Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial.

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Routine use of HbA1c amongst inpatients hospitalised with decompensated heart failure and the association of dysglycaemia with outcomes.

Diabetes is an independent risk factor for development of heart failure and has been associated with poor outcomes in these patients. The prevalence of diabetes continues to rise. Using routine HbA1c measurements on inpatients at a tertiary hospital, we aimed to investigate the prevalence of diabetes amongst patients hospitalised with decompensated heart failure and the association of dysglycaemia with hospital outcomes and mortality. 1191 heart failure admissions were identified and of these, 49% had diabetes (HbA1c ≥ 6.5%) and 34% had pre-diabetes (HbA1c 5.7-6.4%). Using a multivariable analysis adjusting for age, Charlson comorbidity score (excluding diabetes and age) and estimated glomerular filtration rate, diabetes was not associated with length of stay (LOS), Intensive Care Unit (ICU) admission or 28-day readmission. However, diabetes was associated with a lower risk of 6-month mortality. This finding was also supported using HbA1c as a continuous variable. The diabetes group were more likely to have diastolic dysfunction and to be on evidence-based cardiac medications. These observational data are hypothesis generating and possible explanations include that more diabetic patients were on medications that have proven mortality benefit or prevent cardiac remodelling, such as renin-angiotensin system antagonists, which may modulate the severity of heart failure and its consequences.

Left ventricular hypertrophy and cognitive function: a systematic review.

Cognitive impairment is common in patients with hypertension. Left ventricular hypertrophy (LVH) is recognised as a marker of hypertension-related organ damage and is a strong predictor of coronary artery disease, heart failure and stroke. There is evidence that LVH is independently associated with cognitive impairment, even after adjustment for the presence of hypertension. We conducted a systematic review that examined cognitive impairment in adults with LVH. Independent searches were performed in Ovid MEDLINE, Ovid psycInfo and PubMed with the terms left ventricular hypertrophy and cognition. Seventy-three studies were identified when both searches were combined. After limiting the search to studies that were: (1) reported in English; (2) conducted in humans; (3) in adults aged 50 years and older; and (4) investigated the relationship between LVH and cognitive performance, nine papers were included in this systematic review. The majority of studies found an association between LVH and cognitive performance. Inspection of results indicated that individuals with LVH exhibited a lower performance in cognitive tests, when compared to individuals without LVH. Memory and executive functions were the cognitive domains that showed a specific vulnerability to the presence of LVH. A possible mechanism for the relationship between LVH and cognition is the presence of cerebral white matter damage. White matter lesions occur frequently in patients with LVH and may contribute to cognitive dysfunction. Together, the results of this review suggest that memory impairment and executive dysfunction are the cognitive domains that showed a particular association with the presence of LVH.

Beta-blockers are under-prescribed in patients with chronic obstructive pulmonary disease and co-morbid cardiac disease.

The use of beta-blockers in patients with chronic obstructive pulmonary disease and co-morbid cardiovascular disease is controversial, despite increasing evidence to support their use as safe and efficacious. This study retrospectively assessed the rates of beta-blocker prescription in patients admitted to two Australian tertiary hospitals for acute exacerbation of chronic obstructive pulmonary disease. This revealed that less than half of patients (45%) with known cardiac indications were receiving beta-blocker therapy, evident across all degrees of airways disease severity. Further work is needed to ensure that medical management of this patient group is optimised.

Age adjusted Charlson Co-morbidity Index is an independent predictor of mortality over long-term follow-up in infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is associated with high morbidity and mortality. The epidemiology of IE is changing, affecting more elderly patients with increased medical comorbidities. We aimed to assess the ability of the age adjusted Charlson Co-morbidity Index (ACCI) to predict early and late outcomes. METHODS: Between 1998 and 2010, adult patients with definite IE according to the modified Duke criteria were identified. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. RESULTS: 148 patients with IE were followed up for a mean of 3.8 ± 3 years. The mean age was 57 ± 17 years and 66% were male. In-hospital mortality and all-cause mortality were 24 and 47% respectively. Comorbid conditions included diabetes mellitus (DM) (21%); ischaemic heart disease (16%); heart failure (HF) (14%); renal failure (eGFR <60 ml/min/1.73 m(2)) (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59% of patients. Cardiac surgery was performed in 45% of patients. On Cox regression analysis, ACCI >3 (HR=3.0 [1.5-6.0], p<0.002), new onset HF (HR=2.2 [1.3-3.6], p<0.003), anaemia (HR=1.8 [1.1-3.2], p=0.04) and age-per decade (HR=1.4 [1.1-1.7]. p=0.004) were independently associated with all-cause mortality. ACCI >3 was the strongest predictor of in-hospital mortality (OR=8.4 [2.8-24], p<0.001). Of the individual ACCI components, prior HF, DM with complications and metastatic disease were independent predictors of all-cause mortality. CONCLUSION: In-hospital and all-cause mortality of IE remain high. An ACCI >3 was a strong predictor of mortality, in addition to age, new HF and anaemia.

Progression of aortic stenosis in elderly patients over long-term follow up.

BACKGROUND: The natural history of aortic stenosis (AS) in elderly patients remains poorly defined. In an elderly cohort over long-term follow-up, we assessed: 1) rates and predictors of hemodynamic progression and 2) composite aortic valve replacement (AVR) or death endpoint. METHODS: Consecutive Department of Veterans' Affairs patients with AS (>60 years) were prospectively enrolled between 1988 and 1994 (n=239) and followed until 2008. Patients with ≥ 2 trans-thoracic echocardiograms >6 months apart were included in the progression analysis (n=147). Baseline demographics, comorbidities and echocardiography parameters were recorded. Follow-up was censored at AVR/death. RESULTS: The age of patients was 73 ± 6 years; 82% were male. Baseline AS severity was mild (67%), moderate (23%) and severe (10%). Follow-up was 6.5 ± 4 years (range: 1-17 years). Annualized mean aortic valve gradient progression rates were: mild AS 4 ± 4 mmHg/year; moderate AS 6 ± 5 mmHg/year and severe AS 10 ± 8 mmHg/year (p<0.001). Five-year event-free survival was 66 ± 5%, 23 ± 7% and 20 ± 10% for mild, moderate and severe AS respectively. Progression to severe AS occurred in 35% and 74% of patients with mild and moderate AS respectively. Independent predictors of rapid progression were: baseline AS severity (per grade) (OR 2.6, p=0.001), aortic valve calcification (per grade) (OR 2.1, p=0.01), severe renal impairment (OR 4.0, p=0.04) and anemia (OR 2.3, p=0.05). CONCLUSIONS: In elderly patients, hemodynamic progression of AS is predicted by AS severity, renal function, aortic valve calcification and history of anemia. These factors identify patients at high risk of rapid hemodynamic progression, for whom more frequent clinical and echocardiographic surveillance is advisable.

Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis.

AIMS: To assess the capacity of global longitudinal strain (GLS) in patients with aortic stenosis (AS) to (i) detect the subclinical left ventricular (LV) dysfunction [LV ejection fraction (LVEF) ≥50% patients]; (ii) predict all-cause mortality and major adverse cardiac events (MACE) (all patients), and (iii) provide incremental prognostic information over current risk markers. METHODS AND RESULTS: Patients with AS (n = 146) and age-matched controls (n = 12) underwent baseline echocardiography to assess AS severity, conventional LV parameters and GLS via speckle tracking echocardiography. Baseline demographics, symptom severity class and comorbidities were recorded. Outcomes were identified via hospital record review and subject/physician interview. The mean age was 75 ± 11, 62% were male. The baseline aortic valve (AV) area was 1.0 ± 0.4 cm(2) and LVEF was 59 ± 11%. In patients with a normal LVEF (n = 122), the baseline GLS was controls -21 ± 2%, mild AS -18 ± 3%, moderate AS -17 ± 3% and severe AS -15 ± 3% (P< 0.001). GLS correlated with the LV mass index, LVEF, AS severity, and symptom class (P< 0.05). During a median follow-up of 2.1 (inter-quartile range: 1.8-2.4) years, there were 20 deaths and 101 MACE. Unadjusted hazard ratios (HRs) for GLS (per %) were all-cause mortality (HR: 1.42, P< 0.001) and MACE (HR: 1.09, P< 0.001). After adjustment for clinical and echocardiographic variables, GLS remained a strong independent predictor of all-cause mortality (HR: 1.38, P< 0.001). CONCLUSIONS: GLS detects subclinical dysfunction and has incremental prognostic value over traditional risk markers including haemodynamic severity, symptom class, and LVEF in patients with AS. Incorporation of GLS into risk models may improve the identification of the optimal timing for AV replacement.

A comparison of precipitants and mortality when acute decompensated heart failure occurs in the community and hospital settings.

AIM: We aimed to compare the precipitants of acute decompensated heart failure (ADHF) among patients admitted with diagnoses inclusive of ADHF (community patients) and patients admitted without ADHF but who developed it during their stay (hospital patients). METHODS: This was a prospective, analytical, observational study undertaken in the Austin Hospital, a major metropolitan teaching hospital (September 2008-February 2010). Consecutive patients admitted to a general medicine unit, and diagnosed and treated for ADHF were enrolled. The unit medical staff completed a specifically designed data collection document. RESULTS: Three hundred and fifty-nine patients were enrolled (42.9% male, mean age 81.9 years). The community (n=312) and hospital (n=47) patient groups did not differ in age, gender, risk variables (living alone, cognitive impairment, multiple medications, compliance), cardiac failure medication use or cause of known heart failure (ischaemia, hypertension, valve dysfunction, 'other') (p>0.05). The ADHF precipitants comprised infection (39.8% patients), myocardial ischaemia (17.3%), tachyarrhythmia (16.2%), non-compliance with fluid and salt restriction (9.2%), non-compliance with medication (6.7%), renal failure (5.8%), medication reduction (5.0%), intravenous fluid complication (3.9%) and 'other' causes (13.9%). Significantly more hospital patients had their ADHF precipitated by intravenous fluid complications (25.5% versus 0.6%, p<0.001). Hospital patients also had a significantly greater death rate (25.5% versus 9.3%, p<0.01). CONCLUSION: Acute decompensated heart failure precipitated in hospital is a dangerous condition with a high mortality. While infection and myocardial ischaemia are the common precipitants, complications of intravenous fluid use, an iatrogenic condition, may be considerable and are potentially avoidable.

Review article: the pathophysiological roles of the renin-angiotensin system in the gastrointestinal tract.

BACKGROUND: The renin-angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin-angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.

Chronic kidney disease: cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition.

Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg(-1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD.

Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways.

Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7.

ACE2 and AT4R are present in diseased human blood vessels.

A growing body of evidence suggests that the angiotensin II fragments, Ang(1-7) and Ang(3-8), have a vasoactive role, however ACE2, the enzyme that produces Ang(1-7), or AT4R, the receptor that binds Ang (3-8), have yet been simultaneously localised in both normal and diseased human conduit blood vessels. We sought to determine the immunohistochemical distribution of ACE2 and the AT4R in human internal mammary and radial arteries from patients undergoing coronary artery bypass surgery. We found that ACE2 positive cells were abundant in both normal and diseased vessels, being present in neo-intima and in media. ACE2 positive immunoreactivity was not present in the endothelial layer of the conduit vessels, but was clearly evident in small newly formed angiogenic vessels as well as the vaso vasorum. Endothelial AT4R immunoreactivity were rarely observed in either normal and diseased arteries, but AT4R positive cells were observed adjacent to the internal elastic lamine in the internal mammary artery, in the neo-intima of radial arteries, as well as in the media of both internal mammary artery and radial artery. AT4R was abundant in vaso vasorum and within small angiogenic vessels. Both AT4R and ACE2 co-localised with smooth muscle cell alpha actin. This study identifies smooth muscle cell alpha actin positive ACE2 and AT4R in human blood vessels as well as in angiogenic vessels, indicating a possible role for these enzymes in pathological disease.

Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression.

Patients with kidney failure are at high risk of a cardiac death and frequently develop left ventricular hypertrophy (LVH). The mechanisms involved in the cardiac structural changes that occur in kidney failure are yet to be fully delineated. Angiotensin-converting enzyme (ACE) 2 is a newly described enzyme that is expressed in the heart and plays an important role in cardiac function. This study assessed whether ACE2 plays a role in the cardiac remodelling that occurs in experimental acute kidney injury (AKI). Sprague-Dawley rats had sham (control) or subtotal nephrectomy surgery (STNx). Control rats received vehicle (n = 10), and STNx rats received the ACE inhibitor (ACEi) ramipril, 1 mg kg(-1) day(-1) (n = 15) or vehicle (n = 13) orally for 10 days after surgery. Rats with AKI had polyuria (P < 0.001), proteinuria (P < 0.001) and hypertension (P < 0.001). Cardiac structural changes were present and characterized by LVH (P < 0.001), fibrosis (P < 0.001) and increased cardiac brain natriuretic peptide (BNP) mRNA (P < 0.01). These changes occurred in association with a significant increase in cardiac ACE2 gene expression (P < 0.01) and ACE2 activity (P < 0.05). Ramipril decreased blood pressure (P < 0.001), LVH (P < 0.001), fibrosis (P < 0.01) and BNP mRNA (P < 0.01). These changes occurred in association with inhibition of cardiac ACE (P < 0.05) and a reduction in cardiac ACE2 activity (P < 0.01). These data suggest that AKI, even at 10 days, promotes cardiac injury that is characterized by hypertrophy, fibrosis and increased cardiac ACE2. Angiotensin-converting enzyme 2, by promoting the production of the antifibrotic peptide angiotensin(1-7), may have a cardioprotective role in AKI, particularly since amelioration of adverse cardiac effects with ACE inhibition was associated with normalization of cardiac ACE2 activity.

Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research.

Cell culture experiments often employ the use of culture media that contain fetal calf serum (FCS). The angiotensin peptides angiotensin II and angiotensin 1-7 have opposing effects with angiotensin converting enzyme 2 (ACE2) being the enzyme predominantly responsible for generating angiotensin 1-7 from angiotensin II. The effect of FCS on angiotensin peptides has not previously been described. We have shown that FCS has ACE2 enzyme activity capable of degrading angiotensin II and generating angiotensin 1-7. Researchers should be aware that FCS possesses ACE2 activity and that heat-treating FCS to 56 degrees C only partially inhibits this enzyme activity, whereas heat-treating to 70 degrees C completely abolishes ACE2 activity.

Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2.

BACKGROUND: Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known. AIMS: This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta. METHODS: In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis. RESULTS: ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p < 0.01). ACE2 protein increased after BDL (23.5-fold; p < 0.05) as did ACE2 activity (fourfold; p < 0.05). In human cirrhotic liver, gene (>30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p < 0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels. CONCLUSIONS: ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.

Thiazolidinediones and congestive heart failure--exacerbation or new onset of left ventricular dysfunction?

BACKGROUND: Patients with diabetes mellitus have a high incidence of coronary heart disease and congestive heart failure (CHF). Thiazolidinediones (TZD) are a new class of pharmacological agents for the treatment of Type 2 diabetes mellitus, which have many beneficial cardiovascular effects. Peripheral oedema and weight gain have been reported in 4.8% of subjects on TZDs alone, with a higher incidence noted in those receiving combination insulin therapy (up to 15%), but there is limited data on the occurrence of CHF. METHODS AND RESULTS: In this paper, we report on six cases of TZD-induced fluid retention with symptoms and signs of peripheral oedema and/or CHF that occurred in subjects attending our diabetic clinic. The predominant finding in all cases was of diastolic dysfunction. All subjects were obese and hypertensive, with 5/6 having the additional risk factor of LVH, 5/6 subjects had microvascular complications, whilst 3/6 were also on insulin therapy. CONCLUSION: We suggest that obese, hypertensive diabetics may benefit from echocardiographic screening prior to commencement of TZDs, as these agents may exacerbate underlying undiagnosed left ventricular diastolic dysfunction.

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.

AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease.

In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.