutter ablation.

Takotsubo cardiomyopathy (TCM) is a transient acute cardiac disorder often associated with QT prolongation, but this rarely leads to torsades de pointes (TdP). Additionally, it is a rare complication of catheter ablation. Here we report a case of TCM that developed after catheter ablation for common atrial flutter, which led to TdP. The patient was an 85-year-old male who had persistent supraventricular tachycardia, which was considered atrial flutter. The patient was hospitalized for congestive heart failure. Although the response to diuretic administration was unfavorable, heart failure improved with the combined use of rate control by landiolol. Catheter ablation was performed because of the possibility of tachycardia-induced cardiomyopathy. Tachycardia disappeared following ablation to the cavotricuspid isthmus, but the patient complained of severe pain during the ablation. Approximately 2 h after the treatment, the patient's heart failure re-exacerbated. The next day, electrocardiogram confirmed a marked QT prolongation, and TdP occurred. Although the phenomenon we experienced is rarely reported, it should be considered a complication following catheter ablation. Adequate analgesia, care for anxiety about treatment, and evaluation of cardiac condition after treatment are considered important. .

Transition of the ST segment from a J wave to a coved-type elevation before ventricular fibrillation induced by coronary vasospasm in the precordial leads.

We describe the case of a 63-year-old man whose electrocardiogram showed transition of the ST segment from a J wave to a coved-type elevation in precordial leads before ventricular fibrillation induced by right coronary artery vasospasm. Simultaneously, the ST segment in inferior leads was gradually depressed with a J wave. Considering the sudden death of his son, induced ventricular fibrillation by programmed electrical stimulation, and modulations of the ST segment in the precordial and inferior leads by pilsicainide, some abnormalities in repolarization associated with Brugada syndrome or early repolarization syndrome might have caused these atypical ST-segment manifestations.

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

High frequency of a retinoid X receptor gamma gene variant in familial combined hyperlipidemia that associates with atherogenic dyslipidemia.

OBJECTIVE: The genetic background of familial combined hyperlipidemia (FCHL) has not been fully clarified. Because several nuclear receptors play pivotal roles in lipid metabolism, we tested the hypothesis that genetic variants of nuclear receptors contribute to FCHL. METHODS AND RESULTS: We screened all the coding regions of the PPARalpha, PPARgamma2, PPARdelta, FXR, LXRalpha, and RXRgamma genes in 180 hyperlipidemic patients including 60 FCHL probands. Clinical characteristics of the identified variants were evaluated in other 175 patients suspected of coronary disease. We identified PPARalpha Asp140Asn and Gly395Glu, PPARgamma2 Pro12Ala, RXRgamma Gly14Ser, and FXR -1g->t variants. Only RXRgamma Ser14 was more frequent in FCHL (15%, P<0.05) than in other primary hyperlipidemia (4%) and in controls (5%). Among patients suspected of coronary disease, we identified 9 RXRgamma Ser14 carriers, who showed increased triglycerides (1.62+/-0.82 versus 1.91+/-0.42 [mean+/-SD] mmol/L, P<0.05), decreased HDL-cholesterol (1.32+/-0.41 versus 1.04+/-0.26, P<0.05), and decreased post-heparin plasma lipoprotein lipase protein levels (222+/-85 versus 149+/-38 ng/mL, P<0.01). In vitro, RXRgamma Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXRgamma Gly14. CONCLUSION: These findings suggest that RXRgamma contributes to the genetic background of FCHL.

Impact of Distal Protection with Filter-Type Device on Long-term Outcome after Percutaneous Coronary Intervention for Acute Myocardial Infarction: Clinical Results with Filtrap®.

AIM: Although distal embolization during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) deteriorates cardiac function, whether distal protection (DP) can improve prognosis is still controversial. We investigated whether a filter-type DP device, Filtrap®, could improve long-term outcomes after PCI for AMI. METHOD: We studied 164 patients (130 men, mean age: 65.7 years) who underwent PCI. Patients were divided into two groups based on the use of Filtrap®. The occurrence of congestive heart failure (CHF) and major adverse cardiac events (MACE) defined as cardiac death, recurrent AMI, and target vessel revascularization were compared. RESULT: Between DP (n=53, 41 men, mean age: 65.5 years) and non-DP (n=111, 89 men, mean age: 65.8 years) groups, although there was significantly greater plaque area in the DP group than in the non-DP group, there were no significant differences in coronary reperfusion flow after PCI. Interestingly, patients with CHF in the non-DP group exhibited a higher CK level than those in the DP group. During a 2-year follow-up period, cumulative CHF was significantly lower in the DP group than in the non-DP group (log-rank p=0.018), and there was no significant difference in the MACE rate (log-rank p=0.238). The use of DP device could not predict MACE, but could predict CHF by multivariate analysis (odds ratio=0.099, 95% CI: 0.02-0.42, p=0.005). CONCLUSION: These results demonstrate that favorable clinical outcomes could be achieved by the filter-type DP device in AMI, particularly in patients with CHF.

Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis.

CONTEXT: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by LPL gene mutation and is characterized by severe hyperchylomicronemia. Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, but the underlying mechanisms are not fully understood. CASE REPORT: A 22-yr-old male Japanese patient with severe hyperchylomicronemia was admitted to our hospital in 1973. He had no consanguinity and no family history of hyperlipidemia. He was genetically diagnosed as LPL deficiency (homozygous for LPL(Arita)) with no LPL mass or activity in postheparin plasma. He has experienced recurrent acute pancreatitis 22 times during our 31-yr clinical follow-up, but no pancreatic pseudocyst, irregularity of the pancreatic duct, or abnormal pancreatic calcification was observed in computed tomography. Moreover, his pancreatic endocrine function, as assessed by the oral glucose tolerance test, has preserved more than 30 yr. Although he was a current smoker, no clinically significant atherosclerotic lesion had been observed. CONCLUSIONS: From the long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

Comparison of sirolimus-eluting, paclitaxel-eluting, and bare-metal stents in a patient with angina pectoris: histopathological autopsy findings of the third month.

A 67-year-old man with a more than 15-year-old history of hypertension, dyslipidemia, and glucose intolerance presented at our hospital with exertional angina. Coronary angiography showed considerable stenosis of 3 vessels. A diffuse calcified lesion in the left anterior descending coronary artery was pre-treated using rotational atherectomy followed by sirolimus-eluting stent (SES) implantation. A lesion in the proximal right coronary artery was treated by bare-metal stent (BMS) implantation, and the tandem lesion in the left circumflex artery was treated using paclitaxel-eluting stent (PES) implantation. All the procedures were performed within 1 month of the initial presentation and yielded good angiographic results. 3 months after the final stenting, the patient was re-admitted because of congestive heart failure (CHF). While recovering from CHF, he suddenly developed cardiopulmonary arrest and died during hospitalization. Autopsy examination of the coronary arteries showed that both drug-eluting stents (DESs: SES and PES) and the BMS had characteristic histopathological features. Inflammatory responses in the neointima were greater in both the DESs than in the BMS. SES and PES showed different inflammatory infiltration pattern or fibrin deposition status; these histopathological differences observed in the DES environments have implication to cause adverse clinical events such as late stent thrombosis or late catch-up phenomena.

Spontaneous healing of posttraumatic focal coronary aneurysm: a case report.

We report on the spontaneous healing of a posttraumatic focal coronary aneurysm in a previously healthy 61-year-old man after his involvement in a motor vehicle accident, resulting in blunt chest trauma that injured the anterior wall of his left ventricle. Left-sided cardiac catheterization and selective coronary angiography 1 month after the accident showed an aneurysm in the proximal part of the left anterior descending artery, and normal coronary arteries otherwise. Intravascular ultrasound revealed that the lesion was a pseudoaneurysm protruding toward the myocardium. Surgical removal of the aneurysm was not considered, and the patient was discharged after 2 months of uneventful hospitalization. Follow-up coronary angiography and intravascular ultrasound at 3 months and 1 year after the accident showed a total regression of the aneurysm. The patient has remained asymptomatic, with no residual ischemia 3 years after the accident. This case indicates that careful conservative treatment is a therapeutic option for posttraumatic coronary pseudoaneurysms.

Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects.

BACKGROUND: The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1G>A), some rare CETP mutations are found in Japanese HALP subjects. METHODS: CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector. RESULTS: Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells. CONCLUSIONS: Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively.

Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia: results from stable isotope kinetic study in vivo.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy. METHODS AND RESULTS: We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [(2)H(3)]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450±0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2±2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months. CONCLUSIONS: These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.

Complete atrioventricular block associated with takotsubo cardiomyopathy.

An 82-year-old woman was admitted to the hospital due to repeated episodes of syncope with incontinence. Electrocardiography showed torsades de pointes, complete atrioventricular (AV) block, T-wave inversions and a prolonged QTc interval. Urgent coronary angiography showed no significant coronary stenosis and left ventriculography demonstrated typical abnormal wall motion of takotusbo cardiomyopathy. Electrophysiology study suggested that the damaged structure might be the bundle of His. After temporary transvenous pacing and administration of intravenous lidocaine, no recurrence of torsade de pointes was found. Symptoms of worsening heart failure were not found. Although abnormal left ventricular wall motion improved, a complete AV block remained and the patient needed pacemaker implantation on Day 18 after admission. This case demonstrated that complete AV block associated with takotsubo cardiomyopathy may persist after improvement of left ventricular wall motion, and implantation of a pacemaker may be needed.

Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients.

BACKGROUND: The role of CETP in the development of atherosclerosis is debatable, and few data exist regarding the total impact of CETP inhibition on cholesterol efflux. METHODS: Acceptor capacities of whole serum and HDL subfractions separated by HPLC were compared using 2 different cell systems. Subjects with CETP deficiency (2 homozygous, 1 compound heterozygous, and 5 heterozygous) were analyzed along with 10 normolipidemic controls. The fractional efflux from cholesterol-labeled Fu5AH hepatoma cells was determined to be SR-BI mediated. The efflux difference between control and liver X receptor (LXR) agonist-induced ABCA1-upregulated J774 macrophages was considered as a measure of ABCA1-mediated efflux. RESULTS: For the Fu5AH cell system, the total acceptor capacities of whole serum and HPLC-separated HDL fraction 2 obtained from the homozygous subjects were 38% and 116% higher than the corresponding values for the controls, respectively (p<0.05). For the J774 cell system, the total acceptor capacities of whole serum and HPLC-separated HDL fractions were similar among the CETP-deficient subjects and controls. CONCLUSIONS: Serum from homozygous subjects with CETP-null defects exhibited enhanced acceptor capacity via an SR-BI dependent pathway, which is regulated by the middle HPLC-separated HDL fraction. Further, the cholesterol acceptor capacity of serum obtained from patients having complete and partial CETP deficiency was preserved via an ABCA1-dependent pathway.

Tumor-to-tumor metastasis: report of an autopsy case of lung adenocarcinoma metastasizing to renal cell carcinoma.

Metastasis of one tumor to another tumor within the same individual is considered rare. Lung cancer metastatic to renal cell carcinoma represents the most common combination of such tumor-to-tumor metastases. We present the autopsy case of a 97-year-old woman with metastatic adenocarcinoma of the lung to renal cell carcinoma.