Renal Target Organ Damage Research Articles

Percutaneous transluminal angioplasty for peripheral artery disease confers cardiorenal protection

The effects of percutaneous transluminal angioplasty (PTA) on hemodynamic parameters are not established. We tested the hypothesis that PTA would achieve reductions in hemodynamic and target organ damage (TOD) measures in patients with peripheral artery disease (PAD). We enrolled 56 consecutive PAD patients who were scheduled to undergo elective PTA procedures. Brachial blood pressure (BP), central BP, left ventricular mass index (LVMI) and urinary microalbumin excretion ratio (UACR) were assessed at baseline and follow-up. The ankle-brachial index in the diseased leg significantly improved after the PTA (P<0.001). Compared with the pretreatment levels, brachial and central BPs, the carotid augmentation index (AI) and central augmentation pressure (AP) were significantly reduced after the PTA, as were LVMI and UACR. The change in AI in the PTA group was significantly associated with the extent of change in LVMI (P=0.002) and marginally associated with the change in UACR (P=0.07), independently of other covariates. In conclusion, in patients with PAD, significant reductions in carotid AI were observed by PTA treatment; these changes may be attributable to improvements in measures of cardiac and renal target organ damage.

Heart rate variability and target organ damage in hypertensive patients

BackgroundWe evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD).MethodsA retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index.ResultsSignificantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors.ConclusionsDepressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD.

Sodium loading and cutaneous microvascular function: more than skin deep

For several years the human cutaneous circulation has been utilized as a representative vascular bed to assess microvascular function in clinical and pre-disease model populations. With relevance to hypertension, deficits in cutaneous microvascular function are related to impairment in indices of renal vascular function and target organ damage (Coulon et al. 2011). While the skin serves mainly thermoregulatory purposes, several skin-specific methodologies including both thermal and pharmacological stimuli and interventions have been successfully utilized to pharmacodissect underlying mechanisms of vascular dysfunction (Holowatz et al. 2008). The most commonly explored signalling pathways in human skin most relevant to globalized vascular dysfunction are nitric oxide synthase (NOS)-dependent vasodilatory mechanisms, and noradrenaline-mediated vasoconstrictor mechanisms. Moreover, specific pathology-relevant oxidant stress mechanisms have been explored using both specific and non-specific antioxidants including allopurinol, apocynin and ascorbate (Medow et al. 2011). In this issue of The Journal of Physiology, Greaney et al. (2012) published an elegant study examining the effects of dietary sodium loading on microvascular function, independent of an increase in blood pressure. This study is the first to show that dietary sodium loading in normotensive salt-resistant humans impairs cutaneous eNOS-dependent vasodilatation utilizing a local skin heating stimulus. Furthermore, when the non-specific antioxidant ascorbate was locally delivered, eNOS-dependent vasodilatation was restored. Together, the data from Greaney et al. show that dietary sodium-induces decrements in cutaneous microvascular function that occur through ascorbate-sensitive oxidant stress mechanisms. The results from this study bring to light several interesting points to consider from both a globalized vascular health perspective and for methodological reasons when examining the neurovascular regulation of skin blood flow. Human skin has been used as a model for examining decrements in vascular function with hypertension-induced vascular pathology for several decades. While as a regional circulation the compliant cutaneous circulation contributes minimally to the increase in systemic vascular resistance in comparison to more nutritive vascular beds, decrements in microvascular function are clearly apparent. Even before the technology was available to image or measure more precise changes in microcirculatory function through laser-Doppler or laser-speckle imagery, Carberry et al. (1992) utilized venous occlusion plethysmography and a whole limb heating technique to show that subjects with essential hypertension have lower forearm blood flows to increasing temperature and lower maximal blood flow, indicating a degree of endothelial dysfunction and inward vessel remodelling. Moreover, progressive decrements in vascular function to endothelium-dependent agonists with the severity of hypertensive disease have been consistently observed (Farkas et al. 2004). More recently with the development of skin-specific methodologies the underlying mechanisms of hypertension-induced vascular dysfunction are being extensively explored (Smith et al. 2011). The study by Greaney et al. adds another piece to the puzzle suggesting that dietary salt loading alone without increases in mean arterial pressure induces changes in vascular function that are consistent with a pre-clinical hypertensive vascular pathology state. From a methodological perspective, the results from Greaney et al. highlight the need for cautious experimental controls in all studies examining the neurovascular regulation of skin blood flow whether in healthy or clinical populations. Controlling or documenting sodium intake in human subjects may be a necessary experimental control especially when examining clinical populations. Finally, meaningful physiological interpretations of studies like that of Greaney et al. are not possible without tightly controlled mechanistic work in healthy populations. More of this work is necessary so that clinical test of microvascular function in the skin can be utilized on a broader scale (Minson, 2010).

Ambulatory Blood Pressure Monitoring in Pediatric Renal Transplantation

Hypertension is a common and serious complication after renal transplantation. It is an important risk factor for graft loss and adverse cardiovascular outcomes. Blood pressure (BP) in transplanted children should be measured not only by clinic BP (cBP) measurement, but also by ambulatory blood pressure monitoring (ABPM), because ABPM has distinct advantages over cBP, specifically the ability to reveal nocturnal, masked or white-coat hypertension. These types of hypertension are common in transplanted children (nocturnal hypertension 36-71 %, masked hypertension 24-45 %). It may also reveal uncontrolled hypertension in treated children, thereby improving control of hypertension. Regular use of ABPM and ABPM-guided therapy of hypertension may help to decrease cardiovascular and renal target organ damage in transplanted children. Therefore, ABPM should be routinely performed in all transplanted children at least once a year, regardless of the values of cBP.

Protocol for Measuring Carotid Intima-Media Thickness That Best Correlates With Cardiovascular Risk and Target Organ Damage

To assess which measurement of common carotid intima-media thickness (CC-IMT) is associated to a greater overall cardiovascular risk (CVR), and vascular cardiac and renal target organ damage (TOD), in diabetic, hypertensive patients and healthy subjects. A cross-sectional study, inclusion of 305 patients (113 hypertensive, 100 diabetics, and 92 healthy), aged 30-75 years. Mean CC-IMT and maximum CC-IMT in near and far walls and in the anterior, lateral and posterior projections. Ankle/brachial index (ABI), pulse wave velocity (PWV), glomerular filtration rate (GFR), albumin/creatinine ratio, Cornell voltage-duration product (VDP) and CVR with the Framingham equation and the SCORE. CC-IMT shows a positive correlation with CVR, PWV, and Cornell VDP, and a negative correlation with ABI and GFR (P < 0.001), with no difference between mean and maximum values, near and far wall, or projections. The odds ratio (OR) for the presence of TOD was greatest in mean CC-IMT (OR = 1.85 (95% confidence interval (CI): 1.335-2.58)) and lowest in maximum CC-IMT in the posterior projections OR = 1.42 (95% CI: 1.12-1.80). For each unit increase in mean CC-IMT, a risk increase by 1.98 may be expected (95% CI: 0.69-3.26), whereas the risk increase for each unit increase in maximum CC-IMT is 1.75 (95% CI: 0.70-2.79) (P < 0.001) with Framingham and with no significant association with SCORE. The CC-IMT measurement protocol best predicting for the occurrence of TOD and CVR estimated with Framingham is the mean of 120 measures of mean values in the near and far walls in all three projections of both carotid arteries.

Office and 24-hour heart rate and target organ damage in hypertensive patients

BackgroundWe investigated the association between heart rate and its variability with the parameters that assess vascular, renal and cardiac target organ damage.MethodsA cross-sectional study was performed including a consecutive sample of 360 hypertensive patients without heart rate lowering drugs (aged 56 ± 11 years, 64.2% male). Heart rate (HR) and its standard deviation (HRV) in clinical and 24-hour ambulatory monitoring were evaluated. Renal damage was assessed by glomerular filtration rate and albumin/creatinine ratio; vascular damage by carotid intima-media thickness and ankle/brachial index; and cardiac damage by the Cornell voltage-duration product and left ventricular mass index.ResultsThere was a positive correlation between ambulatory, but not clinical, heart rate and its standard deviation with glomerular filtration rate, and a negative correlation with carotid intima-media thickness, and night/day ratio of systolic and diastolic blood pressure. There was no correlation with albumin/creatinine ratio, ankle/brachial index, Cornell voltage-duration product or left ventricular mass index. In the multiple linear regression analysis, after adjusting for age, the association of glomerular filtration rate and intima-media thickness with ambulatory heart rate and its standard deviation was lost. According to the logistic regression analysis, the predictors of any target organ damage were age (OR = 1.034 and 1.033) and night/day systolic blood pressure ratio (OR = 1.425 and 1.512). Neither 24 HR nor 24 HRV reached statistical significance.ConclusionsHigh ambulatory heart rate and its variability, but not clinical HR, are associated with decreased carotid intima-media thickness and a higher glomerular filtration rate, although this is lost after adjusting for age.Trial RegistrationClinicalTrials.gov: NCT01325064

Metabolic syndrome and multiple organ damage in essential hypertension

ObjectiveTo investigate the influence of the metabolic syndrome (MS) on essential hypertention-related target organ damage (TOD), and assess the value of a systematic search for cardiac and extra-cardiac TOD in...

Double-Barreled Assault by Aldosterone and Salt on the Heart

Aldosterone, a mineralocorticoid hormone secreted by the adrenal zona glomerulosa, is generally regarded as the end product of the renin-angiotensin-aldosterone system. Aldosterone is a major regulator of body fluid and electrolyte homeostasis by virtue of its classic actions at renal collecting duct principal cells, mediated by mineralocorticoid receptors (MR), to induce sodium (Na ) and water reabsorption and potassium (K ) excretion. In addition to these classic effects, aldosterone induces nonclassical actions in both epithelial and nonepithelial tissues, including inflammation and fibrosis that lead to cardiac, vascular, and renal target organ damage. Indeed, a large body of evidence supports the concept that aldosterone induces deleterious effects on the cardiovascular system independently of both angiotensin II and blood pressure (1, 2). The detrimental effects of MR activation in patients with heart failure have been amply demonstrated in large clinical outcome trials. The Randomized Aldactone Evaluation Study showed that adding MR antagonist spironolactone to usual therapy in patients with moderate-severe symptoms decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons (3). The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy Survival Study showed that the selective MR antagonist eplerenone, added to conventional therapy, reduced the rates of death from any cause and hospitalization for cardiovascular reasons in patients with acute myocardial infarction complicated by left ventricular (LV) systolic dysfunction and heart failure (4). This year, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure reported that eplerenone significantly reduced the risks of death and hospitalization in patients with systolic heart failure and mild symptoms (5). Impressively, in that study the number of patients with heart failure needed to treat to prevent one primary outcome was only 19, placing MR antagonist therapy at the forefront of choices for heart failure with mild symptoms (5). Recent studies have convincingly demonstrated that MR can be activated by both cortisol and aldosterone (6, 7). Cardiac MR activation contributes to infarct size after experimental myocardial infarction in rodents (7). Spironolactone not only reversed the resultant tissue damage but acted as an inverse protective agonist in the absence of the steroid receptor ligand (aldosterone or cortisol). These results encourage the initiation of human clinical trials aimed to determine whether starting MR antagonist therapy early after myocardial infarction can limit tissue damage. Taken together, the results of the animal and human studies discussed above emphasize the importance of MR in the pathophysiology of cardiac structural damage. MR are overexpressed in the failing heart and contribute to cardiac inflammation and fibrosis, and patients with even mild heart failure may have increased aldosterone and cortisol levels in spite of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and -blocker therapy. Both dietary Na intake and aldosterone secretion have been linked to the pathogenesis of hypertension and related cardiovascular disease. A core issue in the pathophysiology of target organ damage is the relationship of salt to aldosterone. It is clear that elevated levels of aldosterone inappropriate for Na status (high salt intake) can induce cardiovascular hypertrophy and fibrosis in a variety of experimental animal models. However, during

Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models

The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low-renin and high-renin rat models of hypertension. The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage.

Aldosterone and cardiovascular disease

The renin-angiotensin-aldosterone system is a co-ordinated hormonal cascade of major importance in the control of fluid and electrolyte homeostasis and blood pressure. During the past decade, the scientific community has realized that this system is also of paramount importance in pathophysiology of cardiovascular and renal target organ damage. In particular, inappropriately elevated aldosterone levels in the face of body sodium expansion have been incriminated in cardiac and vascular inflammation and fibrosis leading to remodeling and disease. Substantial advances on the role and mechanisms of aldosterone-induced tissue damage and novel findings on the genetic control of aldosterone secretion have been reported during the past year, and these are the subjects of this brief review. A novel control mechanism for aldosterone secretion may be circadian clock genes, disruption of which leads to increased aldosterone secretion and hypertension. Animal models for human idiopathic hyperaldosteronism have been reported for the first time. Glucocorticoids have now been found to activate cardiac mineralocorticoid receptors during certain cardiovascular disease states. Crosstalk between mineralocorticoid and angiotensin AT1 receptors contributes to target organ damage. Endogenous cardiotonic steroids may explain at least some of the tissue damage during sodium loading previously attributed to aldosterone. Insights on aldosterone and cardiovascular disease gained during the past year provide new avenues for research and applications for treatment in the future.

PREVALENCE AND SIMULTANEOUS OCCURENCE OF MRI ASSESSED CARDIAC AND CEREBRAL TARGET ORGAN DAMAGE AND MICROALBUMINURIA: 7A.07

Objective: Target organ damage (TOD) contributes importantly to treatment decisions in patients with arterial hypertension. However, available evidence on the prevalence of multiple TOD is limited. We examined the prevalence and simultaneous occurrence of microalbuminuria (MA) and MRI assessed subclinical TOD of the heart and brain in patients with hypertension. Methods: Seventy-three patients with treated hypertension without known overt cardiovascular disease (41 women; 32 men; mean age ± sd, 44.5years ± 13.3; mean systolic blood pressure, 149.1 mmHg ± 23.9; mean diastolic blood pressure, 89.6 mmHg ± 13.1) were enrolled for the evaluation of subclinical TOD at our hypertension referral center. Patients underwent cardiac and cerebral MRI assessment in addition to standard evaluation including 24-h urine collection for MA. MA was used as a marker of renal TOD, increased left ventricular mass index (left ventricular hypertrophy -LVH- male >85.1 g/m2, female >66.9 g/m2) as marker for cardiac TOD, lacunar brain infarcts, periventricular and deep white matter hyperintensities (PWMH and DWMH) and brain-micro-bleeds (BMB) as markers for cerebral TOD. Results: In 49.3% of the patients TOD was observed. The prevalence of involvement of one, two or three organs was 38.8%, 9.0% and 1.5%, respectively. Microalbuminuria was present in 21.9% and LVH in 9.7% of the patients. Cerebral TOD was present in 30.1% of the patients defined as positive for at least one of following cerebral changes: PWMH (20.5%), SWMH (17.8%), lacunar brain infarcts (9.6%) and BMB (5.5%). The most frequent combinations were MA and cerebral TOD: 5.5% and LVH and cerebral TOD: 4.1%. Conclusions: This is the first time that clustering of MRI assessed TOD and MA are reported. Our results show that: (i) subclinical cerebral TOD is a frequently present phenotypic expression of hypertensive TOD; (ii) multiple target organ abnormalities were observed in approximately 10% of the patients, cerebral/renal and cerebral/cardiac being the most frequent combinations. Early recognition of patients developing organ damage with MRI should be further studied regarding treatment outcome since this may select a target population needing more intensive treatment.

Serum Uric Acid Levels and Renal Damage in Hyperuricemic Hypertensive Patients Treated With Renin-Angiotensin System Blockers

A correlation between hyperuricemia and renal target organ damage (TOD) was shown in hypertensive patients, locally mediated by the activation of renin-angiotensin system (RAS). We investigated whether high serum uric acid (UA) levels could negatively affect tubulointerstitial damage in hyperuricemic essential hypertensive patients with normal renal function, on treatment with RAS-blocking drugs. We studied 40 patients with World Health Organization stage I-II essential hypertension, 9 with high serum UA levels (hyperuricemic group) and 31 with normal serum UA levels (normouricemic group, either normouricemics, n = 15, or formerly hyperuricemics in chronic allopurinol treatment, n = 16). All patients were on RAS-blocking drugs (either angiotensin-converting enzyme inhibitors or angiotensin II receptors blockers). Evaluation of renal TOD included urinary albumin excretion (UAE), Doppler ultrasound renal resistive index (RRI) and renal volume-to-resistive index ratio (RV/RRI) measurements. Hyperuricemics had significantly higher RRI and lower RV/RRI values than normouricemics. Creatinine clearance and UAE were similar between groups. Linear regression analysis showed that RV/RRI values were inversely related to serum UA levels (r = -0.57, P < 0.01). The logistic regression analysis selected serum UA as an independent predictor of decreased RV/RRI (odds ratio 4.45, 95% CI 1.47-13.45, P = 0.01). In hyperuricemic hypertensives normal serum UA levels are associated with normal RV/RRI, integrated marker of tubulointerstitial damage and renal arteriolopathy, independently of RAS activation.

Secondary Hypertension and Essential Thrombocythaemia

A 26-year-old man visited the Outpatient Hypertension Unit, Department of Internal Medicine, University of Pisa, Italy, for uncontrolled hypertension under a two-drug antihypertensive treatment. He had been previously diagnosed with essential thrombocythaemia and had been prescribed aspirin (acetylsalicylic acid) 100 mg/day since he was 20 years old, with a stable platelet count of about 700 000–800 000. High blood pressure lasted 3 months and was treated with lisinopril 20 mg/day. One month before the visit he had an acute coronary syndrome, with normal coronary angiogram, and clopidogrel 75 mg/day and amlodipine 5 mg/day were added at discharge. At the Hypertension Unit, a bilateral renal artery stenosis was diagnosed, accompanied by cardiac and renal target organ damage. Moreover, a total occlusion of the right carotid artery was found. The patient underwent bilateral percutaneous renal angioplasty with stent placement. He was discharged with interferon-α-2b, aspirin and warfarin and with no antihypertensive therapy, having blood pressure values of 100/70 mmHg. A few months later he became hypertensive again and lisinopril 20 mg/day was prescribed, while platelet count was reduced to 500 000. Nine months later he died of a sudden death.

Pulse pressure and nocturnal fall in blood pressure are predictors of vascular, cardiac and renal target organ damage in hypertensive patients (LOD-RISK study)

To analyse the relationship between various parameters derived from ambulatory blood pressure monitoring (ABPM) and vascular, cardiac and renal target organ damage. A cross-sectional, descriptive study. It included 353 patients with short-term or recently diagnosed hypertension. ABPM, carotid intima-media thickness (IMT), Cornell voltage-duration product (Cornell VDP), glomerular filtration rate and albumin/creatinine ratio to assess vascular, cardiac and renal damage. Two hundred and twenty-three patients (63.2%) were males, aged 56.12+/-11.21 years. The nocturnal fall in blood pressure was 11.33+/-8.41, with a dipper pattern in 49.0% (173), nondipper in 30.3% (107), extreme dipper in 12.7% (45) and riser in 7.9% (28). The IMT was lower in the extreme dipper (0.716+/-0.096 mm) and better in the riser pattern (0.794+/-0.122 mm) (P<0.05). The Cornell VDP and albumin/creatinine ratio were higher in the riser pattern (1818.94+/-1798.63 mm/ms and 140.78+/-366.38 mg/g, respectively) than in the other patterns. In the multivariate analysis after adjusting for age, sex and antihypertensive treatment, with IMT as dependent variable the 24-h pulse pressure (beta = 0.003), with Cornell VDP the rest pulse pressure (beta = 12.04), and with the albumin/creatinine ratio the percentage of nocturnal fall in systolic blood pressure (beta = -3.59), the rest heart rate (beta = 1.83) and the standard deviation of 24-h systolic blood pressure (beta = 5.30) remain within the equation. The estimated pulse pressure with ABPM is a predictor of vascular and cardiac organ damage. The nocturnal fall and the standard deviation in 24-h systolic blood pressure measured with the ABPM is a predictor of renal damage.

Association of Arterial Hypertension With Renal Target Organ Damage in Kidney Transplant Recipients: The Predictive Role of Ambulatory Blood Pressure Monitoring

Although arterial hypertension is a powerful predictor of graft failure, only few studies have evaluated 24-hr blood pressure (BP) profile in renal transplant recipients (RTRs). We performed ambulatory blood pressure monitoring (ABPM) in 94 RTRs (65 men; age 28-71 years) with 1-year functioning grafts. Serum biochemical parameters, daily proteinuria, and transplantation-related data were evaluated in all subjects. ABPM showed that only 5% of RTRs were normotensives (BP<130/80 mm Hg) and identified 29% of patients with nocturnal hypertension. A strong, direct correlation was shown between each set of both systolic BP and diastolic BP measured by ABPM and serum creatinine, daily proteinuria, and serum triglycerides (P at least <0.025 for each). Serum creatinine immediately after transplantation and 1-yr asleep diastolic BP were the only significant predictors of 1-yr creatinine (P<0.0001; r=0.49), whereas awake systolic BP was the only predictor of daily proteinuria (r=0.39; P=0.005) by multiple regression analysis. BP assessed by ABPM proved to be a stronger predictor of renal graft damage than traditional immunologic factors. ABPM improved the diagnostic accuracy of arterial hypertension in RTRs and was the only effective tool in disclosing the association of BP with 1-year renal transplant outcome.

Seemingly healthy 71‐year‐old men with minor elevations of cardiac troponin I and at risk of premature death in CVD have elevated levels of NT‐proBNP: Report from the ULSAM study

Background. Hypersensitive cardiac troponin I (cTnI) assays detect even minor elevations of cTnI. Previous findings identifying a group of seemingly healthy elderly men with very minor elevations of cTnI have shown that these men were at risk of premature cardiovascular death. Objectives. To study the association between cTnI concentrations and cardiovascular risk factors and subclinical cardiac and renal target organ damage in a community‐based sample of elderly men. Methods. Biomarkers reflecting glucose and lipid metabolism, renal function, cardiac function and inflammation were measured in the ULSAM study (n = 1205, mean age 71 years). The participants were placed in three subgroups based on the cTnI concentrations: a low group with cTnI <0.02 µg/L, an intermediate group with cTnI between 0.02 and 0.039 µg/L and a high group with cTnI >0.039 µg/L. Results. In the entire cohort of 71‐year‐old men, most markers of glucose and lipid metabolism, renal function, inflammation and NT‐proBNP were significantly related to the concentrations of cTnI, and most obviously in the high‐cTnI group. In subjects with no signs of CVD (cardiovascular disease), only levels of NT‐proBNP related to cTnI, and with the highest NT‐proBNP levels in the high‐cTnI group (p<0.01). A multiple regression analysis showed that NT‐proBNP was independently related to cTnI (p<0.001). Conclusions. Measurement of cardiac troponins with highly sensitive assays identifies those at risk of premature CVD death who have hitherto remained unrecognized. The associated elevations of NT‐proBNP in these participants support the fact that these elevations reflect ongoing pathological processes in the myocardium.

Relationship between renal resistive index and early target organ damage in patients with never treated essential hypertension

The aim of our study was to evaluate renal resistive index (RI) value in never treated hypertensive patients in relation to ambulatory blood pressure measurement (ABPM) values and early target organ damage. The study included 318 subjects: 223 patients with never treated essential hypertension (mean age 37.1 years) and 95 normotensive healthy subjects (mean age 37.9 years). ABPM, echocardiography and carotid and renal arteries duplex color Doppler examinations were performed. RI values in patients with never treated essential hypertension were no different from the normotensive control group (0.59 ± 0.05 vs 0.59 ± 0.05; NS). In the untreated patients RI correlated significantly with 24‐h pulse pressure (r=0.234; p<0.01) and ambulatory arterial stiffness index (AASI) values (r=0.274; p<0.001), intima‐media thickness (IMT) (r=0.249; p<0.001), E′/A′ (rho= −0.279; p<0.001) and relative wall thickness (RWT; r=0.185; p<0.01). In the multivariate stepwise analysis, RI values correlated independently with carotid IMT (β=0.272; p=0.020) and 24‐h AASI values (β=0.305; p=0.009). In normotensive healthy controls, significant independent correlation between RI and carotid IMT and 24‐h AASI values were also found. Our study may indicate limited value of RI in differentiating patients with uncomplicated hypertension with healthy controls. Renal resistive values were independently correlated with carotid IMT and AASI. These may suggest that renal vascular resistance is related to two markers for cardiovascular events both in the hypertensive and normotensive subjects.

The effects of nocturnal dipping on cardiovascular outcomes and proteinuria in essential hypertensive patients

Abstract Individuals who do not have a 10% to 20% reduction in blood pressure (BP) during the night are known as ‘nondippers’. Non-dipping patterns in hypertensive patients have been shown to be associated with an excess of target organ damage and other adverse outcomes. The present study was designed to investigate the relationship between nocturnal BP pattern, defined on the basis of the ambulatory blood pressure monitoring (ABPM) recording, and cardiac and renal target organ damage in a population of at least one year treated essential hypertensive subjects. The present analysis involved 123 patients with treated essential hypertension attending the outpatient clinic of our centre. Each patient was subjected to the following procedures: blood sampling for routine blood chemistry, spot urine for proteinuria, 24-hour periods of ABPM, and echocardiography. In the ABPM period, a dipping pattern was observed in 65 of the 123 patients, and a non-dipping pattern in 58 patients. Body mass index was higher in the non-dippers (26 ± 4 versus 28 ± 4, p&lt;0.05). The proteinuria in spot urine was significantly higher in the non-dippers (10 ± 6 versus 24 ± 48, p&lt;0.03). Left ventricular mass, interventricular septum thickness, posterior wall thickness and left ventricular systolic diameter were significantly higher in the non-dippers compared to the dippers. Left ventricular diastolic function was similar in non-dipper cases, except E-wave deceleration time. In treated essential hypertensives the blunted or absent nocturnal fall in blood pressure can be a strong predictor of cardiac and renal events. Hypertensive patients should be evaluated by ambulatory blood pressure monitoring. To prevent patients at risk for morbidity and mortality casualities as a result of hypertension, patients should be evaluated by ambulatory blood pressure monitoring. This method can be utilized for exacting future follow-ups with the patient.

Vasopeptidase Inhibition Prevents Target Organ Damage and Improves Survival in Spontaneously Hypertensive Rats

Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension. One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107+/-54 microg/mg), which was significantly reduced by ramipril to 57+/-34 microg/mg, and practically abolished in the AVE7688 group (22+/-12 microg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%). Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival. At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.

NO‐independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy

1. Chronic renal disease is associated with oxidative stress, reduced nitric oxide (NO) availability and soluble guanylate cyclase (sGC) dysfunction. Recently, we discovered BAY 58-2667, a compound activating heme-deficient or oxidized sGC in a NO-independent manner. 2. We assessed potential of BAY 58-2667 in preventing cardiac and renal target organ damage in rats with 5/6 nephrectomy. 3. Male Wistar rats were allocated to three groups: 5/6 nephrectomy, 5/6 nephrectomy treated with BAY 58-2667 and sham operation. Study period was 18 weeks: blood pressure and creatinine clearance were assessed repeatedly. At study end blood samples were taken and hearts and kidneys harvested for histological studies. 4. BAY 58-2667 markedly lowered blood pressure in animals with 5/6 nephrectomy (untreated versus treated animals: 189+/-14 versus 146+/-11 mmHg, P<0.001). Left ventricular weight, cardiac myocyte diameter as well as cardiac arterial wall thickness significantly decreased in comparison to untreated animals with 5/6 nephrectomy. Natriuretic peptide plasma levels were also improved by BAY 58-2667. Kidney function and morphology as assessed by creatinine clearance, glomerulosclerosis, interstitial and perivascular fibrosis of intrarenal arteries were likewise significantly improved by BAY 58-2667. 5. This is the first study showing that BAY 58-2667 effectively lowers blood pressure, reduces left ventricular hypertrophy and slows renal disease progression in rats with 5/6 nephrectomy by targeting mainly oxidized sGC. Therefore, BAY 58-2667 represents a novel pharmacological principle with potential clinical value in treatment of chronic renal disease.