Activation of Peroxisome Proliferator-activated Receptor γ Prevents Development of Heart Failure With Preserved Ejection Fraction; Inhibition of Wnt-ß-catenin Signaling as a Possible Mechanism.

Left ventricular (LV) fibrosis plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). We investigated whether chronic peroxisome proliferator-activated receptor gamma agonism with pioglitazone can prevent the development of HFpEF. We also evaluated the role of Wnt-ß-catenin signaling in the development of HFpEF, and its relationship to peroxisome proliferator-activated receptor gamma signaling. Dahl salt-sensitive rats placed on an 8% NaCl diet from age 6 weeks were used as HFpEF model. Rats placed on 0.3% NaCl diet served as controls (n = 7). HFpEF model rats were randomized to no treatment (n = 7) or treatment with pioglitazone (2.5 mg/kg per day, n = 7) at age 13 weeks. Pioglitazone administration from age 13 to 21 weeks attenuated the development of LV fibrosis and stiffening (both P < 0.05), and subsequently prevented the development of HFpEF. In the untreated HFpEF model, Wnt1, 2, 10b messenger RNA and ß-catenin protein expression levels in the left ventricle increased in the heart failure stage, along with the increase in type I collagen messenger RNA expression levels. Administration of pioglitazone attenuated the activation of Wnt-ß-catenin signaling. Our results show that pioglitazone prevented the development of LV fibrosis and HFpEF in a rat model, at least partly due to attenuated Wnt-ß-catenin signaling.

Relationship between coronary flow reserve evaluated by phase-contrast cine cardiovascular magnetic resonance and serum eicosapentaenoic acid.

BACKGROUND: Long-term intake of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA) is associated with a low risk for cardiovascular disease. Phase-contrast cine cardiovascular magnetic resonance (PC cine CMR) can assess coronary flow reserve (CFR). The present study investigates the relationship between CFR evaluated by PC cine CMR and the serum EPA. METHODS: We studied 127 patients (male, 116 (91%); mean age, 72.2 ± 7.4 years) with known or suspected coronary artery disease (CAD). X-ray coronary angiography revealed no significant coronary arterial stenoses (defined as luminal diameter reduction ≥ 50% on quantitative coronary angiogram (QCA) analysis) in all study participants. Breath-hold PC cine CMR images of the coronary sinus (CS) were acquired to assess blood flow of the CS both at rest and during adenosine triphosphate (ATP) infusion. We calculated CFR as CS blood flow during ATP infusion divided by that at rest. Patients were allocated to groups according to whether they had high (n = 64, EPA ≥ 75.8 µg/mL) or low (n = 63, EPA < 75.8 µg/mL) median serum EPA. RESULTS: CFR was significantly lower in the low, than in the high EPA group (2.54 ± 1.00 vs. 2.91 ± 0.98, p = 0.038). Serum EPA positively correlated with CFR (R = 0.35, p < 0.001). We defined preserved CFR as > 2.5, which is the previously reported lower limit of normal flow reserve without obstructive CAD. Multivariate analysis revealed that EPA is an independent predictor of CFR > 2.5 (odds ratio, 1.01; 95% confidence interval, 1.00 - 1.02, p = 0.008). CONCLUSIONS: The serum EPA is significantly correlated with CFR in CAD patients without significant coronary artery stenosis.

Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension.

BACKGROUND: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. METHODS AND RESULTS: 23 PAH patients were treated with either placebo (10/2 females/males, 51 ± 16 years, idiopathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47 ± 14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hydroxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. CONCLUSIONS: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynamics in patients with PAH.

Sustained inhibition of oxidized low-density lipoprotein is involved in the long-term therapeutic effects of apheresis in dialysis patients.

OBJECTIVE: Low-density lipoprotein (LDL) apheresis is a potential therapy for conventional therapy-resistant peripheral artery disease. In the present study, we examined the chronic effects of LDL apheresis on clinical parameters in vivo and endothelial cell functions in vitro in hemodialysis patients who had the complication of peripheral artery disease. METHODS AND RESULTS: Twenty-five patients were enrolled, and the responses of 19 patients to LDL apheresis were analyzed. Patients were classified into 2 groups according to change in ankle-brachial pressure index (ABI) after treatment: patients with improved ABI (responders, n=10) and patients with worsened ABI (nonresponders, n=9). In the responders, apheresis resulted in a long-term reduction of circulating levels of oxidized LDL, C-reactive protein, and fibrinogen. In human umbilical vein endothelial cells (HUVECs), the serum from the responders increased expression of activated endothelial nitric oxide synthase protein and proliferative activity. Furthermore, there was a significant correlation between ABI and activated endothelial nitric oxide synthase protein level in HUVECs treated with responder serum (R=0.427, P<0.05). CONCLUSION: These results demonstrate that LDL apheresis decreases oxidized LDL and inflammation and improves endothelial cell function in the responders. This may be one of the mechanisms involved in the long-term therapeutic effect of LDL apheresis on peripheral circulation in hemodialysis patients.

Clinical usefulness of additional treatment with ezetimibe in patients with coronary artery disease on statin therapy. - From the viewpoint of cholesterol metabolism.-.

BACKGROUND: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). METHODS AND RESULTS: A total of 171 patients with CAD whose LDL-C level was ≥ 100 mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5 mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0 ± 15.6 mg/dl vs. -19.2 ± 14.2 mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35 ± 0.90 µg/mg vs. 0.33 ± 0.74 µg/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3 ± 15.6 mg/dl vs. -21.5 ± 16.7 mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group. CONCLUSIONS: Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers.

A case of nemaline myopathy with associated dilated cardiomyopathy and respiratory failure.

Nemaline myopathy is a representative form of congenital myopathy, and is characterized by nemaline bodies in muscle fibers. Here we report a 47-year-old man with congenital nemaline myopathy complicated with dilated cardiomyopathy-related heart failure, and restrictive respiratory failure. The complication of dilated cardiomyopathy in nemaline myopathy has rarely been reported. In this case, nemaline bodies were detected in the cardiac muscle fibers, demonstrating the presence of underlying disease-related myocardial degeneration. The patient responded to the combination of conventional therapy for heart failure including ß-blocker and noninvasive continuous positive-pressure ventilation for respiratory failure. His general condition has been stable during a 10-month follow up period.

Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L.

Epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminal of the protein for subsequent degradation. One of the isoforms of human Nedd4L with evolutionarily new C2 domain was reported to play a significant role for degradating cell surface ENaC with interfering with wild isoforms by us previously. We focused the current analyses on isolating the binding molecules with C2 domain using yeast two-hybrid screening to elucidate further molecular interactions between ENaC and Nedd4L. We found NPC2, also known as HE-1, bind C2 domain of human Nedd4L and express along ASDN colocalized with Nedd4L. Additionally, in experiments using a model of salt-sensitive hypertension in Dahl rats, we provided evidence suggesting that transcriptional regulation and activation of NPC2 protein depends on sodium intake. NPC2 might regulate sodium reabsorption in the terminal nephron by interacting with ENaC-Nedd4L system.

Optimal programming of the atrioventricular delay using the phonocardiogram.

PURPOSE: To predict the optimal atrioventricular (AV) delay using the phonocardiogram (PCG). METHODS: We studied 12 recipients of cardiac resynchronization therapy (CRT) system and eight recipients of dual-chamber pacemakers implanted for AV block with normal left ventricular (LV) function. The amplitude of the first heart sound (S1) was recorded by PCG and the LV outflow tract (OT) time-velocity integral (TVI) was measured by pulsed Doppler echocardiography. The AV delay was prolonged in 20-ms increments, from 60 ms to 240 ms. Ishikawa's method was used for the echocardiographic optimization of the AV delay. The relation between S1 amplitude and the AV delay was analyzed. RESULTS: The correlation between the amplitude of S1 and the length of AV delay showed an S-shaped curve. The AV delay at the inflection point of each patient's S-shaped curve (161.2 +/- 19.5 ms) was positively correlated with the optimal AV delay determined by echocardiography (148.3 +/- 16.9 ms, r = 0.83, P < 0.001). In addition, there was a positive correlation between the AV delay at the maximal TVI of LVOT (150.8 +/- 22.7 ms) and the AV delay at the inflection point of the S-shaped curve (159.5 +/- 24.9 ms, r = 0.87, P < 0.001). In two CRT system recipients, an optimal AV delay could not be found by echocardiography; however, an optimal AV delay could be determined by PCG. CONCLUSIONS: A high correlation was observed between the optimal AV delay determined by phonocardiography versus echocardiography.

Effects of angiotensin II type 1 receptor blocker on blood pressure variability and cardiovascular remodeling in hypertensive patients on chronic peritoneal dialysis.

AIMS: In this study, we examined whether addition of an angiotensin II type 1 receptor blocker (ARB), candesartan or valsartan, to conventional antihypertensive treatment could improve blood pressure (BP) variability in hypertensive patients on peritoneal dialysis. METHODS: 45 hypertensive patients on chronic peritoneal dialysis therapy were randomly assigned to the ARB treatment groups either by candesartan (n = 15) or valsartan (n = 15), or the control group (n = 15). At baseline and 6 months after the treatment, 24-hour ambulatory BP monitoring, echocardiography, and measurement of brachial-ankle pulse wave velocity (baPWV) were performed. RESULTS: After the 6 months of treatment, 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups. However, short-term BP variability assessed on the basis of the standard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups, but remained unchanged in the control group. Furthermore, parameters of cardiovascular remodeling assessed by natriuretic peptides, echocardiography, and baPWV were significantly improved in the ARB groups but not in the control group. CONCLUSION: ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. However, ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability.

Utility and feasibility of a new programmable home blood pressure monitoring device for the assessment of nighttime blood pressure.

BACKGROUND: Recent evidence indicates that both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) are more useful than the measurement of office blood pressure for evaluating cardiovascular risks in subjects with hypertension. The major advantage of ABPM over HBPM is the ability to measure nighttime blood pressure and ambulatory blood pressure during the day. A newly developed, programmable HBPM device (HEM-5041, Omron Healthcare, [corrected] Kyoto, Japan) can record blood pressure up to 600 [corrected] times and measure nighttime blood pressure automatically. METHODS: To validate the utility, feasibility, and safety of this device, we measured blood pressure by HBPM using HEM-5041 and by ABPM and compared the values in healthy volunteers. RESULTS: As compared with ABPM, daytime blood pressures, coefficients of variation for systolic blood pressure, diastolic blood pressure, and pulse rate, and the percentage nighttime fall in these variables were significantly lower with HBPM. However, nighttime blood pressures did not significantly differ between HBPM and ABPM. The results of a questionnaire survey indicated that the subjects were more comfortable when blood pressure was measured by HBPM than by ABPM, whereas the quality of sleep was similar. CONCLUSIONS: Our results suggest that HEM-5041 is useful for evaluating nighttime blood pressures as well as nighttime blood pressure falls, without causing clinically significant discomfort.

Combining chronic kidney disease with 201thallium/123iodine beta methyliodophenyl pentadecanoic acid dual myocardial single-photon emission computed tomography findings is useful for the evaluation of cardiac event risk.

OBJECTIVE: Chronic kidney disease is a noteworthy pathophysiology as a risk factor of cardiovascular disease. We investigated the usefulness of combining glomerular filtration rate and 201thallium(201TI)/123iodine-beta-methyliodophenyl pentadecanoic acid (123I-BMIPP) dual myocardial scintigraphic findings for predicting cardiac events. METHODS: Seventy-five patients suspected of coronary artery disease underwent 201TI/123I-BMIPP dual myocardial scintigraphy. Clinical and nuclear variables were included in the multivariate analysis for predicting hard events (cardiac death and nonfatal myocardial infarction) and soft events (unstable angina, heart failure, and coronary revascularization). Glomerular filtration rate was estimated by the modification of diet in renal disease formula. Kaplan-Meier analysis was performed to investigate the incremental prognostic value of glomerular filtration rate. RESULTS: During the mean follow-up period of 425 days, eight patients had hard events and 20 patients had soft events. Multivariate analysis revealed that glomerular filtration rate and the sum of total defect score in 123I-BMIPP image were independent predictors of total cardiac events, whereas sex, diabetes, glomerular filtration rate, and the number of abnormal segments in 201TI image were those of hard events. Kaplan-Meier analysis revealed that greater risk stratification was achieved by adding a glomerular filtration rate of lesser than 60 ml/min/1.73 m2 to the sum of the total defect score > or = 5 in the 123I-BMIPP image. Greater risk stratification for hard events was also achieved by adding a glomerular filtration rate of lesser than 30 ml/min/1.73 m2 to the number of abnormal segments > or = 2 in 201TI image. CONCLUSION: Better risk stratification can be achieved by adding glomerular filtration rate to 201TI/123I-BMIPP dual myocardial scintigraphic findings.

The novel angiotensin II type 1 receptor (AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy.

Activation of angiotensin II (Ang II) type 1 receptor (AT1R) signaling is reported to play an important role in cardiac hypertrophy. We previously cloned a novel molecule interacting with the AT1R, which we named ATRAP (for Ang II type 1 receptor-associated protein). Here, we report that overexpression of ATRAP significantly decreases the number of AT1R on the surface of cardiomyocytes, and also decreases the degree of p38 mitogen-activated protein kinase phosphorylation, the activity of the c-fos promoter and protein synthesis upon Ang II treatment. These results indicate that ATRAP significantly promotes downregulation of the AT1R and further attenuates certain Ang II-mediated hypertrophic responses in cardiomyocytes.

Infected left atrial myxoma.

A 47-year-old Japanese woman with a continuing high fever was promptly diagnosed as having infected atrial myxoma one day after admission based on transthoracic echocardiographic findings and positivity for bacteria in blood culture. The mass was removed by an urgent open heart surgery. Histopathological examination confirmed that this mass was a myxoma with gram-positive bacterial colonies. Generally, antemortem diagnosis is difficult and there is a high mortality of patients with infected myxoma; however, this patient completely recovered from the illness because of the prompt diagnosis. This is the 37th case of definite infected myxoma reported in the literature. The cause of infection of this patient might have been the acupuncture therapy she underwent for weight reduction.

Anti-tachycardia therapy can improve altered cardiac adrenergic function in tachycardia-induced cardiomyopathy.

We investigated whether anti-tachycardia therapy might improve the altered cardiac adrenergic and systolic function in tachycardia-induced cardiomyopathy (TC) in contrast to dilated cardiomyopathy (DCM). The subjects were 23 patients with heart failure, consisting of 8 patients with TC (43.6 +/- 10.0 yrs) and 15 with DCM (45.3 +/- 8.2 yrs). TC was determined as impairment of left ventricular function secondary to chronic or very frequent arrhythmia during more than 10% of the day. All patients were receiving anti-tachycardia treatment. Cardiac 123I-MIBG uptake was assessed as the heart/mediastinum activity ratio (H/M) before and after treatment. LVEF was also assessed. In the baseline study, H/M and LVEF showed no difference between TC and DCM (2.21 +/- 0.44 vs. 2.10 +/- 0.42, 35.3 +/- 13.1 vs. 36.0 +/- 10.9%, respectively). After treatment, the degree of change in H/M and LVEF differed significantly (0.41 +/- 0.34 vs. 0.08 +/- 0.20, 20.5 +/- 14.4 vs. -2.1 +/- 9.6%, p < 0.01). In TC, heart failure improved after a shorter duration of treatment (p < 0.05). In conclusion, anti-tachycardia therapy can improve altered cardiac adrenergic function and systolic function in patients with TC over a shorter period than in those with DCM.

Clinical usefulness of ECG-gated 18F-FDG PET combined with 99mTC-MIBI gated SPECT for evaluating myocardial viability and function.

OBJECTIVES: This study sought to evaluate an imaging approach using gated 99mTc-MIBI (MIBI) SPECT and gated 18F-FDG (FDG) PET for assessment of myocardial viability and cardiac function. METHODS: Forty-eight patients (38 men, mean age 68.1 +/- 9.6 years) underwent ECG-gated FDG PET and MIBI SPECT within a week. The baseline diagnoses were coronary artery disease (31), mitral regurgitation (1), paroxysmal arrhythmia (10), and dilated cardiomyopathy (6). The gated FDG PET data were analyzed using pFAST software, and the gated MIBI SPECT data were analyzed using QGS software. Fifteen patients were diagnosed with myocardial infarction, and follow-up study was performed to assess the functional outcome four months later. An improvement in LVEF of >5% was defined as significant. The LV myocardium was divided into 17 segments, and regional defect scores were visually assessed using a 4-point scale for each segment (0 = normal, 1 = mildly reduced, 2 = moderately reduced, 3 = absent). A segment with a greater defect score on MIBI SPECT than on FDG PET was defined as a mismatch. The patients were divided into two groups: those with at least two mismatched segments (MM-group), and those with none or one (M-group). RESULTS: LVEF, EDV and ESV measured by gated FDG PET were highly correlated with those obtained by gated MIBI SPECT (r = 0.848, 0.855 and 0.911, p < 0.0001, respectively). The mean values of LVEF did not differ significantly, but EDV and ESV obtained by gated FDG PET were significantly grater than those obtained by gated MIBI SPECT (p < 0.0001). In 15 patients diagnosed with myocardial infarction, a significant association (p < 0.05) was found between the relative uptake of FDG PET and MIBI SPECT and the functional outcome 4 months later. Global LV function improved in 6 of the 8 patients showing mismatch but in only 1 of the 7 patients with matched defects, resulting in a sensitivity of 86% and specificity of 75%. The overall accuracy to predict global functional outcome was high (80%). CONCLUSION: This imaging approach allows accurate evaluation of myocardial viability. Furthermore, the high correlations of gated FDG PET and gated MIBI SPECT measurements hold promise for the assessment of left ventricular function using gated FDG PET.

Small proximal aortic diameter is associated with higher central pulse pressure and poor outcome in patients with congestive heart failure.

BACKGROUND: A small proximal aortic diameter (AoD) is thought to be associated with a higher characteristic impedance of the proximal aorta. However, there has been no evidence of a relationship between directly evaluated AoD and directly measured central aortic pressure or the outcome of patients with cardiovascular diseases. METHODS AND RESULTS: (a) In 135 patients without heart failure (HF), who underwent coronary catheterization, we retrospectively examined the relationship between the AoD and the central aortic pressure or aortic elastance. The AoD adjusted with covariates was inversely correlated with the central pulse pressure (cPP; coefficient=-0.75; P=0.04; model R(2)=0.575) and the effective arterial elastance index (coefficient=-0.12; P=0.001; model R(2)=0.366). (b) In 197 patients who were hospitalized due to HF, we examined the relationship between the AoD (evaluated using echocardiography) and the outcome using a Cox proportional hazard model. Fifty-three patients died from various causes during the follow-up period (2.2±1.1 years). Multivariable analysis revealed that the AoD remained an independent risk factor for all-cause death (hazard ratio for 1 s.d. increase of the AoD: 0.68, 95% confidence interval: 0.50-0.92, P=0.013) and cardiovascular death (hazard ratio for 1 s.d. increase of the AoD: 0.63, 95% confidence interval: 0.43-0.93, P=0.019). CONCLUSIONS: A small AoD was associated with a higher cPP and aortic stiffening in the patients without HF, as well as with a poor outcome for HF patients. Although it is easy to evaluate the AoD, it may offer important information regarding the pulsatile load and may be useful for risk stratification of HF patients.

Impact of renal insufficiency on long-term clinical outcome in patients with heart failure treated by cardiac resynchronization therapy.

BACKGROUND: Renal insufficiency is recognized as a predictor of mortality and adverse outcome in heart failure (HF) patients. However, the long-term clinical outcome of cardiac resynchronization therapy (CRT) in Japanese HF patients with renal insufficiency remains uncertain. METHODS: We evaluated 67 consecutive patients who underwent CRT at our hospital. The patients were divided into two groups according to a baseline estimated glomerular filtration rate (e-GFR) cut-off value of 50ml/min, which is defined as the time at which patients should be referred to a nephrologist, by the Japanese Society of Nephrology. Follow-up echocardiographic findings and renal function were examined at 3-6 months after CRT. Then, we compared long-term clinical outcomes between the two groups, and analyzed the effect of CRT on renal function, echocardiographic parameters and cardiac survival. RESULTS: During a mean follow-up period of 30.3 months, patients with advanced renal insufficiency (e-GFR<50ml/min) had significant higher all-cause mortality (log-rank p=0.033) and higher cardiac mortality combined with HF hospitalization (log-rank p=0.017) than patients with e-GFR≥50ml/min. Multivariate analysis revealed that advanced renal insufficiency was an independent predictor of cardiac mortality combined with HF hospitalization (odds ratio=3.01, p=0.008). Subgroup analysis in the baseline advanced renal insufficiency group revealed that patients with preserved renal function by CRT (<10% reduction in e-GFR) had a higher rate of decrease of left ventricular end-systolic diameter (-14.0% vs. -0.8%, p=0.023) and lower cardiac mortality combined with HF hospitalization (log-rank p=0.029) compared with patients with deterioration of renal function (≥10% reduction in e-GFR). CONCLUSIONS: The present study suggests that advanced renal insufficiency is quite useful for the prediction of worsening clinical outcomes in HF patients treated by CRT. Preservation of renal function by CRT brings about better cardiac survival through prevention of adverse cardiac events, even in HF patients with advanced renal insufficiency.

Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.

Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151 ± 11 mm Hg vs 132 ± 11 mm Hg; clinic diastolic BP, 91 ± 13 mm Hg vs 82 ± 9 mm Hg; 24-hour systolic BP, 144 ± 12 mm Hg vs 133 ± 11 mm Hg; 24-hour diastolic BP, 88 ± 8 mm Hg vs 81 ± 9 mm Hg; central BP, 162 ± 16 mm Hg vs 148 ± 14 mm Hg; baPWV, 1625 ± 245 cm/s vs 1495 ± 199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.

Long-term effects of ezetimibe-plus-statin therapy on low-density lipoprotein cholesterol levels as compared with double-dose statin therapy in patients with coronary artery disease.

OBJECTIVE: To assess the mechanism of long-term LDL-C-lowering effect of ezetimibe-plus-statin. METHODS: Coronary artery disease patients whose LDL-C ≥ 70 mg/dL after treatment with atorvastatin 10 mg/day or rosuvastatin 2.5 mg/day were randomly assigned to receive ezetimibe 10 mg/day + statin (n = 78) or double-dose statin (n = 72) for 52 weeks. RESULTS: Greater LDL-C reduction was observed and maintained until 52 weeks in ezetimibe-plus-statin, while LDL-C levels re-increased after 12 weeks in double-dose statin. Although lathosterol/TC increased, campesterol/TC decreased more in ezetimibe-plus-statin. In contrast, lathosterol/TC unchanged and campesterol/TC increased, increasing campesterol/lathosterol ratio for 52 weeks in double-dose statin. Plasma PCSK9 levels were higher in double-dose statin than in ezetimibe-plus-statin at 12 weeks, but similar at 52 weeks. CONCLUSION: Although the difference in PCSK9 between 2 groups was transient, that in both campesterol and lathosterol persisted until 52 weeks. These results demonstrated simultaneous inhibition of cholesterol absorption and synthesis provides stable and greater decrease in LDL-C levels.