Hiroki Uchiwa

Laronidase replacement therapy improves myocardial function in mucopolysaccharidosis I

We assessed whether laronidase (recombinant human α-L-iduronidase) replacement therapy could improve left ventricular (LV) myocardial function in a 49-year-old woman with mucopolysaccharidosis I (MPS I) and valvular heart disease. After 6 months of laronidase treatment, the concentration of urinary uron acid decreased by 78.8%. Hepatosplenomegaly improved and LV weight decreased by 19.6%. LV ejection fraction assessed by two-dimensional echocardiogram did not change after laronidase treatment. However, in two-dimensional ultrasound speckle tracking imaging method, LV myocardial longitudinal strain (shortening ratio) increased from -13.2 to -17.4%. LV myocardial radial strain (thickening ratio) increased from 26.6 to 83.4%. LV myocardial torsion increased from +6 to +18°. These indexes of myocardial function were normalized after laronidase treatment. Thus, our findings were a first report that laronidase treatment had a beneficial effect on LV myocardial function in an adult patient with MPS I.

BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease

The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.

Benefit of losartan/hydrochlorothiazide-fixed dose combination treatment for isolated morning hypertension: The MAPPY study

Abstract Morning hypertension is an established risk factor for cardiovascular events. In the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study, a 50-mg losartan/12.5-mg hydrochlorothiazide combination (Los/HCTZ) lowered morning blood pressure (BP) more effectively than 100-mg losartan (High-Los) in treated hypertensive patients with morning hypertension. The aim of this MAPPY study sub-analysis was to determine whether Los/HCTZ was effective for controlling isolated morning hypertension (morning BP ≥ 135/85 mmHg and evening BP < 135/85 mmHg), sustained hypertension (morning and evening BP ≥ 135/85 mmHg), or both. Of the 110 patients studied, 25 (22.7%) had isolated morning hypertension, and 85 (77.3%) had sustained hypertension at baseline. After 3-month treatment, isolated morning hypertension developed into controlled hypertension (morning and evening BP < 135/85 mmHg) in 9 of 11 Los/HCTZ patients (81.8%) and 3 of 14 High-Los patients (21.4 %) (p = 0.003, chi-square test). Sustained hypertension developed into controlled hypertension in 21 of 44 Los/HCTZ patients (47.7%) and 13 of 41 High-Los patients (31.7%)(NS). The rates of achievement of SBP < 135 mmHg both in the morning and evening were: 81.8% and 21.4% in Los/HCTZ- and High-Los-treated isolated morning hypertension (p = 0.003), respectively; and 61.4% and 36.6% in Los/HCTX- and High-Los-treated sustained hypertension (p = 0.022), respectively. In conclusion, Los/HCTZ was effective for controlling both types of morning hypertension, especially isolated morning hypertension. Los/HCTZ was superior to High-Los in treating both types of morning hypertension.

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients

ABSTRACT Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.

[BP.02.07] LOSARTAN/HCTZ COMBINATION THERAPY IS SAFE AND USEFUL IN CONTROLLING MORNING HYPERTENSION IN VERY ELDERLY PATIENTS

Objective: Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the incidence of morning hypertension increases with age, treatment of morning hypertension has not been established particularly in late-elderly patients. Among various combinations, ARB combined with a small dose of thiazide diuretic is desirable because the two drugs have complementary mechanisms of action, and effectively reduce BP. Thus, we investigated the safety and efficacy of ARB/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension in the very elderly. Design and method: This is a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study, which compared the effects of a combination of 50-mg losartan/12.5-mg HCTZ (Combination) and 100-mg losartan (High ARB) on morning SBP levels after 3-month treatment in on-treatment hypertensive patients with morning SBP greater than 135/85 mmHg on home BP self-measurement. Patients were allocated to very elderly group (more than 75 years) and young/elderly group (below 75 years). Results: Effects of 3-month Combination therapy and High ARB therapy were summarized in Table (*P < 0.05 and **P < 0.01 vs. baseline; #P < 0.05 and ##P < 0.01 vs. High ARB group). More than 98% of patients in all groups showed the adherence to medications of 80% or more. The incidence of adverse events of both treatments was similar in both groups. Conclusions: In the elderly patients, ARB/HTCZ combination induced further morning SBP reduction and greater target achievement ratio of morning BP (<135/85 mmHg), than high-dose ARB, to the similar levels seen in the young/elderly patients. And, ARB/HTCZ combination was safe and tolerable in either age group. Figure. No caption available.

Cerebral Micro bleeds in Coronary Artery Disease Patients during Antiplatelet Therapy

Background: Brain hemorrhage is a serious complication of antiplatelet therapy, particularly dual antiplatelet therapy (DAPT), in patients with coronary artery disease (CAD) who undergo percutaneous coronary intervention (PCI). It has been suggested that cerebral micro bleeds (CMBs) detected on magnetic resonance imaging (MRI) are a risk factor for future cerebral haemorrhage. However, little is known about CMBs in CAD patients during antiplatelet therapy. We investigated the temporal changes of CMBs and determined the risk factors for CMBs in patients with CAD on antiplatelet therapy. Methods: This study prospectively enrolled 14 CAD patients who underwent antiplatelet therapy (DAPT in 13 patients) and had no history of symptomatic stroke. Brain MRI was performed at baseline and after 8-month follow-up. Results: Baseline MRI revealed CMBs in two patients (14%). New CMBs were detected by follow-up MRI in two other patients (14%). CMB-positive patients had a greater number of coronary artery lesions (p=0.04) and a tendency to have a higher SYNTAX score at baseline (p=0.06) than CMB-negative patients. Although blood pressure (BP) at baseline did not differ between the CMB-positive and CMB-negative patients, BP after 8 months was significantly higher in CMB-positive than in CMB-negative patients (systolic BP: p=0.03, diastolic BP: p=0.02). Conclusions: CAD patients with severe coronary artery lesions and poor BP control appear to be at higher risk for CMBs during antiplatelet therapy. Accordingly, strict coronary risk control, especially BP control, is necessary to prevent new CMBs in CAD patients receiving long-term antiplatelet therapy

OS 18-07 SAFETY AND EFFICACY OF ARB/HCTZ COMBINATION THERAPY IN CONTROLLING MORNING HYPERTENSION IN VERY ELDERLY PATIENTS

Objective: Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the incidence of morning hypertension increases with age, treatment of morning hypertension has not been established particularly in late-elderly patients. Among various combinations, ARB combined with a small dose of thiazide diuretic is desirable because the two drugs have complementary mechanisms of action, and effectively reduce BP. Thus, we investigated the safety and efficacy of ARB/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension in the very elderly. Design and Method: This is a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study, which compared the effects of a combination of 50-mg losartan/12.5-mg HCTZ (Combination) and 100-mg losartan (High ARB) on morning SBP levels after 3-month treatment in on-treatment hypertensive patients with morning SBP greater than 135/85 mmHg on home BP self-measurement. Patients were allocated to very elderly group (≥ 75 years) and young/elderly group (< 75 years). Results: Effects of 3-month Combination therapy and High ARB therapy were summarized in Table (*P < 0.05 and **P < 0.01 vs. baseline; #P < 0.05 and ##P < 0.01 vs. High ARB group). More than 98% of patients in all groups showed the adherence to medications of 80% or more. The incidence of adverse events of both treatments was similar in both groups. Conclusions: In the elderly patients, ARB/HTCZ combination induced further morning SBP reduction and greater target achievement ratio of morning BP (<135/85 mmHg) than high-dose ARB, to the similar levels seen in the young/elderly patients. And, ARB/HTCZ combination was safe and tolerable in either age group.