Greater Autonomic Dysfunction Research Articles

Genetic mutations in Parkinson's disease: screening of a selected population from North-Eastern Italy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings. Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features. A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion "age of onset < 55years" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03). Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.

Isolated REM sleep behaviour disorder in the Tasmanian ISLAND Sleep Study: prevalence and profiles of prodromal dementia

AbstractBackgroundIdentifying people with isolated REM sleep behaviour disorder (iRBD) provides important opportunities for targeted dementia prevention as iRBD is a prodrome of Lewy Body dementia (LBD) and other neurodegenerative diseases (NDD). There have been no prevalence studies of iRBD in Australia and little is known about whether associated motor, cognitive, olfactory and circadian features influence the progression to different NDD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study aims to identify the iRBD prevalence in Tasmania and determine how different iRBD profiles predict progression to dementia and other NDD.MethodAdults aged 50+ years in Tasmania completed online questionnaires including the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ), RBD single question screen (RBD1Q), Pittsburgh Sleep Quality Index (PSQI), and questions regarding dreaming, autonomic, motor s, and pain symptoms.Result2,905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).Conclusion2905 participants have been recruited (mean (SD) age 64 (7.7) years; 26% male). 273 (9.4%) have ‘probable’ iRBD (pRBD) based on the RBDQ1. Compared to those without pRBD, the pRBD group have poorer sleep quality (66% vs 57%), greater autonomic dysfunction (median score 18 vs 13), more pain (particularly stabbing and itching pain), higher risk for sleep apnoea (30% vs 13%), more intense dreams (21% vs 8%), and more motor symptoms, including shaky limbs (16% vs 6%) and slurred speech (12% vs 6%).

Development of anxiety in early Parkinson's disease: A clinical and biomarker study.

Anxiety affects approximately 40% of Parkinson's disease (PD) patients. However, little is known about its predictors and development over time. To identify the clinical factors and biomarkers associated with development of anxiety in patients with newly diagnosed PD, and to test which risk factors predict increases in anxiety over time. Data from the Parkinson's Progression Markers Initiative (PPMI) were utilized. The primary outcome was the State-Trait Anxiety Inventory (STAI). Covariates were demographics, motor and non-motor symptoms, cognitive functions, dopamine transporter imaging data, and cerebrospinal fluid (CSF) biomarkers. We examined the association of risk factors at baseline and over 4 years with changes in anxiety scores over time. A total of 252 patients met the inclusion criteria (mean age: 61.36 years, SD 9.53). At year 4, 42 patients had developed anxiety. Baseline predictors of increase in anxiety scores were greater autonomic dysfunction, dysexecutive function, CSF t-tau levels, excessive daytime sleepiness, and lower olfactory function scores but not motor scores. Over 4 years, change in anxiety scores correlated with deterioration in overall cognitive function, excessive daytime sleepiness, as well as depression and disability, and to a lesser degree worsening of Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor scores and caudate dopaminergic uptake changes. These findings suggest that development of anxiety in PD is not primarily based on a dopaminergic deficit in the basal ganglia but related to non-dopaminergic or extrastriatal pathology. Early dysexecutive function predicts development of anxiety but increase in anxiety levels correlates most strongly with more global cognitive decline.

The longitudinal progression of autonomic dysfunction in Parkinson's disease: A 7-year study.

Autonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Furthermore, the relationship between the presence of autonomic symptoms in early-stage PD and olfactory dysfunction, a possible marker of central nervous system involvement, has not been fully investigated. We aimed to investigate the occurrence and progression of autonomic dysfunction in recently diagnosed (< 2 years) untreated PD patients and determine any coexistence of symptoms in individual patients. We also investigated the relationship between autonomic symptoms, olfactory dysfunction, and motor impairment. Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. The simultaneous occurrence of different autonomic symptoms was also examined. Finally, the relationships between SCOPA-AUT scores, olfactory dysfunction, and motor impairment were investigated using the University of Pennsylvania Smell Identification Test (UPSIT) and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), respectively. Follow-up data were available for 7 years for 171 PD patients and for 5 years for 136 HCs. Mean SCOPA-AUT score increased significantly from baseline to the 7-year follow-up for each autonomic domain, except for female sexual dysfunction. Most patients reported three or more autonomic symptoms. Common clusters of symptoms were composed of combinations of gastrointestinal, urinary, thermoregulatory, and sexual dysfunction. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = -0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004). Autonomic dysfunction, often with coexistence of autonomic manifestations, is common in early PD and progressively worsens over the first 7 years of disease, suggesting that these symptoms should be addressed with appropriate treatments early in the disease. The association between greater autonomic dysfunction and greater olfactory impairment, coupled with the association with more severe motor scores at baseline, indicates that patients who show more severe autonomic dysfunction could also have more severe involvement of the central nervous system at the time of diagnosis.

Cutaneous α-synuclein is correlated with autonomic impairment in isolated rapid eye movement sleep behavior disorder.

To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson's disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Speech difficulties in early de novo patients with Parkinson's disease

IntroductionSpeech difficulties are a common debilitating feature of Parkinson's disease and we aimed to investigate whether speech difficulties are associated with striatal dopaminergic deficits and faster disease progression. MethodsUsing the Parkinson's Progression Markers Initiative database, 143 early de novo Parkinson's disease patients with speech difficulties were identified and matched 1:1 with 143 Parkinson's disease patients without speech difficulties for age, disease duration and motor symptom severity. We investigated differences in clinical features and striatal [123I]FP-CIT single photon emission computed tomography (SPECT) uptake in Parkinson's disease patients with and without speech difficulties. Cox proportional hazards analysis was carried out to investigate whether speech difficulties were predictive of a faster motor progression and cognitive decline. ResultsSpeech difficulties were more common in patients with an akinetic-rigid motor phenotype compared to those with a tremor-dominant phenotype. Parkinson's disease patients with speech difficulties had lower resting tremor (P = 0.027), higher autonomic dysfunction (P = 0.034), increased daytime sleepiness (ESS; P = 0.048), and a higher prevalence of REM sleep behaviour disorder (RBD) symptoms (P = 0.007) compared to those without speech difficulties. Parkinson's disease patients with speech difficulties had significantly lower [123I]FP-CIT uptake in the striatum (P < 0.001), caudate (P = 0.003) and putamen (P = 0.003) compared to those without speech difficulties. The presence of speech difficulties was a predictor of cognitive decline [Hazard Ratio (HR): 0.341, 95% Confidence Interval (CI): 0.153–0.759; Wald: 6.945; P = 0.008), whereas it had no influence on motor progression (HR: 0.885, 95% CI: 0.662–1.183; Wald: 0.680; P > 0.10). ConclusionSpeech difficulties are associated with greater autonomic dysfunction, sleep disturbances and striatal dopaminergic deficit, and can serve as a predictor of faster cognitive decline in early Parkinson's disease.

Autonomic Dysfunction in Early Parkinson's Disease: Results from the United Kingdom Tracking Parkinson's Study.

Autonomic dysfunction is common in the later stages of Parkinson's disease (PD), but less is known about its presence and severity in early disease. To analyze features of autonomic dysfunction in recent onset PD cases, and their relationship to motor severity, medication use, other nonmotor symptoms (NMS), and quality-of-life scores. Detailed patient-reported symptoms of autonomic dysfunction were assessed in a multicenter cohort study in PD cases that had been diagnosed within the preceding 3.5 years. There were 1746 patients (1132 males, 65.2%), mean age 67.6 years (SD 9.3), mean disease duration 1.3 years (SD 0.9), mean Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score 22.5 (SD 12.1). Orthostatic symptoms were reported by 39.6%, male erectile dysfunction by 56.1%, and female anorgasmia by 57.4%. Sialorrhea was an issue in 51.4% of patients, constipation in 43.6%, and dysphagia in 20.1%. Autonomic features increased with higher modified Hoehn and Yahr stages (P < 0.001). The severity of autonomic dysfunction was associated with the postural instability gait difficulty motor phenotype [β-coefficient 1.7, 95% confidence interval (CI) 0.7, 2.6, P < 0.001], depression (β-coefficient 4.1, CI 3.0, 5.2, P < 0.001), and excess daytime sleepiness (β-coefficient 3.1, CI 1.9, 4.2, P < 0.001). Dopamine agonists were the only drug class associated with greater autonomic dysfunction (P = 0.019). The severity of autonomic dysfunction strongly correlated with the presence of other NMS (ρ = 0.717, P < 0.001), and with poorer quality-of-life scores (ρ = 0.483, P < 0.001). Autonomic dysfunction is common in early PD. Autonomic dysfunction correlates with the presence of other NMS, and with worse quality of life.

Gender-dependent profile of heart rate turbulence parameters in patients after acute myocardial infarction treated invasively.

The aim of this study was to determine whether gender is related to differences in heart rate turbulence (HRT) parameters and the authors' own predefined HRT categories comprising turbulence timing (TT) in patients at the early stage of acute myocardial infarction (AMI) treated invasively. We analysed 489 consecutive patients (147 females and 342 males, aged 63.9 ± 11.7 years) with AMI admitted to our department and treated invasively on admission to the hospital. On the fifth day after MI 24-h digital Holter recordings were performed to assess HRT, and the following HRT parameters were calculated in all patients using the HRTView pro-gram: turbulence onset (TO, %), slope (TS, ms/RR interval), and TT. The following values of HRT parameters were considered abnormal: TO ≥ 0, TS ≤ 2.5, and TT ≥ 10. Based on the abovementioned parameters, the authors defined their own HRT categories (A, B, C): A - comprising three normal parameters, B - one abnormal parameter, C - three abnormal parameters. TT was significantly later in women than in men: 7.5 ± 3.1 vs. 6.8 ± 3.1 (p < 0.05), respectively. When analysing the authors' own predefined HRT categories, significant differences between women and men were present in the occurrence of the category C, including all three abnormal HRT parameters: TO, TS, and TT. In women worse TT was present and all three abnormal HRT parameters occurred more frequently. HRT in women after AMI is profoundly altered compared to in men. This indicates greater autonomic dysfunction and higher risk for sudden cardiac death in women after AMI.

Inside the mind of poor Tom – A multidimensional approach to determine causes for redundant clothing in patients with schizophrenia

Redundant clothing (RC) is a readily observable feature of schizophrenia. While abnormal thermoregulation, thyroid dysfunction and autonomic dysregulation have been postulated to account for RC, no identified factor yet conclusively explains this enigmatic behaviour. This study attempted to determine the cause(s) of RC in schizophrenia. Two groups of 20 age- and sex-matched patients with and without RC were studied. Socio-demographic and clinical characteristics were recorded, and patients were assessed for psychopathology (Positive and Negative Syndrome Scale (PANSS)), cognitive function (Schizophrenia Cognition Rating Scale (SCoRS)), and autonomic and thyroid function. Those with RC differed significantly from those without RC in education, occupation, marital status and duration of untreated psychosis (DUP). They were more disorganised, more withdrawn, and had significant affective impairment. The RC group also had significantly higher negative, general and total psychopathology scores on the Positive and Negative Syndrome Scale, significantly poorer cognitive function, greater autonomic dysfunction, and lower free T3 and free T4 concentrations. We propose that the dimension of RC could define a subgroup with poorer premorbid functioning and a longer DUP, in whom cognitive dysfunction and prominent negative symptoms coloured the manifestations of deranged thermoregulation secondary to lower thyroid hormone levels and autonomic dysfunction, ultimately resulting in redundant clothing.

Autonomic and metabolic changes induced by fructose overload: role of baroreflex (1086.4)

The aim of this experiment was to identify the changes in autonomic and metabolic parameters in a model of metabolic syndrome induced by fructose overload, with focus on the role of baroreflex, as evaluated by sinoaortic denervation. Four experimental groups (rats) were used, followed by 90 days: control(C), denervated control (D), treated with fructose(F) and denervated treated with fructose(DF). The treated groups were submitted to a fructose overload(10%) in drinking water. The caloric intake was higher in F(32%) and DF(18%) groups compared to C, inducing higher body weight gain in F(41%) and DF(27%) when compared to C group. The consumption of D was lower (12%) than the C group as well as body weight gain(8%). The overload of fructose was able to change the fasting plasma glucose baselines values, promoting increasing of glycaemia in both F and DF groups and leading to insulin resistance in the F group. Blood pressure values were also increased in F(17%) and DF(18%) compared to C group. The variability parameters were altered in the three experimental groups (D, F and DF), evidenced by the reduction of the pulse interval variance. Furthermore, the vagal modulation indicators are decreased and blood pressure variability was increased, as expressed by the total variance, in both denervated groups (D and DF). Treatment with fructose was able to induce characteristic changes of metabolic syndrome, such as hypertension, obesity, increased blood sugar and dysautonomia. The absence of the baroreflex was able to mitigate metabolic changes, but when associated with fructose overload caused a greater autonomic dysfunction. The results of the present study indicate a marked influence of baroreflex in the development of metabolic syndrome.Grant Funding Source: Supported by FAPESP 2011/04111‐6

α-Synuclein in cutaneous autonomic nerves

To develop a cutaneous biomarker for Parkinson disease (PD). Twenty patients with PD and 14 age- and sex-matched control subjects underwent examinations, autonomic testing, and skin biopsies at the distal leg, distal thigh, and proximal thigh. α-Synuclein deposition and the density of intraepidermal, sudomotor, and pilomotor nerve fibers were measured. α-Synuclein deposition was normalized to nerve fiber density (the α-synuclein ratio). Results were compared with examination scores and autonomic function testing. Patients with PD had a distal sensory and autonomic neuropathy characterized by loss of intraepidermal and pilomotor fibers (p < 0.05 vs controls, all sites) and morphologic changes to sudomotor nerve fibers. Patients with PD had greater α-synuclein deposition and higher α-synuclein ratios compared with controls within pilomotor nerves and sudomotor nerves (p < 0.01, all sites) but not sensory nerves. Higher α-synuclein ratios correlated with Hoehn and Yahr scores (r = 0.58-0.71, p < 0.01), with sympathetic adrenergic function (r = -0.40 to -0.66, p < 0.01), and with parasympathetic function (r = -0.66 to -0.77, p > 0.01). We conclude that α-synuclein deposition is increased in cutaneous sympathetic adrenergic and sympathetic cholinergic fibers but not sensory fibers of patients with PD. Higher α-synuclein deposition is associated with greater autonomic dysfunction and more advanced PD. These data suggest that measures of α-synuclein deposition in cutaneous autonomic nerves may be a useful biomarker in patients with PD.

Is Chronic Fatigue Syndrome in Older Patients a different disease? – a clinical cohort study

Chronic fatigue syndrome (CFS) is a disabling disorder characterised by persistent fatigue with a typical age of diagnosis of 35-50 years. CFS does present in those aged over 50 but whether this is a different disease in older age groups has not been considered. Therefore, we performed a clinical cohort study to examine and differentiate the clinical and autonomic features in CFS patients aged over 50. A total of 179 Fukuda diagnosed CFS patients were recruited, and 25 older CFS patients (50 + years) were matched case by case for gender and length of history to 25 younger CFS patients (16-29 years). A range of symptomatic-based questionnaires were used in addition to heart rate variability and baroreceptor sensitivity to assess autonomic function. Chronic fatigue syndrome can present for the first time in an older population. Older CFS patients demonstrate increased fatigue (Fatigue impact scale; 85 ± 33 vs. 107 ± 27, P = 0·02) (Chalder fatigue scale; 9 ± 3 vs. 11 ± 1, P = 0·002) and caseness for depression (Hospital Anxiety and Depression scale; 7 ± 3 vs. 10 ± 4; P = 0·005). There is a greater autonomic dysfunction in older CFS patients, with reduced parasympathetic function (HFnu; 49·1 ± 18 vs. 36·2 ± 18, P = 0·01, RR30 : 15; ± , P = 0·02) and increased sympathetic function (LFnu; 51·5 ± 17 vs. 63·8 ± 18, P = 0·01). Baroreflex sensitivity was substantially reduced (BRS; 19·7 ± 12 vs. 9·9 ± 5, P = 0·0004), and left ventricular ejection time prolonged (LVET; 274·6 ± 16 vs. 285·8 ± 9, P = 0·004). Older CFS patients demonstrate a disease phenotype very different from younger patients. The combination of differing underlying pathogenic mechanisms and the physiological aspects of ageing result in a greater disease impact in older CFS patients.

Hyperglycemia can delay left ventricular dysfunction but not autonomic damage after myocardial infarction in rodents

BackgroundAlthough clinical diabetes mellitus is obviously a high risk factor for myocardial infarction (MI), in experimental studies disagreement exists about the sensitivity to ischemic injury of an infarcted myocardium. Recently, our group demonstrated that diabetic animals presented better cardiac function recovery and cellular resistance to ischemic injury than nondiabetics. In the present study, we evaluated the chronic effects of MI on left ventricular (LV) and autonomic functions in streptozotocin (STZ) diabetic rats.MethodsMale Wistar rats were divided into 4 groups: control (C, n = 15), diabetes (D, n = 16), MI (I, n = 21), and diabetes + MI (DI, n = 30). MI was induced 15 days after diabetes (STZ) induction. Ninety days after MI, LV and autonomic functions were evaluated (8 animals each group). Left ventricular homogenates were analyzed by Western blotting to evaluate the expression of calcium handling proteins.ResultsMI area was similar in infarcted groups (~43%). Ejection fraction and +dP/dt were reduced in I compared with DI. End-diastolic pressure was additionally increased in I compared with DI. Compared with DI, I had increased Na+-Ca2+ exchange and phospholamban expression (164%) and decreased phosphorylated phospholamban at serine16 (65%) and threonine17 (70%) expression. Nevertheless, diabetic groups had greater autonomic dysfunction, observed by baroreflex sensitivity and pulse interval variability reductions. Consequently, the mortality rate was increased in DI compared with I, D, and C groups.ConclusionsLV dysfunction in diabetic animals was attenuated after 90 days of myocardial infarction and was associated with a better profile of calcium handling proteins. However, this positive adaptation was not able to reduce the mortality rate of DI animals, suggesting that autonomic dysfunction is associated with increased mortality in this group. Therefore, it is possible that the better cardiac function has been transitory, and the autonomic dysfunction, more prominent in diabetic group, may lead, in the future, to the cardiovascular damage.

Painful Diabetic Neuropathy Is Associated With Greater Autonomic Dysfunction Than Painless Diabetic Neuropathy

OBJECTIVEAlthough a clear link between diabetic peripheral neuropathy (DPN) and autonomic neuropathy is recognized, the relationship of autonomic neuropathy with subtypes of DPN is less clear. This study aimed to investigate the relationship of autonomic neuropathy with painless and painful DPN.RESEARCH DESIGN AND METHODSEighty subjects (20 healthy volunteers, 20 with no DPN, 20 with painful DPN, 20 with painless DPN) underwent detailed neurophysiological investigations (including conventional autonomic function tests [AFTs]) and spectral analysis of short-term heart rate variability (HRV), which assesses sympathovagal modulation of the heart rate. Various frequency-domain (including low frequency [LF], high frequency [HF], and total power [TP]) and time-domain (standard deviation of all normal-to-normal R-R intervals [SDNN] and root mean square of successive differences [RMSSD]) parameters were assessed.RESULTSHRV analysis revealed significant differences across the groups in LF, HF, TP, SDNN, and RMSSD (ANOVA P < 0.001). Subgroup analysis showed that compared with painless DPN, painful DPN had significantly lower HF (3.59 ± 1.08 [means ± SD] vs. 2.67 ± 1.56), TP (5.73 ± 1.28 vs. 4.79 ± 1.51), and SDNN (2.91 ± 0.65 vs. 1.62 ± 3.5), P < 0.05. No significant differences were seen between painless DPN and painful DPN using an AFT.CONCLUSIONSThis study shows that painful DPN is associated with significantly greater autonomic dysfunction than painless DPN. These changes are only detected using spectral analysis of HRV (a simple test based on a 5-min electrocardiogram recording), suggesting that it is a more sensitive tool to detect autonomic dysfunction, which is still under-detected in people with diabetes. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fiber involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN.

Depression, Heart Rate Variability, and Acute Myocardial Infarction

Clinical depression is associated with an increased risk for mortality in patients with a recent myocardial infarction (MI). Reduced heart rate variability (HRV) has been suggested as a possible explanation for this association. The purpose of this study was to determine if depression is associated with reduced HRV in patients with a recent MI. Three hundred eighty acute MI patients with depression and 424 acute MI patients without depression were recruited. All underwent 24-hour ambulatory electrocardiographic monitoring after hospital discharge. In univariate analyses, 4 indices of HRV were significantly lower in patients with depression than in patients without depression. Variables associated with HRV were then compared between patients with and without depression, and potential confounds were identified. These variables (age, sex, diabetes, and present cigarette smoking) were entered into an analysis of covariance model, followed by depression status. In the final model, all but one HRV index (high-frequency power) remained significantly lower in patients with depression than in patients without depression. We conclude that greater autonomic dysfunction, as reflected by decreased HRV, is a plausible mechanism linking depression to increased cardiac mortality in post-MI patients.