Luigi Tubani

Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus.

BackgroundIn type 2 diabetes mellitus both insulin resistance and hyperglycemia are considered responsible for autonomic dysfunction. The relation between the autonomic activity, impaired fasting glycemia and impaired glucose tolerance is, however, unclear. The purpose of this study was to evaluate and compare the circadian autonomic activity expressed as heart rate variability (HRV) measured by 24-hours ECG recording in insulin resistant subjects (IR) with characteristics as follow: IR subjects with normal oral glucose tolerance test results, IR subjects with impaired fasting glucose, IR subjects with impaired glucose tolerance and subjects with type 2 diabetes mellitus.MethodsEighty Caucasian insulin resistant subjects (IR) and twenty five control subjects were recruited for the study. IR subjects were divided into four groups according to the outcoming results of oral glucose tests (OGTTs): IR subjects with normal glucose regulation (NGR), IR subjects with impaired fasting glycemia (IFG), IR subjects with impaired glucose tolerance (IGT) and subjects with type 2 diabetes mellitus (DM). Autonomic nervous activity was studied by 24-hours ECG recording. Heart rate variability analysis was performed in time and frequency domains: SDNN, RMS-SD, low frequency (LF) and high frequency (HF) were calculated.ResultsThe total SDNN showed statistically significant reduction in all four groups with insulin resistant subjects (IR) when compared to the control group (p <0,001). During night LF normalized units (n.u.) were found to be higher in all four groups including IR subjects than in the control group (all p < 0,001) and subjects with normal glucose regulation (NGR), with impaired fasting glycemia (IFG) and with impaired glucose tolerance (IGT) were found to have higher LF n.u. than those in the type 2 diabetes mellitus group. The linear regression model demonstrated direct association between LF values and the homeostasis model assessment-index (HOMA-I), in the insulin resistant group (r = 0,715, p <0,0001).ConclusionThe results of our study suggest that insulin resistance might cause global autonomic dysfunction which increases along with worsening glucose metabolic impairment. The analysis of sympathetic and parasympathetic components and the sympathovagal balance demonstrated an association between insulin resistance and sympathetic over-activity, especially during night. The results indicated that the sympathetic over-activity is directly correlated to the grade of insulin resistance calculated according to the HOMA-I. Since increased sympathetic activity is related to major cardiovascular accidents, early diagnosis of all insulin resistant patients should be contemplated.

Body mass index is related to autonomic nervous system activity as measured by heart rate variability

Autonomic nervous system activity is involved in body weight regulation. We assessed whether the body mass index (BMI) is related to the autonomic nervous system activity as assessed by heart rate variability (HRV). Twenty-five adult normotensive, euglycemic healthy males (M) and females (F) were studied (M/F=13/12). BMI was assessed in each individual. HRV was assessed and the domains of low frequencies (LF, index of the sympathetic modulation) and high frequencies (HF, index of the parasympathetic modulation) were measured. Data were statistically analyzed and are presented as mean±s.d. Mean BMI did not correlate with either HF or LF. It inversely related to HF (r=−0.50, P<0.01), whereas its relationship with LF was marginally significant (r=−0.39, P=0.05). The HF in individuals with BMI <20 kg/m2 was significantly higher from those measured in the remaining subjects (P<0.05). The results support the role of parasympathetic activity in influencing BMI through likely modulation of body weight.

Technetium-99m sestamibi single-photon emission tomography detects subclinical myocardial perfusion abnormalities in patients with systemic lupus erythematosus

Abstract. In patients with systemic lupus erythematosus, involvement of the cardiovascular system is the third leading cause of death. However, although autopsy studies have demonstrated a high incidence of abnormalities in both the myocardium and coronary vessels, clinical manifestations have been reported in only a small percentage of cases. The aim of this study was to evaluate myocardial perfusion in asymptomatic lupus patients using technetium-99m sestamibi single-photon emission tomography (SPET). Twenty-eight patients without overt cardiac involvement and risk factors were studied with 99mTc-sestamibi SPET at rest and after dipyridamole infusion. Perfusion abnormalities were detected in 18 cases: six had persistent defects, three had reversible defects, seven had both persistent and reversible defects, and two showed rest defects which normalized on dipyridamole images (”reverse redistribution pattern”). Coronary angiography was performed in eight patients with positive 99mTc-sestamibi SPET, and showed normal epicardial vessels in all the cases. These results indicate that 99mTc-sestamibi SPET reveals a high prevalence (18 out of 28 patients in this study, i.e. 64%) of myocardial perfusion abnormalities in asymptomatic lupus patients, probably due to the primary immunological damage of this autoimmune disease. In conclusion, rest/dipyridamole 99mTc-sestamibi SPET can be a useful non-invasive method to identify subclinical myocardial involvement in systemic lupus erythematosus, and patients potentially at risk of later cardiac events.

Circadian rhythm of autonomic activity in non diabetic offsprings of type 2 diabetic patients.

The aim of the present study was to evaluate, by heart rate variability (HRV) with 24-hours ECG Holter (HRV), the circadian autonomic activity in offspring of type 2 diabetic subjects and the relation with insulin-resistance. METHODS: 50 Caucasian offsprings of type 2 diabetic subjects were divided in two groups: insulin-resistant offsprings (IR) and non insulin-resistant offsprings (NIR). Autonomic nervous activity was studied by HRV. Time domain and spectral analysis (low frequency, LF, and high frequency, HF, provide markers of sympathetic and parasympathetic modulation when assessed in normalized units) were evaluated. RESULTS. Time domain showed a reduction of total SDNN in IR (p < 0.001) and NIR (p 0.047) versus controls. Spectral analysis showed a total and night LF higher in IR and NIR than in control group (all p < 0.001). CONCLUSION. In frequency domain, the analysis of sympathetic (LF) and parasympathetic (HF) component evidenced an association between the offspring of type 2 diabetic subjects and a sympathetic overactivity. A global reduction and alteration of circadian rhythm of autonomic activity are present in offspring of type 2 diabetic patients with and without insulin resistance. The data of our study suggested that an autonomic impairment is associated with the familiarity for type 2 diabetes independently to insulin resistance and that an impairment of autonomic system activity could precede the insulin resistance.

Lupus Carditis: Evaluation with Technetium-99m MIBI Myocardial SPECT and Heart Rate Variability:

The objective of this paper was to investigate the incidence of myocardial perfusion defects in patients with systemic lupus erythematosus (SLE) associated with dysauto nomic alterations. Twenty patients without any sign or symptoms of heart disease, selected from a larger population of patients with SLE, underwent technetium-99m sestamibi (Tc-99m MIBI) single photon emission computed tomography (SPECT), at rest and after dipyridamole infusion; they also underwent heart rate variability (HRV) exam ination by a 24 hour ambulatory electrocardiography, analyzing in the time domain the standard deviation of the R-R intervals average (SDNN) and the percentage of R-R adjacent intervals differing from each other more than 50 msec (pNN50); in the frequency domain the low (LF) and high frequencies (HF) were analyzed. Twenty healthy volunteers served as control group for heart rate variability. At MIBI-SPECT examina- tion, the scan was found abnormal in 15 patients and normal in five: three patients demonstrated reversible defects in the anteroseptal region, four had irreversible defects in a region (two in the anteroseptal region and two in the lateral region), two had rest defects in two different regions (lateral and inferior, lateral and anteroseptal) that improved during dipyridamole scan, and six had both reversible and irreversible defects: four in a single segment (three anteroseptal and one lateral, and two in two different regions, particularly anteroseptal and lateral, lateral and inferior). All 20 patients showed significantly lower HRV parameters in comparison with the control group, except for pNN50, which indicates decreased physiologic periodic fluctuations of the autonomic nervous system. In six patients who underwent coronary angiography, the epicardial vessels were found completely normal. In view of the high incidence of myocardial hypoperfusion in patients with HRV alterations, the authors hypothesize that autonomic dysfunction may be associated with microvascular disease or metabolic alteration. They also believe that MIBI scintigraphy is a suitable technique in detecting myocardial damage in SLE patients free of clinical manifestation.

The correlation among QTc interval, hyperglycaemia and the impaired autonomic activity

BACKGROUND The QT interval reflects the duration of the intracellular action potential. Little is known on the interval QT duration in non diabetic insulin-resistant subjects. OBJECTIVE The aims of the current study were to evaluate the QTc interval in three groups of non diabetic insulin-resistant subjects and the possible correlation between QTc and the autonomic nervous systems activity. DESIGN 90 subjects were divided in subjects with impaired fasting glycaemia (IFG) and, by the results of OGTT, according to the criteria of ADA, in subjects with normal glucose regulation (NGR) and impaired glucose tolerance (IGT). Insulin resistance was evaluated by the homeostasis model assessment-index (HOMA-I). Heart rate variability and Qtc were calculated. RESULTS QTc interval is correlated with SDNN, LF n.u. and LF/HF. CONCLUSION We have observed that the QTc interval is prolonged in insulin-resistant subjects with associated impaired glucose metabolism, while no difference was reported between insulin-resistant and non insulin-resistant subjects with normal glucose regulation. We hypothesize that hyperglycaemia could play a major role than hyperinsulinemia on the QTc prolongation.

Myocardial Infarction with Normal Coronary Arteries in a Patient with Primary Antiphospholipid Syndrome Case Report and Literature Review

Primary antiphospholipid syndrome is associated with an increased risk of vascular throm bosis. The authors describe a young patient without any risk factor for coronary artery disease who was admitted to the hospital because of a transient cerebral ischemic attack. Standard EKG showed signs of a previous silent inferior wall myocardial infarction, confirmed by echocar diography, technetium-99 scintigraphy, and left ventricular angiography. Coronary arteries appeared normal at angiography. Blood tests showed the presence of antiphospholipid anti bodies and lupus anticoagulant. Since there is evidence that these antibodies are associated with an increased risk of microvascular thrombosis, the authors conclude that this silent myocardial infarction could be caused by a cardiac microvascular disease accompanying the antiphospholipid syndrome.

Autonomic dysfunction in patients with systemic sclerosis: Correlation with intrarenal arterial stiffness

Systemic sclerosis (SSc) is a systemic disease of connective tissue,characterized by endothelial dysfunction and fibrosis of the skin andvisceral organs [1]. Autonomic dysfunction (AD) is a feature of SSc,starting early in the disease and possibly preceding the developmentof fibrosis [2].Several manifestations of renal involvement occur in SSc and wehave recently demonstrated that renal resistive index (RI) correlateswith glomerular filtration rate (GFR), digital microvascular damage [3]and in monitoring scleroderma renal crisis [4].Accordingly, the aim of the study is to assess intrarenal arterialstiffness by Doppler ultrasound and examine the correlation with ADusing heart rate variability (HRV) analysis.The protocol is in accordance with the Declaration of Helsinki andwas approved by the Ethics Committee at our Institution. NineteenCaucasian subjects fulfilling the American Rheumatism Association(ARA) criteria for classification and diagnosis of SSc [5] and nineteenhealthysubjectswereexaminedbeforeinclusioninthestudy.Allexam-ined patients underwent clinical evaluation, 24-h Holter monitoring,electrocardiography (ECG) and transthoracic echocardiogram.Scleroderma patients with coronary artery disease, congestiveheartfailure, left ventricular dysfunction, significant valvular abnormalitiesand arrhythmias were not included in the study.Patients with pulmonary function abnormalities were not includedeither. Patients with diabetes mellitus, renal failure, hepatic or thyroiddysfunction and anaemia were excluded.Patients were not taking β-blockers, antiarrhythmic drugs, ACE-inhibitors or angiotensin receptor antagonists. GFR was calculatedwith CKD-EPI equation [6].Autonomic nervous activity was evaluated by heart rate variability(HRV) analysis during 24-hour ECG recording. Autonomic nervousactivity was analyzed following the recommendations of the TaskForce of the European Society of Cardiology and the North AmericanSociety of Pacing and Electrophysiology [7]. Total power in the fre-quency range (0–0.40 Hz) was divided into low frequency (LF:0.04–0.15 Hz, modulated mainly by sympathetic system) and highfrequency (HF: 0.15–0.40 Hz, modulated by parasympathetic system).The power of LF and HF components was considered in normalizedunits (nu). LF/HF rate is sympathovagal balance. Artificial data andarrhythmic were excluded. Data analyses were performed with soft-ware Del Mar Avionics Accuplus 363, Irvine California, USA.Renal Doppler ultrasound was performed using a Toshiba AplioUltrasound System SSA-790 (Tokyo, Japan) equipped with convex 3.5-MHz probe. RI was calculated as (peak systolic frequency shift −minimum diastolic frequency shift) / peak systolic frequency shift.All the ultrasound examinations were performed by same blindedphysician in order to reduce variability in the assessment managementof the study.Thedatawereexpressedasmedianandrange.Multivariateanalysiswas applied for the estimation of relationship of HRV variables withrenal Doppler indices or disease variables. The Mann–Whitney U-testor Kruskal–Wallis was used to test differences between two individualstudy groups. Spearmans rank order correlation coefficient (r) wasused to test for an association between numerical variables. p-Valuesb0,05 were considered significant. Commercially software (SPSSversion 20.0) was used for statistical analysis.Nineteen scleroderma patients were enrolled in the current study.Median age of 45 years (range 23–58) and a median SSc duration of6,5 years (range 2–25) were investigated in the Clinical ImmunologyUnit-Scleroderma Center. Six patients had limited cutaneous SSc and

Long-term effect of liver transplantation on cirrhotic autonomic cardiac dysfunction

There is little information on the long-term effect of liver transplantation (LT) on cardiac autonomic dysfunction in cirrhotic patients. We compared cardiac autonomic function before and in the long-term after LT. In a transversal study, we investigated 30 cirrhotics awaiting LT, 15 clinically stable patients 2-6 years after LT and 27 healthy controls. Seven cirrhotic patients were studied before LT, and 6, 12 and 33 months after LT, in a prospective fashion. Cardiac autonomic function was measured by heart rate variability (HRV) analysis during 24-h electrocardiogram recording. In the transversal study, patients with cirrhosis as compared to healthy controls had significantly reduced standard deviation of normal-to-normal RR intervals (SDNN) (p<0.001) and of the square root of the mean of squared differences between adjacent NN intervals (RMS-SD) (p<0.01), while the ratio between low frequency (LF) and high frequency (HF) at night was significantly (p<0.05) increased. Liver transplanted patients had significantly (p<0.001) higher SDNN values than cirrhotics, while RMS-SD and LF/HF at night did not differ. In the prospective study, SDNN progressively increased after LT and was significantly (p<0.05) higher at 12 and 33 months, compared to the pre-operative value. RMS-SD and LF/HF at night did not change after LT. In conclusion, the overall HRV decrease present in cirrhosis, measured by SDNN values, is partially corrected in the long-term after LT. However, parasympathetic impairment, measured by RMS-SD and LF/HF at night, is not affected even in the long-term after operation.

QTc interval prolongation in systemic sclerosis: Correlations with clinical variables

Systemic sclerosis (SSc) is an autoimmune disease characterized byendothelial dysfunction and fibrosis of the skin and internal organs [1].Cardiac involvement in the course of SSc could be primary or sec-ondary to pulmonary arterial hypertension and kidney pathology. Pri-mary cardiac involvement may manifest as myocardial involvement,arrhythmias,fibrosisoftheconductionsystem,pacemakerandintracar-diac defibrillator implantation, sudden death and autonomic dysfunc-tion [2,3].Amongtheabnormalities in SSc,QTc intervalprolongation hasbeenreportedandassociatedwithanti-RNApolymeraseIIIantibodies,longerdisease duration, and greater disease severity [4].Accordingly,theaimofthestudyistoassessQTcprolongationinSScand evaluate correlations with clinical variables and complications ofthe disease.The protocol is in accordance with the Declaration of Helsinki andwas approved by the Ethics Committee at our Institution. Twenty Cau-casian subjects fulfilling the American Rheumatism Association (ARA)criteria for classification and diagnosis of SSc [5] and twenty healthysubjectswereexaminedbeforeinclusioninthestudy.All examined pa-tientsunderwentclinicalevaluation,ambulatory24-hourECGmonitor-ing, transthoracic echocardiogram.Scleroderma patients with coronary artery disease, congestiveheartfailure, left ventricular dysfunction, significant valvular abnormalitiesand arrhythmias were not included in the study.Patients with pulmonary function abnormalities were not includedeither. Patients with diabetes mellitus, renal failure, hepatic or thyroiddysfunction, and anemia were excluded.Patients were not takingβ-blockers, antiarrhythmic drugs,ACE-inhibitors or angiotensin receptor antagonists. QTc interval,assessed by 24-hour Holter ECG recording, was defined as prolongedwhen N440 ms [6].Nailfold videocapillaroscopy (NVC) was performed by an opticalprobe, equipped with magnification 200× contact lens and connectedto image analysis software (Pinnacle Studio Version 8). The identifiedpatterns were classified as early, active or late [7]. Skin thickening wasassessed by a modified Rodnan total skin score (mRSS) [8]. In all pa-tientswemeasuredtheDiseaseActivityIndex(DAI)andDiseaseSever-ity Scale (DSS) [9].Thedatawereexpressedasmedianandrange.Multivariateanalysiswas applied for the estimation of relationship of QTc with disease vari-ables. The Mann–Whitney U-test or Kruskal–Wallis were used to testdifferences between two individual study groups. Spearmans rankorder correlation coefficient (r) was used to test for an association be-tweennumericalvariables.p-Valuesb0.05wereconsideredsignificant.Commercial software (SPSS version 20.0) was used for statisticalanalysis.Twentysclerodermapatientswereenrolledinthecurrentstudy.Theepidemiological and clinical features of SSc are shown in Table 1.ThemedianvalueofQTcissignificantly(pb0.0001)increasedinSScpatients than healthy controls [447 (414–566) vs 386 (342–447)].The medianvalueof QTc is significantly (p b 0.01) different in threecapillaroscopicgroups:early425(421 –454),active437(416–467),late471 (445–566).ThemedianvalueofQTcissignificantly(pb 0.05)augmentedin SScpatients with digital ulcers than in SSc patients without digital ulcers[459(422–566)vs436(416–454)].Apositivecorrelation (p b0.05)ex-ists between QTc and mRSS (r = 0.53).NocorrelationswerefoundbetweenQTcanddiseasesubset,diseaseduration, Disease Activity Index, and Disease Severity Scale.Amongthe causes of suddencardiacdeath in SScpatients,ventricu-lar late potentials, autonomic dysfunction, pro-arrhythmogenic drugsand increased QT dispersion were found.