Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation.

BACKGROUNDS: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by hypercholesterolemia, tendon xanthomas, and premature coronary heart disease. FH is caused by mutations of "FH genes," which include the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). We evaluated the usefulness of FH gene analysis for diagnosing homozygous FH (homo-FH), particularly in cases caused by gain-of-function (g-o-f) mutations in PCSK9 (PCSK9 E32K). OBJECTIVES: To evaluate the frequency of homo-FH caused by PCSK9 E32K compared with FH due to other genetic causes and to report the phenotypic features of homo-FH caused by PCSK9 E32K. METHODS: Genomic DNA was prepared from white blood cells, and LDLR and PCSK9 mutations were identified using the Invader assay method. RESULTS: Of the 1055 hetero-FH patients, 62 patients (5.9%) carried the PCSK9 E32K mutation, while in the 82 alleles of 41 homo-FH patients, 13 (15.9%) had double mutations of LDLR allele and PCSK9 E32K mutation. Mean plasma total cholesterol (TC) (9.93 ± 2.95 mmol/L, mean ± SD) in true homo-FH cases with PCSK9 E32K or double hetero-FH cases with PCSK9 E32K and LDLR mutations were significantly lower than those in true homo-FH (18.06 ± 4.96 mmol/L) and compound heterozygous cases with LDLR mutations (14.84 ± 1.62 mmol/L). Mean plasma TC concentrations in the 59 hetero-FH cases with PCSK9 E32K (7.21 ± 1.55 mmol/L) were significantly lower than those (8.94 ± 1.53 mmol/L) in the hetero-FH by LDLR mutations. CONCLUSIONS: FH caused by PCSK9 g-o-f mutations is relatively common in Japan and causes a mild type of homo- and hetero-FH compared with FH caused by LDLR mutations.

Risk evaluation of coronary heart disease and cerebrovascular disease by the Japan Atherosclerosis Society Guidelines 2002 using the cohort of the Holicos-PAT study.

Our purpose in this study was to evaluate the new JAS guidelines as a risk assessment tool in Japanese patients with hypercholesterolemia, using the cohort of the Holicos-PAT study. The Holicos-PAT study was designed as a prospective observational study. 2039 patients were followed with or without pravastatin for 5 years. We assessed coronary heart disease (CHD) and cerebrovascular disease (CVD) risks by the patient categories described in the JAS guidelines. In the Holicos-PAT study, the primary endpoints were CHD, and the secondary endpoints were CVD and total mortality. CHD event includes onset and worsening of angina pectoris, performing CABG or PTCA, non-fatal and fatal myocardial infarction, and death from CHD including heart death and sudden death. CVD events are onset or recurrence of cerebral infarction, onset of cerebral hemorrhage, and death from cerebral infarction or hemorrhage. The event rates were calculated by the person-years method, and the differences in event rates between category groups were analyzed by chi-square test. The event rates of CHD in Category A, B1, B2, B3, B4 and C, were 1.1, 4.0, 2.8, 5.7, 18.2 and 38.8 per 1,000 person-years. The rates of CHD events in the higher risk category groups, Category B4 group (p = 0.004 in whole patients) and C group (p < 0.001 in whole patients), were significantly higher than that in the combined category groups A + B1 + B2. The event rates of CVD in Category A, B1, B2, B3, B4 and C, were 2.1, 1.8, 1.8, 0.6, 10.8 and 6.4 per 1,000 person-years. The event rates of CHD in men were significantly higher than those in women, in categories B4 (p < 0.001) and C (p < 0.001). From these results, each category classified by accumulation of risk factors, showed increasing event rates of CHD and CVD. The categories in the JAS guidelines are useful to assess CHD and CVD risk in Japanese patients with hypercholesterolemia. However, the risk evaluation by the JAS guideline categories may underestimate the risk in men and overestimate it in women.

Spontaneous development of left ventricular aneurysm in a patient with untreated cardiac sarcoidosis.

A young adult patient with untreated sarcoidosis spontaneously developed a left ventricular (LV) aneurysm in the anterolateral free wall. Single-photon emission computed tomography (SPECT) using Gallium-67 clearly demonstrated widespread abnormal uptake, including the LV aneurysm. Thallium-201 SPECT revealed a perfusion defect in the anterolateral wall, and abnormal uptake of technetium-99m pyrophosphate was seen, especially in the borders of the defect lesion.