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.

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.

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.

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.

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.

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.

Changes in myocardial energy metabolism in elective coronary angioplasty.

STUDY OBJECTIVE: The aim was to investigate the effect of coronary angioplasty on myocardial energy metabolism, and to assure the safety of the procedure in patients with coronary heart disease. DESIGN: Before angioplasty a catheter was introduced into the coronary sinus. Blood samples were taken simultaneously from femoral artery and coronary sinus before balloon inflation, upon balloon deflation, and two minutes later, and arteriovenous differences in myocardial substrates, pH, PCO2, oxygen saturation, and adenosine catabolites were determined. PATIENTS: 14 patients with angiographically documented coronary artery disease with lesions in the left coronary artery suitable for elective coronary angioplasty were included in the study. RESULTS: During balloon inflation the positive femoroarterial-coronary sinus difference of lactate turned negative, from 0.21(SEM 0.05) mM to -0.10(0.11)mM, p less than 0.02. At the same time pH and PCO2 differences increased: from 0.04(0.00) U to 0.07(0.01) U, p less than 0.01, and from -1.15(0.10) kPa to -1.41(0.10) kPa, p less than 0.01, respectively. The changes were, however, transient and the arteriovenous differences in these metabolic variables rapidly returned towards preinflation levels after balloon deflation. The femoroarterial-coronary sinus concentration differences in glucose and free fatty acids became positive in coronary angioplasty. The energy state remained good during the procedure as assessed from the negligible net efflux of adenosine and its degradation products. CONCLUSIONS: Elective coronary angioplasty can be performed without any persistent derangements in myocardial metabolism, and may in fact lead to improvement of utilisation of some myocardial substrates. Lactate appears to be a more sensitive indicator of short term ischaemia than adenosine degradation products.

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.

Comparison of dipyridamole-handgrip test and bicycle exercise test for thallium tomographic imaging.

Seventy-three patients with angina pectoris and 20 with atypical chest pain, who underwent coronary angiography, were examined by single-photon emission computed thallium tomography (TI-SPECT) using a combined dipyridamole-handgrip stress test. Perfusion defects were detected in 78 of 81 patients with angiographically significant coronary artery disease (CAD) (sensitivity 96%). In 9 of 12 patients without CAD, the thallium images were normal (specificity 75%). Thirty-five patients with CAD were reexamined by TI-SPECT using a dynamic bicycle exercise stress test. The sensitivity of the dipyridamole-handgrip test did not differ from the bicycle exercise test in diagnosing the CAD (97% vs 94%). Multiple thallium defects were seen in 19 of 22 (86%) patients with multivessel CAD by the dipyridamole-handgrip test but only in 14 of 22 (64%) by the bicycle exercise test. Noncardiac side-effects occurred in 17 of 93 (18%) patients after dipyridamole infusion. Cardiac symptoms were less common during the dipyridamole-handgrip test than during the bicycle exercise (15% vs 76%, p less than 0.01). These data suggest that the dipyridamole-handgrip test is a useful alternative stress method for thallium perfusion imaging, particularly in detecting multivessel CAD.

Prevalence and significance of gallium-67 uptake in the heart after open-heart surgery.

Radioactive gallium-67 (Ga-67) has been shown to accumulate within areas of pericardial inflammation. The present study estimated prospectively the prevalence and clinical significance of Ga-67 uptake in the heart in 62 patients 10 to 16 days after open-heart surgery. Of 62 patients studied, markedly diffuse Ga-67 uptake was detected in 21 (34%) and focal or mild diffuse uptake in 23 (37%). Results were negative in 18 (29%). Nine patients with a negative scan result (50%) had received corticosteroid therapy before imaging, whereas only 2 patients with a positive scan result (5%) were receiving steroids. The erythrocyte sedimentation rate and C-reactive protein level were both higher in patients with Ga-67 uptake compared with those with a negative scan result (p less than 0.01 in both). No other clinical, echocardiographic or electrocardiographic indicators of postpericardiotomy syndrome were related to Ga-67 uptake. No patient developed cardiac tamponade or constrictive pericarditis during the 12-week follow-up and the Ga-67 scan results did not predict the occlusion of coronary artery bypass grafts. Thus, pericardial inflammation manifested as Ga-67 uptake is a common finding after open-heart surgery and appears to be a benign condition.

Increase in cerebral blood flow of right prefrontal cortex in man during orgasm.

The functional anatomy of human emotional responses has remained poorly understood, mainly because invasive experiments in humans are unacceptable due to ethical reasons. The new functional imaging techniques such as positron emission tomography and single photon emission computed tomography have made it possible to study the neurophysiology of living humans noninvasively. We studied the regional cerebral blood flow with semi-quantitative 99mTc-HMPAO single photon emission computed tomography in eight healthy right-handed heterosexual males during organism. The results showed decrease of cerebral blood flow during orgasm in all other cortical areas except in right prefrontal cortex, where the cerebral blood flow increased significantly (P < 0.005).

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.

Twin study on cup/disc ratio of the optic nerve head.

Seventeen healthy twin pairs (10 monozygotic and seven dizygotic) from the Finnish Twin Cohort Study were examined to study the impact of heredity v environment in the determination of cup-to-disc area ratio. These twins were free from any known eye disease. The cup/disc ratio was determined using stereo photography and a computer assisted analysis technique. The zygosity of all twin pairs was confirmed with the DNA 'fingerprint' technique. The intrapair correlations were high among monozygotic pairs compared with those among dizygotic twin pairs. The difference of cup/disc area ratios between the right eyes of members of monozygotic twin pairs was statistically significantly smaller than that of dizygotic twin pairs (p < 0.001). The same was true for left eyes (p < 0.01). This result confirms a genetic determination in cup/disc area ratio in normal eyes.

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.

Rheumatoid arthritis as a cause of cardiac compression. Favourable long-term outcome of pericardiectomy.

In order to clarify the significance of rheumatoid arthritis (RA) as a cause of cardiac compression, we scrutinized pericardiectomy files of 47 patients over a ten-year period at two university hospitals in Finland. Five patients with RA were found. All the patients with RA were men with seropositive disease and subcutaneous rheumatoid nodules. Two of the patients had pulmonary fibrosis, one had cutaneous vasculitis and three had had rheumatoid pleurisy. There was a mean delay of 10 months from the first cardiac symptom to the diagnosis of cardiac compression, the most common misdiagnosis being primarily a liver disease. On the basis of clinical and operative data, four out of the five patients had constrictive pericarditis and one had an effusive-constrictive form of the disease. The histopathological findings in all cases were consistent with chronic fibrosing pericarditis. A follow-up of seven to seventeen years of four patients has not revealed any signs of recurrent pericardial disease. Our results demonstrate that RA is an important aetiological factor for cardiac compression. The long-term outcome of this manifestation seems to be good after pericardiectomy.

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.