A Pilot Evaluation of the Long-term Effect of Combined Therapy With Intravenous Iron Sucrose and Erythropoietin in Elderly Patients With Advanced Chronic Heart Failure and Cardio-Renal Anemia Syndrome: Influence on Neurohormonal Activation and Clinical Outcomes

BackgroundThe prognosis in elderly patients with advanced chronic heart failure (CHF) and cardio-renal anemia syndrome (CRAS) is ominous, and treatment alternatives in this subset of patients are scarce.Methods and ResultsTo assess the long-term influence of combined therapy with intravenous (IV) iron and erythropoietin (rHuEPO) on hemoglobin (Hb), natriuretic peptides (NT-proBNP), and clinical outcomes in elderly patients with advanced CHF and mild-to-moderate renal dysfunction and anemia (CRAS) who are not candidates for other treatment alternatives, 487 consecutive patients were evaluated. Of them, 65 fulfilling criteria for entering the study were divided into 2 groups and treated in an open-label, nonrandomized fashion: intervention group (27, combined anemia therapy) and control group (38, no treatment for anemia). At baseline, mean age was 74 ± 8 years, left ventricular ejection fraction was 34.5 ± 14.1, Hb was 10.9 ± 0.9 g/dL, creatinine was 1.5 ± 0.5 mg/dL, NT-proBNP was 4256 ± 4952 pg/mL, and 100% were in persistent New York Heart Association (NYHA) Class III or IV. At follow-up (15.3 ± 8.6 months), patients in the intervention group had higher levels of hemoglobin (13.5 ± 1.5 vs. 11.3 ± 1.1; P < .0001), lower levels of natural log of NT-proBNP (7.3 ± 0.8 vs. 8.0 ± 1.3, P = .016), better NYHA functional class (2.0 ± 0.6 vs. 3.3 ± 0.5; P < .001), and lower readmission rate (25.9% vs. 76.3%; P < .001). In the multivariate Cox proportional hazards model, combined therapy was associated with a reduction of the combined end point all-cause mortality or cardiovascular hospitalization (HR 95%CI 0.2 [0.1-0.6]; P < .001).ConclusionLong-term combined therapy with IV iron and rHuEPO may increase Hb, reduce NT-proBNP, and improve functional capacity and cardiovascular hospitalization in elderly patients with advanced CHF and CRAS with mild to moderate renal dysfunction.     

Effects of epalrestat,an aldose reductase inhibitor,on diabetic peripheral neuropathy in patients with type 2 diabetes,in relation to suppression of Nɛ-carboxymethyl lysine

ObjectiveWe investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes.MethodsA total of 38 type 2 diabetic patients (22 men and 16 women; mean±S.E.M. age 63.3±1.0 years; duration of diabetes 9.6±0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N^?-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean±S.E.M. duration of diabetes 8.2±0.7 years) as control (C group).ResultsThe EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (?0.18±0.13 mU/ml in the EP group vs. +0.22±0.09 mU/ml in the C group, P<.05) after 1 year.ConclusionsEpalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.     

Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy

PurposeDiabetic cardiac neuropathy, which is characterized by reduced heart rate variability (HRV), frequently coexists with peripheral neuropathy. Gabapentin has been used for the treatment of diabetic neuropathy. We aimed to evaluate the possible effect of gabapentin treatment on autonomic function in patients with type 2 diabetes via HRV.MethodsThirty patients with type 2 diabetes mellitus and peripheral neuropathy and 28 age- and sex-matched healthy controls were consecutively registered. Each patient underwent HRV measurements, and diabetic patients were administered gabapentin. After 3 months of gabapentin therapy, HRV parameters were measured again.ResultsBaseline HRV parameters were blunted in patients with diabetes mellitus according to the controls [standard deviation of all NN intervals (SDNN, ms): 106.3±29.9 vs. 148.8±36.5, P=.001; power spectrum of the high-frequency band (HF, ms²): 133.6±98.3 to 231.4±197.6, P=.02; power spectrum of the low-frequency band (LF, ms²): 341.8±247.8 to 511.5±409.4, P=.048; LF/HF ratio: 3.3±2.4 to 2.6±1.5, P=.33]. After 3 months of treatment with gabapentin, some HRV parameters showed some improvement. SDNN (106.2±29.8 to 119.4 ± 25, P=.016) and HF (133.6±98.3 to 167.6±118.3, P=.021) increased significantly. LF/HF ratio decreased (from 3.3±2.4 to 2.3±1.9, P=.039) and LF remained unchanged (341.8±247.8 to 352.3±228.9, P=.88).ConclusionsTherapeutic doses of gabapentin not only alleviate neuropathic symptoms but also improve cardiac autonomic function in diabetic patients with peripheral neuropathy.     

Modified orthostatic load for spectral analysis of short-term heart rate variability improves the sensitivity of autonomic dysfunction assessment

AimTo evaluate the impact of orthostatic load for sensitivity of short-term spectral analysis of heart rate variability (HRV) assessment of potential early autonomic dysfunction in diabetes mellitus.MethodsComparison of results of short-term time- and frequency-domain analysis of HRV during single positions and during modified orthostatic load (supine 1–standing–supine 2, each position 300 s) in diabetic subjects with good glycemic control (n=80, age 38±14, diabetes duration 16±10 years) and without autonomic neuropathy as assessed by a standard bedside reflex test battery, and in nondiabetic controls (n=150, age 40±13 years).ResultsNone of the short-term frequency-domain parameters [absolute and logarithmic (LN) values of spectral powers in total- (TF), low- (LF), and high-frequency (HF) bands and its centroid frequencies] as obtained in single positions “supine” or “standing” revealed a significant difference between well-controlled patients and healthy controls (P>.3). However, during modified orthostatic load, significant differences in ΔLN TF_{(supine 1–supine 2)} and in ΔLN LF_{(supine 1–supine 2)} as well as in ΔLN LF_{(standing–supine 2)} values between diabetic and healthy subjects were recorded [?0.2±0.5 vs. ?0.1±0.4 LN (ms²), P=.05; ?0.3±0.8 vs. 0.1±0.7 LN (ms²), P=.001 and 0.2±1.0 vs. 0.4±0.9 LN (ms²), P=.05, respectively] with insignificant intergroup differences in related centroid frequencies. This finding suggests a delayed recovery of LF spectral power in diabetic subjects after orthostatic challenge.ConclusionsWhen compared with single position measurements, the modified orthostatic load protocol improves the sensitivity of short-term HRV examination. In well-controlled diabetic subjects without cardiovascular autonomic neuropathy (as excluded by standard cardiovascular reflex testing), the delayed recovery of LF band spectral power after orthostatic load with standing up indicates diminished parasympathetic activation.     

Anemia in diabetic patients at an internal medicine ward: Clinical correlates and prognostic significance

BackgroundCharacteristics and prognostic significance of anemia in hospitalized diabetic patients are unknown.MethodsWe studied 3145 unselected patients admitted to two Internal Medicine Departments, 872 (27.7%) of whom were diabetic. Forty diabetic patients died during the first hospitalization period. Out of the remaining 832 patients, 334 (40.2%) were anemic and evaluated for survival. In 87 diabetic patients, the cause of anemia was evident on admission, whereas the other 247 had to be further investigated for etiology of anemia.ResultsCompared to non-anemic diabetic patients, the diabetic anemic patients were older (mean age 71.4 vs. 64.4 years, P < .001) and predominantly females (52.4% vs. 44.4%, P < .02). Of the 247 evaluated patients, 38% were deficient in iron, 12% in vitamin B₁₂ and/or folate, 54% had anemia of chronic disease, 47% suffered from heart failure, 39% had renal dysfunction and 22% were complex nursing care patients and/or had diabetic foot. On median follow-up of 19.2 months, mortality rate was higher in anemic compared to non-anemic diabetic patients (17.3% vs. 4%, P < .001), the main cause of death being infection. Male sex (P = .03), albuminuria (P = .01) and heart failure (P = .06) were associated with shorter survival, male sex being the most significant (OR 2.02, 95% CI 1.04 ? 4.00).ConclusionFrequency of anemia was increased in diabetic patients admitted to the Internal Medicine Departments, compared to the studies performed on ambulatory patient populations. Anemia was multifactorial and associated with higher mortality, predominantly from infections. Males with albuminuria and heart failure were at higher risk of death.     

Day and night variation in ambulatory blood pressure in type 1 diabetes mellitus with nephropathy and autonomic neuropathy

Abstract. The objective was to study ambulatory blood pressure and heart rate variability between day and night in patients with type 1 (insulin-dependent) diabetes mellitus with different degrees of diabetic nephropathy, and to evaluate the influence of autonomic neuropathy and type of antihypertensive treatment. Twenty type 1 diabetic patients with diabetic nephropathy and antihypertensive treatment were studied with 24-h ambulatory blood pressure monitoring using an oscillometric method. They were compared with eight insulin-treated diabetic patients with short duration of diabetes (1–5 years) and with 10 apparently healthy subjects. The degree of autonomic neuropathy was evaluated by measuring the RR-interval during deep breathing and uprising. The 24-h blood pressure was generally higher in patients with diabetic nephropathy compared to those other two groups. These patients also had a lower ratio between day and night in diastolic blood pressure compared to the control subjects (1.15 ± 0.12 vs. 1.25 ± 0.76, P < 0.05) and heart rate compared to the diabetic patients without nephropathy, as well as the control subjects (1.15 ± 0.08 vs. 1.26 ± 0.09 vs. 1.27 ± 0.08, P < 0.01, respectively). All patients with diabetic nephropathy had clinical signs of autonomic neuropathy as judged by RR-interval measurements during deep breathing and uprising.     

Sensitive detection of hemodynamic failure during orthostatic stress in patients with diabetic polyneuropathy using a mini laser Doppler blood flowmeter

Autonomic dysfunction in diabetes is serious but often underestimated. The purpose of this study was to evaluate hemodynamics within the important initial phase just after standing, which cannot be evaluated by conventional instruments for orthostatic hypotension. Earlobe blood flow (EBF), which indirectly reflects the blood pressure response on standing, was evaluated using a mini laser Doppler flowmeter during standing from the sitting position in 58 healthy controls and 56 diabetic patients categorized as without (11), mild (27), and advanced diabetic polyneuropathy (18). The response area of the EBF waveform within 30 seconds after standing was calculated. An increased response area indicates poor recovery of EBF. Response area increased significantly with the degree of neuropathy (P < .001 for linear trend). Orthostatic hypotension was detected in two patients in the mild neuropathy group. The present approach may be sensitive and practical for detecting autonomic dysfunction not detected with the conventional orthostatic test.     

Comparison of percutaneous coronary intervention in native coronary arteries vs. bypass grafts in patients with prior coronary artery bypass graft surgery

ObjectiveTo compare the procedural and clinical outcomes of prior coronary artery bypass graft surgery (CABG) patients undergoing percutaneous coronary intervention (PCI) in native arteries vs. bypass grafts.MethodsThe medical and catheterization records and the angiograms of 142 consecutive prior CABG patients who underwent 165 PCI of 247 lesions at our institution between January 1, 2003, and December 31, 2006, were retrospectively reviewed.ResultsMean age was 66±10 years and 99% were men: 79 and 63 patients underwent native coronary or bypass graft PCI, respectively. Compared to patients undergoing bypass graft PCI, those undergoing native coronary artery PCI were younger (mean age 64±10 vs. 68±10 years, P=.008), more likely to present with stable angina (29% vs. 8%, P=<.001), and presented earlier after CABG (after a mean of 9±6 vs. 12±5 years, P<.01). Compared to bypass graft PCI, native coronary PCI was more likely to be performed with drug-eluting stents (88% vs. 57%, P<.001) and was associated with lower risk of no-reflow (3% vs. 24%, P<.001). After a mean follow-up of 2.5±1.1 years, both groups of patients had similar but high incidence of myocardial infarction, repeat PCI, and death.ConclusionsPrior CABG patients undergoing native coronary artery PCI have lower procedural risk, but similar postprocedural clinical outcomes compared to patients undergoing bypass graft PCI. If feasible, native coronary arteries may be the preferred PCI target in prior CABG patients.     

Mortality after major amputation in diabetic patients with critical limb ischemia who did and did not undergo previous peripheral revascularization: Data of a cohort study of 564 consecutive diabetic patients

BackgroundTo evaluate the survival after major lower limb amputation, at a level either below (BKA) or above (AKA) the knee, in diabetic patients admitted to hospital because of critical limb ischemia (CLI).MethodsFrom January 1999 to December 2003, 564 diabetic patients were consecutively admitted to our Foot Center because of CLI and followed up until December 2005. A revascularization procedure was performed in 537 patients (95.2%): in 420 with peripheral angioplasty, in 117 with peripheral bypass graft. Neither endoluminal nor surgical revascularization was practicable in 27 (4.8%) patients.ResultsMajor amputation was performed in a total of 55 (9.8%) patients. Among the clinical and demographic variables evaluated, age was significantly lower (67.3±10.1 vs. 76.7±10.4, P<.001), duration of diabetes was higher (17.1±11.1 vs. 13.4±10.0, P=.013), and current smoking was more frequent (38.5% vs. 25.0%, P<.001) in revascularized amputees. The amputation free median time for revascularized patients was 5.11 months, and for nonrevascularized patients, 0.33 months. The log-rank test for equality of survivor function without amputation between amputees with or without revascularization was 31.76 (P<.001).Among the 55 amputees, 11 (28.2%) out of the 39 revascularized patients and 13 (81.2%) out of the 16 nonrevascularized patients died. The log-rank test for equality of survivor function was 6.83 (P=.009).The Cox model performed to evaluate the association between the recorded variables and the mortality showed a significant hazard ratio only with age (hazard ratio for 1 year 1.11, P=.003, confidence interval 1.04–1.19).ConclusionsOur data suggest that the revascularization allows to postpone the major amputation, and that the survival of revascularized amputees is better than that of nonrevascularized amputated patients. All these data offer further encouragement to revascularize all diabetic patients with CLI.     

Effect of cardiovascular autonomic neuropathy (CAN) on left ventricular function in normotensive type 1 diabetic patients: A study by pulsed wave tissue Doppler echocardiography

Background and aimPatients with diabetes mellitus are at increased risk for cardiovascular diseases. Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, as it can contribute in the pathogenesis of diabetic cardiomyopathy (DCM) and has been weakly linked with left ventricular diastolic dysfunction. Our aim was to investigate the effect of presence or absence of cardiovascular autonomic neuropathy (CAN) on systolic and diastolic LV function in normotensive type 1 diabetic patients by using both conventional and tissue Doppler echocardiography.Subjects and methodsFifty two type 1 diabetic patients entered this study. They were divided into two groups. The first group included 24 patients with evidence of cardiovascular autonomic neuropathy. The second group included 28 patients without evidence of cardiovascular autonomic neuropathy. In addition to 18 healthy normal weights non diabetic subjects as a control group. Complete clinical examination, routine laboratory investigations, lipid profile, urinary albumin excretion, HbA1c and 12 leads ECG were done to all participants. Conventional and tissue Doppler indices of systolic and diastolic left ventricular function were recorded.ResultsHeart rate was significantly higher in diabetic patients with CAN compared to both diabetic patients without CAN and normal control subjects (P < 0.001, <0.001, respectively). Glycemic control as assessed by HbA1c was more worse in diabetic patients with CAN compare to diabetic patients without CAN (P < 0.001). As regard conventional echo-Doppler, there were a significant difference in A wave velocity and E/A ratio in diabetic patients with or without CAN compared to control (P < 0.001, <0.001, <0.001, <0.001, respectively). Tissue Doppler indices show a significant difference at the lateral annular side in Em and Am velocity and Em/Am ratio in diabetic patients with or without CAN vs. control (P < 0.001, <0.001, <0.001, <0.05, <0.05, <0.01, respectively) and also, between diabetic patients with CAN vs. diabetic patients without CAN (P < 0.001, <0.05, <0.01, respectively). Also, tissue Doppler indices show a significant difference at the septal annular side in Em and Am velocity and Em/Am ratio in diabetic patients with or without CAN vs. control (P < 0.001, <0.001, <0.001, <0.01, <0.05, <0.05, respectively) and also, between diabetic patients with CAN vs. diabetic patients without CAN (P < 0.001, <0.05, <0.01, respectively). Contrary to that, no significant differences were found in LV systolic function parameters measured by either conventional or tissue Doppler imaging among the three groups.ConclusionOur results demonstrated that, LV diastolic function was impaired in normotensive type 1 diabetic patients and, the presence of CAN is associated with more deterioration in diastolic function. Systolic function is seems to be unaffected. TDI should be the preferred modality in evaluation of LV function as it can detect minimal changes in diastolic function much earlier than conventional echo-Doppler.     

Relationship between Pancreas Exocrine Insufficiency and Cardiac Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus

BackgroundThe exocrine function of the pancreas is controlled by the autonomic nervous system (ANS), and autonomic neuropathy is a common and serious complication of diabetes. There are many factors contributing to the development of autonomic neuropathy in diabetic patients. Cardiovascular tests have been developed to evaluate the function of the ANS. This study investigated the relationship between cardiovascular autonomic neuropathy (CAN) and pancreas exocrine insufficiency (PEI) in diabetic patients.Methods This study evaluated 110 individuals with type 2 diabetes mellitus (T2DM) and 40 healthy volunteers. Autonomous neuropathy tests were utilized to diagnose patients, and Ewing and Clarke’s criteria were employed to assess the severity of autonomous dysfunction. Stool samples were also collected from patients to measure fecal elastase-1 (FE-1). Results A 65.5% incidence of PEI was observed in DM patients. There was no significant correlation among the duration of disease, C-peptide, HbA1c, and PEI, respectively (P = .782, P = .521, P = .580). However, a significant difference between DM patients and controls in terms of cardiac dysautonomia (P = .001) was seen. Moreover, a statistically significant correlation between the degree of cardiac dysautonomia and FE-1 level was observed within the patient group (P =.001).Conclusion It is possible that the disruption of exocrine hormone secretion in the pancreas due to the impairment of enteropancreatic reflexes is secondary to diabetic autonomic neuropathy and resulting in PEI. This study also showed that autonomic neuropathy might develop and cause PEI in diabetic patients without known added confounding factors.     

Complement deposition on renal histopathology of patients with diabetic nephropathy

AimsAs the potential role of the complement system in diabetic nephropathy (DN) is increasingly reported, this study aimed to investigate C1q and C3c deposition as seen on renal histopathology, as well as its association with clinical and pathological parameters, in DN patients.MethodsRenal biopsy specimens from 161 DN patients were investigated using direct immunofluorescence, light, and electron microscopy. For direct immunofluorescence, staining for C1q and C3c on fresh-frozen renal tissue was performed immediately after biopsy. Complement deposition was defined as the presence of C1q or C3c of at least 1 + on a 0–4 + Scale. The association between complement deposition and clinicopathological data was also analyzed.ResultsOn direct immunofluorescence microscopy, C1q and C3c were detected in specimens from 44/161 (27.3%) and 89/161 (55.3%) patients, respectively. Regarding clinical data, patients with C1q deposition had a significantly higher level of urinary protein (7.25 ± 4.20 g/24 h vs. 4.97 ± 3.76 g/24 h; P < 0.01) and significantly lower estimated glomerular filtration rate (eGFR; 34.16 ± 25.21 mL/min/1.73 m² vs. 51.17 ± 31.56 mL/min/1.73 m², respectively; P < 0.01), whereas patients with vs. without C3c deposition had a significantly lower eGFR (40.09 ± 27.97 mL/min/1.73 m² vs. 54.48 ± 32.49 mL/min/1.73 m², respectively; P < 0.01). On renal histopathology, patients with C1q deposition had significantly higher Scores for interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and vascular lesions (P < 0.01, P < 0.05 and P < 0.05, respectively), whereas patients with C3c deposition had significantly higher IFTA Scores and proportions of global sclerosis (P < 0.01 and P < 0.01, respectively).ConclusionComplement deposition of C1q and C3c on renal histopathology is associated with more severe kidney damage in patients with DN.     

Erythropoietin depletion and anaemia in diabetes mellitus.

AIMS: To discover whether Type 1 diabetic patients with autonomic neuropathy might be anaemic and erythropoietin (EPO)-depleted. METHODS: Fifteen Type 1 diabetic patients with serious complications (DM-COMP) were selected because of severe symptomatic autonomic neuropathy, including significant postural hypotension. All had proteinuria from nephropathy (three microalbuminuria and 12 macroalbuminuria), but a normal serum creatinine (< 122 micromol/l). They were compared to age and duration matched Type 1 diabetic controls without autonomic neuropathy (DM-controls) and non-diabetic patients with and without hypochromic, microcytic anaemia. RESULTS: The DM-COMP patients were anaemic (mean haemoglobin (Hb) 11.1+/-1.2 g/dl), sometimes severely (minimum Hb 9.2 g/dl), compared to non-neuropathic DM-controls (Hb 13.7+/-0.7 g/dl; P < 0.001). Furthermore, EPO failed to increase in association with anaemia in the DM-COMP group compared to the progressive increase in the non-diabetic, anaemic patients (difference of regression lines P < 0.001), indicating EPO depletion in the anaemic, diabetic patients. There was no other demonstrable cause for the anaemia. Treatment with EPO in 5 DM-COMP patients led to a rapid increase in haemoglobin (range 1.7-5.0 g/dl) with improvement in wellbeing. CONCLUSION: Some Type 1 diabetic patients with autonomic neuropathy present with an EPO-depleted anaemia, which responds to treatment with EPO. This observation supports the concept of autonomic neuropathy as a cause of anaemia with EPO depletion, although the role of established renal damage cannot be excluded.     

Relationships between dyspeptic symptoms and gastrointestinal motility in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Reports on motor abnormalities in Type 1 (insulin-dependent) diabetes mellitus are inconsistent. In 20 Type 1 diabetic patients and in 11 control subjects antroduodenojejunal manometry was performed under euglycaemic conditions in order to examine the prevalence of gastric and small intestinal motor abnormalities in relation to dyspeptic symptoms and the degree of cardiac autonomic neuropathy. In diabetic patients compared to control subjects phase III (regular, high-amplitude contractile activity at maximal frequency) involved the gastric antrum less often (12 vs 35%,p<0.05), the duration of phase I (motor quiescence) was shorter (6±1 vs 21±4 min,p<0.002) and in phase II (irregular motor activity) the frequency of duodenal and jejunal contractions was higher. After a meal the duration of the fed state was shorter in diabetic patients with symptoms during the study than in diabetic patients without symptoms and than in control subjects (57±27 vs 157±11 and 140±13 min,p<0.02). Postprandial antral hypomotility was seen in diabetic patients with symptoms only in the first 30 min after the meal. One hour after the meal the frequency of duodenal and jejunal contractions was again higher in diabetic patients. In diabetic patients compared to control subjects more burst activity (clusters of non-propagated high-amplitude contractile activity at maximal frequency) was seen (7.9±1.6 vs 0.8±0.5% of the total time of study,p<0.002). No correlation was found between manometric parameters and the degree of cardiac autonomic neuropathy. In conclusion, in Type 1 diabetic patients with cardiac autonomic neuropathy a variety of gastric and small intestinal motor abnormalities can be found. The most important of these is hyperactivity in the interdigestive state. These abnormalities correlate with symptoms, but are not related to the severity of cardiac autonomic neuropathy.     

Signal-averaged Electrocardiogram in Patients with Insulin-dependent (Type 1) Diabetes Mellitus With and Without Diabetic Neuropathy

The purpose of this study was to investigate the presence of ventricular late potentials derived from signal-averaged ECG in patients with IDDM with and without diabetic neuropathy. Eighty patients with IDDM but without evidence of cardiac disease and 80 age-matched healthy control subjects were investigated. The corrected QT interval was measured from the standard surface electrocardiogram. Ventricular late potentials were derived from signal-averaged electrocardiogram. Out of the 80 diabetic patients, 20 had an autonomic neuropathy, 20 had an isolated peripheral neuropathy, and 40 had no symptoms of neuropathy. The corrected QT interval was significantly prolonged in patients with an autonomic neuropathy as compared with the control group (436 ± 23 ms^.5 vs 384 ± 23 ms^.5, p < 0.001). In the other patient groups there was no significant prolongation of the corrected QT interval. Ventricular late potentials were present in 3 diabetic patients with an isolated peripheral neuropathy and in 1 control subject (NS). No diabetic patient with an autonomic neuropathy had ventricular late potentials. Our data did not indicate an increased incidence of ventricular late potentials derived from signal-averaged electrocardiogram in diabetic patients independent of a coexisting diabetic neuropathy or a prolonged corrected QT interval. © 1997 by John Wiley & Sons, Ltd.     

The Prevalence of Autonomic and Peripheral Neuropathy in Insulin-treated Diabetic Sbjects

The prevalence of autonomic and peripheral neuropathy was examined in 506 diabetic sbjects treated with insulin, mean age 43 years, diabetes duration 15 (range 1–54) years. Autonomic neuropathy was present if two or more (of four) cardiovascular autonomic function tests were abnormal using age-related ranges derived from 310 normal control sbjects. Peripheral neuropathy was defined as a vibration threshold >95th centile for age combined with absent/impaired ankle reflexes. Eighty-four (16.6%) of diabetic sbjects had abnormal autonomic function and 119 (23.5%) peripheral neuropathy, concordant in 44/506 (8.7%). Of the diabetic sbjects with autonomic neuropathy 40/84 (47.6%) did not have peripheral neuropathy and only 44/119 (37.0%) with peripheral neuropathy had abnormal autonomic function (p<0.001). The prevalence of both neuropathies increased in relation to diabetes duration (both p<0.001). Autonomic neuropathy was more common in sbjects diagnosed <20 years of age (18.2%) vs age >40 years (11.1%) (p<0.05). In contrast peripheral neuropathy was more common with older age at diagnosis (<20 years 13.5% vs 36.8% >40 years, p<0.001). The age-related prevalence of autonomic neuropathy peaked at age 40–49 years while peripheral neuropathy increased progressively with age (p<0.001). The prevalence of peripheral exceeded autonomic neuropathy 20 years after diagnosis (40.2% vs 30.7%, p<0.001).     

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

Aims/hypothesis. To improve understanding of the pathophysiology of diabetic neuropathy and to establish a primate model for experimental studies, we examined nerve changes in baboons with Type I (insulin-dependent) diabetes mellitus. We also examined the effect of aminoguanidine (an inhibitor of the formation of advanced glycation end products) on nerve function.¶Methods. Male baboons (Papio hamadryas) were assigned to four groups; control, diabetic, control and diabetic treated with aminoguanidine. Diabetes was induced with streptozotocin (60 mg/kg, intravenous). Insulin and aminoguanidine (10 mg/kg) were injected subcutaneously daily. Motor and sensory nerve conduction velocity was measured using standard techniques. Autonomic function was examined by measuring heart rate response to positional change. Sural nerve morphometry was analysed in the diabetic group (mean duration 5.5 years) along with their age-matched controls.¶Results. The diabetic groups were smaller in size with a mean HbA_{1 c} of 8.9 ± 1.2 %. The nerve conduction velocity and heart rate response was reduced in the diabetic groups. Morphometric analysis of the diabetic sural nerve showed smaller axon diameter (2.99 ± 0.06 μm vs 3.29 ± 0.06 μm; p < 0.01) accompanied by thinner myelin (1.02 ± 0.02 μm vs 1.15 ± 0.02 μm, p < 0.01) with no change in the axon density. Treatment with aminoguanidine for 3 years had no effect on glycaemic control and did not restore conduction velocity or autonomic dysfunction in the diabetic animals, contrary to the studies in rats.¶Conclusions/interpretation. These results show that the primate is a good model to study diabetic neuropathy and suggest that the accumulation of advanced glycation end products are not an early mechanism of nerve damage in this disorder. [Diabetologia (2000) 43: 110–116]     

Frequency and predictors of renal artery stenosis in patients with coronary artery disease

BackgroundRenal artery stenosis (RAS) remains underdiagnosed because of nonspecific clinical manifestations, including in patients with coronary artery disease (CAD).AimsTo estimate the prevalence and identify predictors of RAS in patients with CAD undergoing coronary angiography.SettingUniversity-based medical centre.MethodsWe enrolled 650 consecutive patients (mean age=67±10 years, 80% men) with confirmed CAD. All patients underwent selective renal arteriography in the same procedure.We estimated the prevalence of RAS, defined as a >50% lesion. Multiple variable analysis of factors associated with presence of RAS was carried out using a logistic regression model. Variables that emerged as predictors by single-variable analysis were included in the model, along with variables that were tentatively associated with RAS, based on a literature review.ResultsRAS was detected in 94 patients (14.5%, 95% CI: 11.8–17.2%), including 20 (3.1%) with bilateral lesions. By single-variable analysis and presence and number of coronary artery stenoses (P<.001), hypertension (P=.001), and creatinine clearance <90 ml/min (P<.001) were associated with an increased risk of RAS. By multiple variable analysis, male sex (P<.05), presence and number of coronary artery lesions (P<.01), hypertension (P=.001), and renal insufficiency (P<.001) predicted the presence of RAS.ConclusionsThe main clinical predictors of RAS in patients with CAD were hypertension, renal insufficiency, and multivessel CAD. These observations might help defining a high-risk subgroup of patients in need of meticulous investigations of both CAD and RAS.     

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

Background and objectives

Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes.

Design, setting, participants, & measurements

A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) <20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C <−3.3%/year) and incident advanced CKD (stage ≥3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] <60 ml/min per 1.73 m²). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards.

Results

Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P<0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P<0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002).

Conclusions

Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.     

Arterial compliance: a diagnostic marker for atherosclerotic plaque burden?

BackgroundPrevious studies have shown atherogenesis to be related with increased vessel stiffness. Measures of the arterial compliance can be performed noninvasively from pressure pulse contour analysis of arterial waveforms. In this prospective study we aimed to analyze to what extent vessel compliance can reflect the angiographic coronary artery status.MethodsLarge and small arterial elasticity indices (LAEI in milliliters per mm Hg × 10 and SAEI in milliliters per mm Hg × 100) were measured in 151 patients on the radial artery with the PulseWave Sensor HDI device. All patients were classified into diffuse-coronary artery disease (CAD) (defined as stenosis length >15 mm), focal-CAD (defined as stenosis length between 1 and 15 mm), or no-CAD.ResultsWe found both LAEI and SAEI to be reduced in the diabetic group (LAEI: 11.2 ± 2.9 v 13.4 ± 4.5, P = .006; SAEI: 3.7 ± 1.6 v 4.7 ± 2.4, P = .01). Inverse association was seen between age and LAEI (r = −0.41; P < .001) and SAEI (r = −0.38; P < .001). No-CAD was found in 31 patients, focal-CAD in 64 patients, and diffuse-CAD in 56 patients. Mean LAEI were 13.8 ± 3.5, 13.7 ± 4.7, and 11.3 ± 3.5 in the groups no-CAD, focal-CAD, and diffuse-CAD, respectively (P = .004), (no-CAD versus diffuse-CAD: P = .04; focal-CAD versus diffuse-CAD: P = .009). Respective SAEI values were 5.6 ± 2.5, 5.0 ± 2.1, and 3.1 ± 1.6 (P < .001), (no-CAD versus diffuse-CAD: P < .001; focal-CAD versus diffuse-CAD: P < .001). Multivariate analysis revealed SAEI (P < .001), hypercholesterolemia (P = .005), systolic blood pressure (BP) (P < .001), mean arterial BP (P < .001), pulse pressure (P = .003), and male gender (P = .001) to be diagnostic markers of the type of vessel disease.ConclusionsCompliance measurements may be used for identification of patients with diffuse atherosclerotic processes of the coronary arteries.