Martin Ritt

Increased Wall:Lumen Ratio of Retinal Arterioles in Male Patients With a History of a Cerebrovascular Event

Arterial hypertension is a major risk factor for stroke, and retinal vessels can be regarded as a mirror of the cerebral vasculature. Whether vascular remodeling of retinal arterioles with ageing and hypertension plays a role in cerebrovascular risk stratification has not yet been adequately addressed. In study 1, retinal arteriolar structure was assessed in 182 normotensive volunteers and 117 patients with essential hypertension. In study 2, we compared retinal arteriolar structure among 74 normotensive volunteers, 47 patients with treated essential hypertension, and 18 subjects with a history of a cerebrovascular event. Retinal arteriolar structure was assessed using scanning laser Doppler flowmetry and automatic full-field perfusion imaging analysis. In study 1, wall:lumen ratio of retinal arterioles revealed a significant correlation with age (r=0.198; P=0.001). In study 2, wall:lumen ratio was highest in patients with a history of a cerebrovascular event compared with treated hypertensive and normotensive subjects (0.46±0.08, 0.36±0.14, and 0.35±0.12; P=0.007). When the treated group with hypertension was divided into 2 subgroups according to the quality of blood pressure control, patients with poor blood pressure control showed higher wall:lumen ratio than subjects with good blood pressure control (0.40±0.13 versus 0.31±0.13; P=0.025). Thus, assessment of wall:lumen ratio of retinal arterioles emerged as an attractive tool to identify treated patients with hypertension with increased cerebrovascular risk.

Analysis of retinal arteriolar structure in never-treated patients with essential hypertension.

Objective Increased wall-to-lumen ratio of small arteries is a predictor of adverse cardiovascular prognosis. We aimed to analyze retinal arteriolar structure in never-treated patients with essential hypertension and to test whether elevated blood pressure is associated with an increased wall-to-lumen ratio of retinal arterioles. Methods The study cohort comprised 21 untreated male patients with essential hypertension (mean age 39.1 ± 5.4 years) and 29 untreated normotensive men (mean age 36.7 ± 5.9 years). Wall-to-lumen ratio of retinal arterioles was assessed in vivo using scanning laser Doppler flowmetry. Results Patients with essential hypertension had a higher wall-to-lumen ratio of retinal arterioles than normotensive individuals (0.36 ± 0.1 vs. 0.28 ± 0.1, P = 0.028). Wall cross-sectional area of retinal arterioles did not differ between the study groups. The growth index, indicating the percentage of difference in average wall cross-sectional area of retinal arterioles between both groups, was 18%. Both systolic (r = 0.360, P = 0.010) and diastolic (r = 0.536, P < 0.001) blood pressures were related to wall-to-lumen ratio of retinal arterioles. Multiple regression analysis including a variety of known cardiovascular risk factors revealed that blood pressure is independently associated with an increased wall-to-lumen ratio of retinal arterioles (systolic blood pressure: β = 0.417, P = 0.012; diastolic blood pressure: β = 0.548, P = 0.001). Conclusion The changes in arteriolar structure of retinal vessels in our study cohort revealed a similar pattern to that observed previously by other investigators in subcutaneous small arteries in essential hypertension. Blood pressure emerged as an important and independent determinant of wall-to-lumen ratio of retinal arterioles.

Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome

BACKGROUND Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL. METHODS Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner. RESULTS Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025). CONCLUSIONS Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.

Wall-to-lumen ratio of retinal arterioles and arteriole-to-venule ratio of retinal vessels in patients with cerebrovascular damage.

PURPOSE There is evidence that generalized retinal arteriolar narrowing, which can be measured by the arteriole-to-venule ratio (AVR) of retinal vessels, predicts cerebrovascular events. The wall-to-lumen ratio (WLR) and wall cross-sectional area (WCSA) of retinal arterioles reflect structural arteriolar parameters. The primary objective was to test the association between WLR and AVR in a distinct cohort of patients with cerebrovascular damage. METHODS In this cross-sectional study, 23 patients (57.5 +/- 9.4 years) with acute transitory ischemic attack or lacunar cerebral infarct were compared with two age-matched control groups: 83 subjects with essential hypertension (53.7 +/- 5.5 years) and 16 normotensive subjects (52.2 +/- 8.3 years). Retinal arteriolar parameters (WLR, WTH, and WCSA) were assessed in vivo with scanning laser Doppler flowmetry (SLDF). AVR and a qualitative evaluation of retinal vessels were obtained from digital retinal color photographs. The intima-media thickness (IMT) of the carotid artery was measured. RESULTS WLR (0.44 +/- 0.1 vs. 0.34 +/- 0.1 vs. 0.30 +/- 0.1, P < 0.001) and carotid IMT (P < 0.05) were significantly greater in the cerebrovascular event group compared with normotensive subjects. WLR and WCSA were significantly higher in the cerebrovascular event group compared with subjects with mild arterial hypertension. AVR was similar in all three study groups (0.75 +/- 0.07 vs. 0.74 +/- 0.07 vs. 0.78 +/- 0.1, P = 0.18). CONCLUSIONS The increase in WLR and WCSA of retinal arterioles, as well as in IMT in patients with cerebrovascular damage suggests vascular hypertrophy in the microvascular and macrovascular bed. The lack of association between AVR of retinal vessels and WLR of retinal arterioles may point to different stages of cerebrovascular disease and/or different pathophysiological changes in the arteriolar wall.

New software analyses increase the reliability of measurements of retinal arterioles morphology by scanning laser Doppler flowmetry in humans.

Objective The investigation of the retinal arterioles offers the unique opportunity to analyze in vivo arteriolar remodeling in arterial hypertension in humans. We analyzed the reliability of assessing retinal arteriolar morphology with our new version of the software analyses for scanning laser Doppler flowmetry. Method In the test–retest reliability study, 10 eyes of 10 healthy persons were measured during 5 days under routine laboratory conditions with the Heidelberg Retinal Flowmetry. In a second study, interobserver and intraobserver reliability was analyzed from retinal images of 18 patients with three types of arterial hypertension by three readers and the most experienced reader analyzed all images twice on two different days. Images were analyzed by the old and the newly developed software versions. To characterize the reliability, the coefficients of variation were calculated. Results The test–retest study analyzed with the new program showed that the variation coefficients of vessel and lumen diameter, wall thickness, wall/lumen ratio and new calculated parameter: lumen/vessel diameter ratio of retinal arterioles were significantly less than 10%, with the exception of the wall cross-sectional area (12.5%). The interobserver and intraobserver reliability showed in nearly all circumstances coefficients of variations of less than 10% and did not differ across various readers and patient groups. Conclusion The new software ‘SLDF version 4.0’ clearly improved the reliability of assessing the structural parameters of the retinal arterioles. The application delivers reliable measurements of the retinal arteriolar structure in vivo in humans.

Wall-to-lumen ratio of retinal arterioles as a tool to assess vascular changes.

The retina offers a beautiful and unique opportunity to visualize and examine the body’s microvasculature safely, repeatedly, quickly, and noninvasively in vivo. Retinal arterioles appear to undergo similar changes as cerebral and peripheral arterioles in hypertension, indicating that retinal arteriolar abnormalities mirror structural and functional microvascular changes elsewhere in end-organ tissues.1–4 Since the pioneering work by Keith et al5 in 1939, several studies have confirmed the prognostic significance of retinal vascular abnormalities on mortality attributed to a cardiovascular cause.5–7 However, although there is solid evidence for the prognostic significance of advanced retinopathy, the evidence of a prognostic impact of early retinal vascular abnormalities on cardiovascular risk stratification is less well established.1,8 It was suggested that methodological issues might be the cause for the lack of a solid evidence that early retinal vascular abnormalities are closely linked to cardiovascular risk.1,9 Therefore, much research effort over the last decade has focused on the development of new methodological approaches to enable more precise and reliable detection and evaluation of early retinal vascular abnormalities in hypertensive patients. A new approach focuses on retinal arteriolar structural parameters by using scanning laser Doppler flowmetry (SLDF) with automatic full-field perfusion imaging analyses (AFFPIAs).2,10 This approach allows the assessment of both the outer diameter (OD) and inner diameter (ID) of retinal arterioles in vivo and, thus, analyzes vascular remodeling of retinal arterioles by calculating wall:lumen ratio, wall thickness, and wall cross-sectional area (volume of wall per unit of length) of retinal arterioles. These methods do not need to determine diameter of retinal venules, which are also subject to changes in cardiovascular disease. This review introduces and describes this new methodology, explains the improved power of measuring retinal vascular changes, and discusses our recent findings using this tool. The idea of assessing the …

Wall-to-lumen ratio of retinal arterioles is related with urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine.

Objective We hypothesized that wall-to-lumen ratio (WLR) of retinal arterioles might serve as an in-vivo parameter of vascular damage. To test this hypothesis we examined whether WLR of retinal arterioles is related with increased urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA). Methods Thirty-nine never-treated male patients aged 18–65 years with a body mass index at least 25 kg/m2 and without diabetes mellitus or secondary or stage 3 arterial hypertension were examined. WLR of retinal arterioles was assessed using scanning laser Doppler flowmetry. Urinary albumin-to-creatinine ratio (UACR) was measured from first morning spot urine. Vascular reactivity was measured by the change of aortic augmentation index (aAIx) to infusion of L-NMMA. Results UACR was related with WLR of retinal arterioles (r = 0.352, P = 0.032). In response to L-NMMA infusion aAIx increased (from 10.7 ± 11 to 19.7 ± 11%, P < 0.001). The change of aAIx to L-NMMA infusion was inversely related with WLR of retinal arterioles (r = −0.462, P = 0.003) even after adjustment for changes of hemodynamic parameters to L-NMMA infusion (partial r = −0.475, P = 0.005). The relationships of UACR and the change of aAIx to L-NMMA infusion with WLR of retinal arterioles were found to be independently of other cardiovascular risk factors (ß = 0.386, P = 0.006; ß = −0.369, P = 0.004, respectively) in multiple regression analyses with separate models for both parameters. Conclusion Increased WLR of retinal arterioles may thus serve as an in-vivo marker of vascular damage.

Renal Vascular Endothelial Function in Hypertensive Patients With Type 2 Diabetes Mellitus

BACKGROUND Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. STUDY DESIGN Prospective observational-study during a mean follow-up of 2.1 years. SETTING & PARTICIPANTS 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. PREDICTOR Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. OUTCOMES & MEASUREMENTS Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. RESULTS 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). LIMITATIONS Patients were treated according to the discretion of the individual primary care physician. CONCLUSIONS During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.

Gender is related to alterations of renal endothelial function in type 2 diabetes

BACKGROUND Gender has been shown to affect endothelial function of the forearm circulation in patients with type 2 diabetes, but data on the renal circulation are lacking. We hypothesized that renal vascular nitric oxide (NO) availability is higher, and oxidative stress lower, in female compared to male patients with type 2 diabetes. METHODS In 41 male and 39 female patients with type 2 diabetes, renal plasma flow (RPF) was determined by constant infusion input clearance at baseline and following infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4.25 mg/kg) to assess basal renal vascular NO availability. After a subsequent infusion of L-arginine (100 mg/kg) to restore baseline conditions, vitamin C (45 mg/kg) was co-infused to determine levels of oxidative stress in the renal circulation. RESULTS Baseline renal haemodynamics were similar between genders. L-NMMA-induced renal vasoconstriction was more pronounced in females compared to males (-89 +/- 69 versus -60 +/- 52 ml/min/1.73 m(2), P = 0.03). After administration of L-arginine to restore baseline perfusion, the co-infusion of vitamin C led to a lesser increase of RPF in females than in males (+37 +/- 86 versus +60 +/- 52 ml/min/1.73 m(2), P = 0.05). CONCLUSIONS Our data demonstrate that NO availability in the renal circulation is greater in female than in male patients with type 2 diabetes that is associated with reduced levels of oxidative stress in females. The role of this gender-related difference in renal endothelial function for the initiation and progression of diabetic nephropathy should be addressed in future studies.

Analysis of Rockwood et al’s Clinical Frailty Scale and Fried et al’s frailty phenotype as predictors of mortality and other clinical outcomes in older patients who were admitted to a geriatric ward

OBJECTIVES There are few data regarding the accuracy of short frailty tools as predictors of mortality and other clinical outcomes of older patients admitted to a geriatric ward. We therefore analyzed the accuracy of Rockwood et als Clinical Frailty Scale and an easy and quick to perform operationalization of Fried et als frailty phenotype, as predictors of mortality and other clinical outcomes in our cohort of patients. DESIGN Prospective analysis with a follow-up period of 6 months. SETTING AND PARTICIPANTS 307 patients who were 65 years of age or older were included in the study. The patients were assessed in terms of the two frailty measures during their stay in a geriatric ward. RESULTS The Clinical Frailty Scale and the frailty phenotype were both suitable for differentiating between patients who died due to any cause from those who survived during follow-up (primary outcome) (area under the ROC curves (AUC) values 0.867 (95% CI 0.807-0.926), p<0.001 and 0.754 (95% CI 0.688-0.821), p<0.001, respectively). Regarding the secondary outcomes: 1. unplanned admission to hospital and 2. a fall during follow-up, the Clinical Frailty Scale discriminated or tended to discriminate between patients to whom these criteria applied and those to whom they did not (AUC=0.569 (95% CI 0.502-0.636), p=0.046 and AUC=0.574 (95% CI 0.501-0.647), p=0.071, respectively). The frailty phenotype did not show such a differentiation when applied to secondary outcomes (AUC=0.500 (95% CI 0.432-0.568), p=0.994 and AUC=0.518 (95% CI 0.439-0.598), p=0.658, respectively). CONCLUSIONS Both short frailty instruments are suitable predictors of mortality in older patients who were admitted to a geriatric ward. The Clinical Frailty Scale, but not the frailty phenotype, predicted at least some of the secondary outcomes, i.e., the outcome unplanned admission to hospital during follow-up.