Seasonal patterns of sickness absence due to diagnosed mental disorders: a nationwide 12-year register linkage study.

AIMS: Although seasonality has been documented for mental disorders, it is unknown whether similar patterns can be observed in employee sickness absence from work due to a wide range of mental disorders with different severity level, and to what extent the rate of change in light exposure plays a role. To address these limitations, we used daily based sickness absence records to examine seasonal patterns in employee sickness absence due to mental disorders. METHODS: We used nationwide diagnosis-specific psychiatric sickness absence claims data from 2006 to 2017 for adult individuals aged 16-67 (n = 636,543 sickness absence episodes) in Finland, a high-latitude country with a profound variation in daylength. The smoothed time-series of the ratio of observed and expected (O/E) daily counts of episodes were estimated, adjusted for variation in all-cause sickness absence rates during the year. RESULTS: Unipolar depressive disorders peaked in October-November and dipped in July, with similar associations in all forms of depression. Also, anxiety and non-organic sleep disorders peaked in October-November. Anxiety disorders dipped in January-February and in July-August, while non-organic sleep disorders dipped in April-August. Manic episodes reached a peak from March to July and dipped in September-November and in January-February. Seasonality was not dependent on the severity of the depressive disorder. CONCLUSIONS: These results suggest a seasonal variation in sickness absence due to common mental disorders and bipolar disorder, with high peaks in depressive, anxiety and sleep disorders towards the end of the year and a peak in manic episodes starting in spring. Rapid changes in light exposure may contribute to sickness absence due to bipolar disorder. The findings can help clinicians and workplaces prepare for seasonal variations in healthcare needs.

Gene therapy for ischaemic heart disease and heart failure.

Gene therapy has been expected to become a novel treatment method since the structure of DNA was discovered in 1953. The morbidity from cardiovascular diseases remains remarkable despite the improvement of percutaneous interventions and pharmacological treatment, underlining the need for novel therapeutics. Gene therapy-mediated therapeutic angiogenesis could help those who have not gained sufficient symptom relief with traditional treatment methods. Especially patients with severe coronary artery disease and heart failure could benefit from gene therapy. Some clinical trials have reported improved myocardial perfusion and symptom relief in CAD patients, but few trials have come up with disappointing negative results. Translating preclinical success into clinical applications has encountered difficulties in successful transduction, study design, endpoint selection, and patient selection and recruitment. However, promising new methods for transducing the cells, such as retrograde delivery and cardiac-specific AAV vectors, hold great promise for myocardial gene therapy. This review introduces gene therapy for ischaemic heart disease and heart failure and discusses the current status and future developments in this field.

Determinants of re-operation for bleeding in head and neck cancer surgery.

OBJECTIVE: Post-operative bleeding in the head and neck area is potentially fatal. This 'real world' study sought to assess factors that increase the risk of re-operation for post-operative bleeding in head and neck cancer surgery. METHODS: A total of 456 patients underwent surgery for head and neck cancer (591 operations). The primary endpoint was re-operation for bleeding. RESULTS: The rate of re-operation for bleeding was 5 per cent of all operations. Re-operation for bleeding was an independent risk factor for 30-day mortality (odds ratio = 5.27, p = 0.014). Risk factors for re-operation because of bleeding included excessive (more than 4000 ml) fluid administration (over 24 hours) (p < 0.001), heavy alcohol consumption (p = 0.014), pre-operative oncological treatment (p = 0.017), advanced disease stage (p = 0.020) and higher tumour (T) classification (p = 0.034). Operations with more excessive bleeding (700 ml or more) were associated with an increased risk (p = 0.001) of re-operation for post-operative bleeding. Moreover, the risk of re-operation was significantly higher in patients undergoing microvascular surgery compared to those who had no oncological treatment pre-operatively (18 vs 6 per cent, p = 0.001). CONCLUSION: The 30-day mortality risk increased over 5-fold in patients undergoing re-operation for bleeding.

Incidence and predictors of 30-day cardiovascular complications in patients undergoing head and neck cancer surgery.

Incidence and predictors of peri-operative or post-operative cardiovascular complications in head and neck cancer surgery remain poorly elucidated. In this retrospective study, we investigated the rate and pre-operative risk factors for cardiovascular and cerebrovascular complications. This study included all patients (n = 456) operated for head and neck cancer between 1999 and 2008. Patients' medical records were reviewed and the adjudication of endpoints was performed by adjudication committee. The 30-day incidence of cardiovascular and cerebrovascular complications was 7.2 %. Cardiac mortality at 30 days was 1.0 %. Univariate predictors of MACCE (major adverse cardiac and cerebrovascular events) at the 30-day follow-up were history of myocardial infarction (OR 4.56, 95 % CI 1.73-11.97, p = 0.002); history of heart failure (OR 4.14, 95 % CI 1.32-13.02, p = 0.015); pre-existing coronary artery disease (OR 3.98, 95 % CI 1.75-9.06, p = 0.001); prior aspirin medication (OR 3.73, 95 % CI 1.81-7.71, p < 0.001); prior betablocker medication (OR 3.67, 95 % CI 1.79-7.51, p < 0.001); hypertension (OR 2.55, 95 % CI 1.25-5.19, p = 0.010); and increasing age (OR 1.08, 95 % CI 1.05-1.12, p < 0.001). In a multivariate model, independent predictors of MACCE were pre-existing coronary artery disease (OR 2.45, 95 % CI 1.03-5.80, p = 0.042) and increasing age (OR 1.08, 95 % CI 1.04-1.11, p < 0.001). Patients having surgery for head and neck cancer are at high (>5 %) risk of developing vascular complications. Prior coronary artery disease and increasing age are independent risk factors for MACCE.

The effect of prior percutaneous coronary intervention on the immediate and late outcome after coronary artery bypass grafting: systematic review and meta-analysis.

INTRODUCTION: A number of studies reported on a possible increased risk of morbidity and mortality after coronary artery bypass grafting in patients with prior percutaneous coronary intervention. METHODS: A systematic review and meta-analysis of studies comparing the outcome of patients undergoing coronary surgery with or without prior percutaneous coronary intervention was performed. Only studies reporting results of adjusted analysis and excluding acute percutaneous coronary intervention failures were included in this meta-analysis. RESULTS: Literature search yielded nine studies reporting on 68,645 patients who underwent coronary surgery. Of them, 8,358 (12.2%) had a prior percutaneous coronary intervention. Patients without prior percutaneous coronary intervention were significantly older (p=0.002), had significantly higher prevalence of left main stenosis (p=0.005) and three-vessel disease (p<0.0001). Prior percutaneous coronary intervention was associated with higher risk of resternotomy for bleeding (p=0.04) and dialysis (p=0.003). Thirty-day/in-hospital mortality was significantly higher in patients with prior percutaneous coronary intervention (pooled rate: 2.7% vs 2.0%, risk ratio 1.39, 95% confidence interval 1.06-1.84, p=0.02) as confirmed also by generic inverse variance analysis (risk ratio 1.47, 95% confidence interval 1.12-1.93, p=0.005). Prior percutaneous coronary intervention did not affect late outcome (five studies included, risk ratio 1.07, 95% confidence interval 0.90-1.28, p=0.43). CONCLUSIONS: Prior percutaneous coronary intervention seems to be associated with an increased risk of immediate postoperative morbidity and mortality after coronary surgery, but does not affect late mortality. These results are not conclusive and need to be confirmed by studies of better quality evaluating the impact of indication, timing, type of stents, amount of treated vessels and number of previous percutaneous coronary interventions.

White matter damage of the brain is associated with poor outcome in vascular surgery patients with claudication: a pilot study.

OBJECTIVE: Peripheral arterial disease (PAD) is a systemic atherosclerotic syndrome with high post-operative morbidity and mortality. Fractional anisotropy (FA), an index measured by magnetic resonance diffusion tensor imaging (DTI), has been shown to be exceedingly sensitive to microstructural damage in brain white matter tracts. It is hypothesized that pre-operative white matter damage is more extensive in PAD patients scheduled for vascular surgery who experience an adverse long-term outcome. METHODS: Preoperative FA values were obtained in 24 consecutive PAD patients (age >40 years) scheduled for elective infrainguinal revascularization surgery and in 15 healthy age matched participants. All patients had their clinical history taken and underwent physical examination and laboratory tests. After surgery, patients were followed for a median of 52 months (range 40-63) and major adverse cardiovascular and cerebrovascular events (MACCE) were recorded. RESULTS: There were no statistically significant differences in baseline demographic or clinical variables between the MACCE group and the non-MACCE group. During follow up, eight PAD patients suffered a MACCE and they had lower FA values than patients without MACCE or healthy controls (mean ± SD 0.370 ± 0.017 vs. 0.392 ± 0.023 vs. 0.412 ± 0.018, p = .036 and p = .00007, respectively). Voxelwise analysis of the FA data revealed diffuse spatial distribution of white matter damage in PAD patients. There was no statistically significant association between the FA values and other clinical variables. CONCLUSION: Microstructural white matter damage was associated with poor outcome in PAD patients with claudication requiring surgical revascularization, and its extent may have clinical value in risk stratification.

Cardiac positron emission tomography/computed tomography imaging accurately detects anatomically and functionally significant coronary artery disease.

BACKGROUND: Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols. METHODS AND RESULTS: We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with (15)O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT. CONCLUSIONS: Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

Long-term prognosis after coronary artery bypass surgery.

OBJECTIVE: To analyse the risk of coronary heart disease (CHD) events and total mortality among patients who had coronary artery bypass graft (CABG) surgery during 1988-1992. METHODS: A population-based myocardial infarction (MI) register included data on invasive cardiac procedures among residents of the study area. The subjects aged 35-64 years were followed-up for 12 years for non-fatal and fatal CHD events and all-cause mortality, excluding events within 30 days of the CABG operation. CABG was performed on 1158 men and 215 women. RESULTS: The overall survival of men who underwent CABG was similar to the survival of the corresponding background population for about ten years but started to worsen after that. At twelve years of follow-up, 23% (n=266, 95% CI 234-298) of the men who had undergone the operation had died, while the expected proportion, based on mortality in the background population, was 20% (n=231, 95% CI 226-237). The CHD mortality of men who had undergone the operation was clearly higher than in the background population. Among women, the mortality after CABG was about twice the expected mortality in the corresponding background population. In Cox proportional hazards models age, smoking, history of MI, body mass index and diabetes were significant predictors of mortality. CONCLUSIONS: The prognosis of male CABG patients did not differ from the prognosis of the corresponding background population for about ten years, but started to deteriorate after that. History of MI prior to CABG and major cardiovascular risk factors was a predictor of an adverse outcome.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.

Heart rate dynamics during accentuated sympathovagal interaction.

Concomitant sympathetic and vagal activation can occur in various physiological conditions, but there is limited information on heart rate (HR) behavior during the accentuated sympathovagal antagonism. Beat-to-beat HR and blood pressure were recorded during intravenous infusion of incremental doses of norepinephrine in 18 healthy male volunteers (mean age 23 +/- 5 yr). HR and blood pressure spectra and two-dimensional Poincaré plots were generated from the baseline recordings and from the recordings at different doses of norepinephrine. The mean blood pressure increased (from 90 +/- 7 to 120 +/- 9 mmHg, P < 0.001), HR decreased (from 60 +/- 9 to 48 +/- 7 beats/min, P < 0.001), and the high-frequency spectral component of HR variability increased (P < 0.001) during the norepinephrine infusion as evidence of accentuated sympathovagal interaction. Abrupt aperiodic changes in sinus intervals that were not related to respiratory cycles or changes in blood pressure occurred in 14 of 18 subjects during the norepinephrine infusions. These fluctuations in sinus intervals resulted in a complex or parabola-shaped structure of the Poincaré plots of successive R-R intervals and a widening of the high-frequency spectral peak. In four subjects, the abrupt fluctuations in sinus intervals were followed by a sudden onset of fixed R-R interval dynamics with a loss of respiratory modulation of HR, resulting in a torpedo-shaped structure of the Poincaré plots. These data show that HR behavior becomes remarkably unstable during accentuated sympathovagal interaction, resembling stochastic dynamics or deterministic chaotic behavior. These features of HR dynamics can be better identified by dynamic analysis of beat-to-beat behavior of R-R intervals than by traditional analysis techniques of HR variability.

Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm.

The basic feature in the pathogenesis of abdominal aortic aneurysm (AAA) is the degradation of extracellular matrix components. This process is induced partly by cytokines secreted from inflammatory and mesenchymal cells. Circulating levels of inflammatory cytokines were studied in AAA patients and compared with subjects suffering from atherosclerotic disease only. Furthermore, the predictive value of cytokine concentrations was evaluated for aneurysm expansion rate. Circulating levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were measured in 50 AAA patients (40 men, 10 women), 42 patients with coronary heart disease (CHD) (23 men, 19 women), and 38 controls whose angiogram was normal (17 men, 21 women). No differences in cytokine concentrations were found between the CHD patients and the controls. AAA disease was found to be associated with significantly higher IL-1 beta and IL-6 concentrations in both male patients (median concentrations of 19.40 pmol/L and 6.45 pmol/L, respectively) and female patients (19.26 pmol/L and 7.99 pmol/L) than in either the CHD patients or the controls (P < .005). TNF-alpha levels were slightly higher in the AAA patients (1.64 pmol/L in the males and 1.59 pmol/L in the females) than in the other groups (P < .05). IFN-gamma levels were elevated significantly in the female AAA patients (3.75 pmol/L) compared with levels found in the other female (P < .05) or male (P < .01) patient groups. The measured cytokine concentrations were not related to the size of the aneurysm or the maximal thickness of the thrombus within the aneurysm. IFN-gamma concentration showed a significant positive correlation to the aneurysm expansion (R = .37, P < .02) and negative correlation to the concentration of aminoterminal propeptide of type III procollagen during 6-month follow up (R = -.42, P < .005). The results show that circulating levels of inflammatory cytokines are elevated in patients with AAA disease, suggesting that the production of these cytokines is increased in these patients compared with CHD patients and controls. Elevated INF-gamma concentrations seem to predict an increased rate of expansion in AAA.

Lymphocyte responses to Chlamydia antigens in patients with coronary heart disease.

AIMS: To clarify the relationship of Chlamydia pneumoniae infection and coronary atherosclerosis we studied cell-mediated and humoral immune responses to Chlamydia in 93 patients with angiographically confirmed coronary heart disease and in 115 controls without angiographically demonstrable lesions. METHODS AND RESULTS: Cell-mediated responses were analysed by measuring lymphocyte proliferative reactivity to whole elementary body antigens of C. pneumoniae. Control antigens included C. trachomatis and purified protein derivative of tuberculin. Chlamydia-specific antibodies were measured using microimmunofluorescence assay. Marked C. pneumoniae-specific immune reactivity, demonstrated by the high incidence of elevated IgG and IgA antibodies and strong lymphocyte proliferative response, was associated with coronary heart disease in male but not in female patients or controls. In male patients, the cell-mediated responses were strong to C. pneumoniae (median stimulation index 9,6) and to C. trachomatis (stimulation index 6,9). The females with coronary heart disease showed significantly stronger cell-mediated responses to C. pneumoniae (stimulation index 6,5) than to C. trachomatis (3,8; P < 0.001) and were comparable to the controls. CONCLUSION: Marked cell-mediated and humoral immunity to C. pneumoniae in males with coronary heart disease suggest that the immune mechanisms triggered by Chlamydia are a possible contributing factor in the disease pathogenesis of coronary atherosclerosis in males. The Chlamydia-specific cell-mediated responses seem to be predominantly induced by antigenic structures that are similar among different Chlamydia-species.

No evidence for ischemic preconditioning during repeated vessel occlusion in coronary angioplasty.

Coronary angioplasty has been the favoured model in studying ischemic preconditioning in humans, but results have remained controversial, possibly due to some artefacts related to coronary balloon angioplasty as an ischemia model. We examined this issue by monitoring the sequential metabolic, functional and neurohumoral changes during repeated vessel occlusion in coronary angioplasty performed in patients with chronic angina pectoris. Two groups of patients undergoing two successive balloon inflations of approximately 2 min duration were studied. These balloon inflations were preceded by a short inflation performed immediately after introduction of the balloon into the stenosis. The aim of this primary inflation was to establish adequate coronary blood flow with the deflated balloon in the stenosis and to guarantee that the subsequent two balloon inflations were truly comparable in time. Group I consisted of 23 patients, in whom the changes in the degree of angina, pulmonary capillary wedge pressure (PCWP), atrial natriuretic peptide (ANP) and circulating catecholamines during the procedure were studied. The sequential changes in myocardial metabolism were monitored in group II of nine patients by determining the lactate extraction ratios and femoroarterial coronary sinus (Fa-CS) differences in pH and pCO2 before and after each balloon inflation. In group I, PCWP and total catecholamines increased similarly during both balloon inflations, but ANP remained unchanged. In group II patients the lactate extraction ratios turned negative, the Fa-CS pH-differences increased and the pCO2-differences decreased during vessel occlusions, the changes being somewhat more prominent during the second balloon inflation. To study adaptation to ischemia, the group I patients were divided into two subgroups with and without signs of ischemic dysfunction during balloon inflations (PCWP increase > 5 mmHg and < 5 mmHg, respectively), and the group II patients were divided into two subgroups with and without metabolic ischemia (lactate-producers and non-producers). The ANP levels were constantly higher in the patients demonstrating ischemic dysfunction during balloon inflations, but catecholamine levels increased only after the second balloon inflation. The anginal pain experienced by the patients and the signs of metabolic ischemia were identical during both balloon inflations. We conclude that acute ischemic preconditioning does not occur in patients with repeated vessel occlusions of approximately 2 min duration. The patients without ischemia during the procedure had more critical stenoses and pre-existing collaterals. However, other protective mechanisms, such as chronic adaptation at the cellular level or recruitment of new collaterals, cannot be excluded.

Abnormalities in beat-to-beat dynamics of heart rate before the spontaneous onset of life-threatening ventricular tachyarrhythmias in patients with prior myocardial infarction.

BACKGROUND: Beat-to-beat analysis of RR intervals can reveal patterns of heart-rate dynamics, which are not easily detected by summary measures of heart-rate variability. This study was designed to test the hypothesis that alterations in RR-interval dynamics occur before the spontaneous onset of ventricular tachyarrhythmias (VT). METHODS AND RESULTS: Ambulatory ECG recordings from 15 patients with prior myocardial infarction (MI) who had spontaneous episodes of sustained VT during the recording and VT inducible by programmed electrical stimulation (VT group) were analyzed by plotting each RR interval of a sinus beat as a function of the previous one (Poincaré plot). Poincaré plots were also generated for 30 post-MI patients who had no history of spontaneous VT events and no inducible VT (MI control subjects) and for 30 age-matched subjects without heart disease (normal control subjects). The MI control subjects and VT group were matched with respect to age and severity of underlying heart disease. All the healthy subjects and MI control subjects showed fan-shaped Poincaré plots characterized by an increased next-interval difference for long RR intervals relative to short ones. All the VT patients had abnormal plots: 9 with a complex pattern, 3 ball-shaped, and 3 torpedo-shaped. Quantitative analysis of the Poincare plots showed the SD of the long-term RR-interval variability (SD2) to be smaller in all VT patients (52+/-14 ms; range, 31 to 75 ms) than in MI control subjects (110+/-24 ms; range, 78 to 179 ms, P<.001) or the normal control subjects (123+/-38 ms, P<.001), but the SD of the instantaneous beat-to-beat variability (SD1) did not differ between the groups. The complex plots were caused by periods of alternating sinus intervals, resulting in an increased SD1/SD2 ratio in the VT group. This ratio increased during the 1-hour preceding the onset of 27 spontaneous VT episodes (0.43+/-0.20) compared with the 24-hour average ratio (0.33+/-0.19) (P<.01). CONCLUSIONS: Reduced long-term RR-interval variability, associated with episodes of beta-to-beat sinus alternans, is a highly specific sign of a propensity for spontaneous onset of VT, suggesting that abnormal beat-to-beat heart-rate dynamics may reflect a transient electrical instability favoring the onset of VT in patients conditioned by structurally abnormal hearts.

Effects of perfusion of the infarct-related artery on risk markers of life-threatening arrhytmias in patients with prior myocardial infarction

Programmed electrical stimulation (PES), angiographic studies, Holter recording, 12-lead ECG and signal averaged ECG (SAECG, n=63) were performed in 109 consecutive patients with a prior Q-wave myocardial infarction (MI). Sixty-five patients (59 por cento) had TMI-class ) or 1 antegrade perfusion without significant collateral filling of the infarct related artery (IRA) (=poor persuion) and forty four (41 por cento) had either good antegrade or collateral perfusion of the IRA. The severity of corony artery disease or ejection fraction did not differ between the patients with poor or good perfusion of IRA. Heart rate variability and presence of late potentials on SAECG were also similar between the groups. but the dispersion of the QT interval was prolonged in the patients with poor perfusion of IRA (86 +/- 35 ms vs. 69 +/- 27 ms, p<0.01). The patients with poor perfusion of IRA had more often a clinical history of VT compared to those with good perfusion (68 por cento vs 9 por cento, p<0.01). Patets with good filling of the IRA after a prior MI have a low risk for VT, suggesting that preserved perfusion of the infarct scar stabilizes the electrophysiologic substrate.

Acute ethanol-induced changes in cerebral blood flow.

Using high-resolution single photon emission computed tomography, the authors studied changes in cerebral blood flow (CBF) in six healthy men after the men rapidly consumed intoxicating amounts of ethanol. When the subjects were given intravenous placebo before ethanol intake, regional CBF was significantly increased over baseline in the right prefrontal cortex, but no significant change in CBF was observed when the subjects received intravenous naloxone before ethanol intake. The results indicate that euphoria occurring during acute ethanol intake is associated with activation of the right prefrontal cortex and mediated through the endogenous opioid system.