Effects of Direct Renin Inhibition on Myocardial Fibrosis and Cardiac Fibroblast Function

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function

The Lantern, 2012-2013

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Dementia Coding, Workup, and Treatment in the VA New England Healthcare System

Growing evidence suggests that Alzheimer’s disease and other types of dementia are underdiagnosed and poorly documented. In our study, we describe patterns of dementia coding and treatment in the Veteran’s Administration New England Healthcare System. We conducted a retrospective cohort study with new outpatient ICD-9 codes for several types of dementia between 2002 and 2009. We examined healthcare utilization, medication use, initial dementia diagnoses, and changes in diagnoses over time by provider type. 8,999 veterans received new dementia diagnoses during the study period. Only 18.3% received a code for cognitive impairment other than dementia, most often “memory loss” (65.2%) prior to dementia diagnosis. Two-thirds of patients received their initial code from a PCP. The etiology of dementia was often never specified by ICD-9 code, even by specialists. Patients followed up exclusively by PCPs had lower rates of neuroimaging and were less likely to receive dementia medication. Emergency room visits and hospitalizations were frequent in all patients but highest in those seen by dementia specialists. Dementia medications are commonly used off-label. Our results suggest that, for the majority the patients, no prodrome of the dementia syndrome is documented with diagnostic code, and patients who do not see dementia specialists have less extensive diagnostic assessment and treatment

Relationship between intra-operative vein graft treatment with DuraGraft® or saline and clinical outcomes after coronary artery bypass grafting

BACKGROUND Saphenous vein grafts (SVGs) remain the most often used conduits for coronary bypass grafting (CABG). Progressive intimal hyperplasia contributes to vein-graft disease and vein-graft failure (VGF). We compared the impact of intraoperative preservation of SVGs in a storage solution (DuraGraft®) versus heparinized saline on VGF-related outcomes after CABG. METHODS From 1996 to 2004, 2436 patients underwent isolated CABG with ≥ 1 SVG. SVGs were consecutively treated with DuraGraft in 1036 patients (2001-2004) and heparinized saline in 1400 patients (1996-1999). Short- (< 30 days) and long-term (≥ 1000 days) outcomes were assessed using repeat revascularization (primary end point), and major adverse cardiac events (MACE) consisting of the composite of death, nonfatal myocardial infarction, or repeat revascularization. RESULTS Mean follow-up in the DuraGraft group was 8.5 ± 4.2 years and 9.9 ± 5.6 years in controls. Short-term event rates were low and generally did not differ between groups. DuraGraft was associated with a 45% lower occurrence of nonfatal myocardial infarction after 1000 days (hazard ratio 0.55, 95% CI 0.41-0.74; P < 0.0001). There was 35% and 19% lower long-term risk for revascularization (HR 0.65, 95% CI 0.44-0.97; P = 0.037) and MACE (HR 0.81, 95% CI 0.70-0.94; P = 0.0051), respectively, after DuraGraft. Mortality was comparable between both groups at 1, 5, and 10 years. There was no statistically significant association between DuraGraft exposure and time to death starting at 30 or 1000 days (HR 0.91, 95% CI 0.76-1.09; P = 0.29). CONCLUSION In this study, intraoperative treatment of SVGs with DuraGraft was associated with a lower risk of long-term adverse events suggesting that efficient intraoperative SVG treatment may reduce VGF-related complications post-CABG. These data warrant randomized clinical trials to validate these findings

Effects of aliskiren on homocysteine-induced matrix expression in cultured cardiac fibroblasts.

<p>Fibroblasts were cultured in the presence or absence of D,L, homocysteine 200 µmol/L for 24 hours after pretreatment with varying concentrations of aliskiren (0.1–10 µmol/L). Real time PCR was done to measure relative expression of COLIA2 (alpha 2 chain of type I collagen; A) and COL3A1 (alpha 1 chain of type III collagen; B) genes. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081612#pone-0081612-g005" target="_blank">Figure 5C</a> demonstrates the results of real time PCR to compare the effects of losartan and captopril with aliskiren on homocysteine induced expression of COL1A2 gene. Western blotting was conducted to measure the expression of collagen type I protein (D and E) Glyceraldehyde 3 phosphate dehydrogenase (GAPDH) was used as internal control. Hcy-D,L, homocysteine; AL-aliskiren; Los – losartan; and Cap – captopril. *p<0.05.</p

Effects of aliskiren on Hhe-induced diastolic dysfunction.

<p>(n = 5–7/group). A, the relation of balloon volume (normalized to heart weight) to left ventricular developed pressure. There were no differences between the groups. B shows the relation of balloon volume to left ventricular end diastolic pressure. There was a significant displacement of the pressure volume curve upwards in the Hhe group compared to all other groups (ANOVA; p<0.05). Hhe – Hhe-inducing diet; LVEDV – left ventricular end diastolic volume; and LVDevP – left ventricular developed pressure.</p

Role of Akt pathway in aliskiren's effects on attenuating collagen expression.

<p>A and B demonstrate the results of Western blotting for phospho- and total Akt in hearts of mice treated with various diets. C shows changes in the protein levels of collagen type I, phospho- and total Akt in response to 24 hours of exposure to D,L. Homocysteine (200 µmol/L) with or without pre-treatment with aliskiren 10 µmol/L (AL), wortmannin 1 µmol/L or Akt Inhibitor VIII 1 µmol/L. Hhe – Hhe-inducing diet; D,L, homocysteine (lower panel); AL 0.05– aliskiren 0.5 mg/kg/day; AL 5– aliskiren 5 mg/kg/day; AL 50– aliskiren 50 mg/kg/day; Wort – wortmannin; Akt in – Akt inhibitor VIII. *p<0.05; **p<0.01; and ***p<0.001.</p