Association of Endodontic Lesions with Coronary Artery Disease.

An endodontic lesion (EL) is a common manifestation of endodontic infection where Porphyromonas endodontalis is frequently encountered. EL may associate with increased risk for coronary artery disease (CAD) via similar pathways as marginal periodontitis. The aim of this cross-sectional study was to delineate the associations between EL and CAD. Subgingival P. endodontalis, its immune response, and serum lipopolysaccharide were examined as potential mediators between these 2 diseases. The Finnish Parogene study consists of 508 patients (mean age, 62 y) who underwent coronary angiography and extensive clinical and radiographic oral examination. The cardiovascular outcomes included no significant CAD ( n = 123), stable CAD ( n = 184), and acute coronary syndrome (ACS; n = 169). EL was determined from a panoramic tomography. We combined data of widened periapical spaces (WPSs) and apical rarefactions to a score of EL: 1, no EL ( n = 210); 2, ≥1 WPS per 1 apical rarefaction ( n = 222); 3, ≥2 apical rarefactions ( n = 76). Subgingival P. endodontalis was defined by checkerboard DNA-DNA hybridization analysis, and corresponding serum antibodies were determined by ELISA. In our population, 50.4% had WPSs, and 22.8% apical rarefactions. A total of 51.2% of all teeth with apical rarefactions had received endodontic procedures. Subgingival P. endodontalis levels and serum immunoglobulin G were associated with a higher EL score. In the multiadjusted model (age, sex, smoking, diabetes, body mass index, alveolar bone loss, and number of teeth), having WPSs associated with stable CAD (odds ratio [OR] = 1.94, 95% confidence interval [95% CI] = 1.13 to 3.32, P = 0.016) and highest EL score were associated with ACS (OR = 2.46, 95% CI = 1.09 to 5.54, P = 0.030). This association was especially notable in subjects with untreated teeth with apical rarefactions ( n = 59, OR = 2.72, 95% CI = 1.16 to 6.40, P = 0.022). Our findings support the hypothesis that ELs are independently associated with CAD and in particular with ACS. This is of high interest from a public health perspective, considering the high prevalence of ELs and CAD.

Levosimendan: current data, clinical use and future development.

Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.

The role of cardiorenal biomarkers for risk stratification in the early follow-up after hospitalisation for acute heart failure.

CONTEXT: Cardiorenal biomarkers (CBs) predict outcome in acute heart failure (AHF). OBJECTIVE: To evaluate CBs in early follow-up prognostication. METHODS: In 124 AHF patients, levels of CystatinC, NT-proBNP and TroponinI measured five weeks from admission (W5) and relative change from day 2 (D2) were assessed for 6-month prognosis (mortality/HF hospitalization). RESULTS: The combined end-point occurred in 33 patients (27%). D2-, W5-cystatin≥ median, and lack of ≥30%decrease in NT-proBNP were independent predictors of outcome. Additionally, a risk score established from W5 CBs identified patients with very high event rate. CONCLUSIONS: CBs at early follow-up of AHF may guide risk stratification.

Fish consumption, omega-3 fatty acids, and environmental contaminants in relation to low-grade inflammation and early atherosclerosis.

BACKGROUND: Fish consumption and omega-3 polyunsaturated fatty acid (PUFA) intake are shown to protect from cardiovascular diseases (CVD). However, most fish contain environmental contaminants such as dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and methylmercury (MeHg) that may have adverse effects on cardiovascular health. OBJECTIVE: Our aim was to elucidate the associations of fish consumption, omega-3 PUFAs, environmental contaminants with low-grade inflammation, early atherosclerosis, and traditional CVD risk factors. METHODS: The Health 2000 survey participants (n=1173) represented the general Finnish population and the Fishermen study participants (n=255) represented a population with high fish consumption and high exposure to environmental contaminants. Model-adjusted geometric means and tests for linear trend were calculated for CVD risk factors by tertiles of fish consumption and serum omega-3 PUFAs, and additionally in the Fishermen study only, by tertiles of serum PCDD/F+PCB, and blood MeHg. RESULTS: Serum triglyceride decreased across omega-3 PUFA tertiles in both sexes and studies. Insulin resistance, C-reactive protein, tumour necrosis factor α, and interleukin 6 decreased across omega-3 PUFA tertiles among the Health 2000 survey participants. Among the Fishermen study men, insulin resistance and arterial stiffness indicated by ß-stiffness index tended to increase and the RR estimate for carotid artery plaque tended to decrease across tertiles of PCDD/F+PCB and MeHg. CONCLUSION: Previously established hypotriglyceridemic and anti-inflammatory effects of omega-3 PUFAs were seen also in this study. The hypothesised favourable effect on insulin sensitivity and arterial elasticity was suggested to be counteracted by high exposure to environmental contaminants but the effect on plaque prevalence appeared not to be harmful.

Cystatin C, NT-proBNP, and inflammatory markers in acute heart failure: insights into the cardiorenal syndrome.

BACKGROUND: Inflammation is thought to be a mediator in the pathophysiology of the cardiorenal syndrome. We evaluated the interactions between kidney function, cardiac stress, and various inflammatory cytokines in patients with acute heart failure (AHF). The effect on 1-year mortality was also assessed. METHODS AND RESULTS: Plasma levels of cystatin C, NT-proBNP, and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-α [TNF-α], IL-10) were measured in consecutive patients (n = 465) hospitalized for AHF. After adjustment for demographic characteristics and comorbidities, TNF-α had the strongest relation with renal function (ß = 0.39, P < 0.0001). Elevated TNF-α levels were seen in patients with high cystatin C, irrespective of NT-proBNP. Levels of IL-6 (ß = 0.26, P < 0.0001) and IL-10 (ß = 0.15, P < 0.01), but not TNF-α, were associated with NT-proBNP. Moreover, the most elevated levels of IL-6 were seen in patients with combined high NT-proBNP and high cystatin C. Cox regression analysis found IL-6 above median to be independently predictive of mortality (hazard ratio 1.9; 95% CI 1.2-2.9, P = 0.003). TNF-α was not significantly associated with prognosis in the overall population after adjustment for multiple covariates, but improved risk stratification in the subgroup with low cystatin C and NT-proBNP. CONCLUSION: Levels of TNF-α in AHF are related to kidney function, but not to NT-proBNP. IL-6 seems to be more associated with cardiac stress. Patients with severe dual organ dysfunction have the highest levels of IL-6 and TNF-α. Different relations of inflammatory cytokines to renal function and cardiac stress need to be considered when evaluating heart--kidney interactions.

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer.

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A(165) gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9-9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

Common candidate gene variants are associated with QT interval duration in the general population.

OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Lymphotoxin alpha LTA+496C allele is a risk factor for periodontitis in patients with coronary artery disease.

Periodontitis and coronary artery disease (CAD) are inflammatory diseases and associated with each other. The major histocompatibility complex (MHC) region carries genes involved in immune response and inflammation. We investigated whether the MHC genes correlate with the presence of periodontitis or with the occurrence of periodontal pathogens in patients with CAD. Blood and saliva samples from CAD patients (n = 106) were collected at the time of hospitalization. Nine MHC genetic markers [human leukocyte antigen (HLA)-A, HLA-B, HLA-DRB1, lymphotoxin alpha (LTA) +253(a/g), +496(C/T), +633(c/g), +724(C/A), C4A and C4B)] were typed. Based on panoramic tomography, patients were categorized into nonperiodontitis and periodontitis groups. Two major periodontal pathogens, Aggregatibacter (Actinobacillus) actinomycetemcomitans and Porphyromonas gingivalis, were cultivated and polymerase chain reaction-amplified from salivary samples. Serum immunoglobulin (Ig)A and IgG antibody levels to these pathogens were measured. In the univariate analysis, LTA+496C allele (OR = 5.29; 95% CI = 2.07-13.51, P = 0.00027), and the occurrence of P. gingivalis in saliva (OR = 4.74; 95% CI = 1.64-13.70; P = 0.002) were more frequent in periodontitis when compared with nonperiodontitis. Similarly, serum IgA antibody level against the pathogen was increased in periodontitis (P = 0.048). In the multiple logistic regression analysis, when a wide range of covariates was included, the LTA+496C allele (OR = 10.87; 95% CI = 3.23-36.60; P = 0.00012) and the elevated serum IgA antibody level against P. gingivalis (OR = 1.56; 95% CI = 1.05-2.30; P = 0.026) remained as significant risk factors for periodontitis. In conclusion, the major finding of this study is that the LTA+496C allele is associated with periodontitis in patients with CAD.

Human MHC region harbors both susceptibility and protective haplotypes for coronary artery disease.

Aiming to study the role of human major histocompatibility complex (MHC) region on coronary artery disease (CAD), we enrolled two separate patient materials and controls. First, heart transplantation recipients (n = 276) were divided into three subgroups according to the severity of atherosclerosis. The human leukocyte antigen (HLA)-A-B-DR haplotype and gene frequencies were compared between groups. Second, patients with acute coronary syndrome (ACS) (n = 100) and healthy controls (n = 74) were assessed by nine genetic MHC markers (HLA-A, HLA-B, HLA-DRB1, LTA+253(a/g), LTA+496(C/T), LTA+633(c/g), LTA+724(C/A), C4A and C4B), and the frequencies were compared. In the heart transplantation recipients, HLA-DR1 was strongly associated with CAD [severe vs no evidence, odds ratio (OR) 2.37; 95% confidence interval (CI) 1.33-4.25; P = 0.003]. Similarly, in the patients with ACS, HLA-DRB1*01 was associated with CAD (patients vs controls, OR 2.36; 95% CI 1.25-4.44; P = 0.007). HLA-DRB1*01 was associated with low-density-lipoprotein cholesterol (OR 5.32; 95% CI 1.64-17.26; P = 0.005) and smoking habit (OR 3.13; 95% CI 1.09-9.03; P = 0.035) as risk factors. The strongest protective gene was HLA-B*07 alone (OR 0.46; 95% CI 0.24-0.88; P = 0.02) or together with the haplotype LTA+253a-LTA+633g-C4A3-C4B1 (OR 0.36; 95% CI 0.22-0.57; P = 0.00001). In conclusion, human MHC region harbors genes that protect from and predispose to CAD.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1-7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1-7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1-7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Biodegradation of the copolymeric polylactide stent. Long-term follow-up in a rabbit aorta model.

The behavior of biodegradable polylactide as a stent material has not yet been fully established in small vessels such as arteries with a diameter <3 mm. The aim of this study was to investigate the long-term effect of a copolymeric polylactide (PLA96) stent. Appropriately sized spiral PLA96 stents were implanted into the infrarenal aortas of 20 rabbits. Intraoperative systemic heparinization (150 IU/kg), perioperative subcutaneous enoxaheparin sodium (10 mg), ticlopidine (250 mg/day) for 1 month, and acetosalicylic acid (12.5 mg/day) were continuously administered. Animals were euthanized according to a fixed timetable for up to 34 months for histologic and scanning-electron-microscopic assessment. Endothelialization was complete within 1 month. In 2 of the 3 aortas sampled 3 months after implantation, a mild inflammatory reaction was visible, with no sign of granulomatous or foreign-body reaction in the vessel wall. Instead, in 1 sample examined at the same time point, neointimal chondroid metaplasia was detected. After 6 months, inflammatory reaction declined in the vessel wall. Hydrolyzation of the stent was histologically evident at 12 months, with mild foreign-body reaction detectable in 2 of 5 aortas sampled at this time point. The stent disintegrated without fragmentation by 24 months, as it was gradually replaced by fibrosis. The vessel lumen remained patent at all time points. We conclude that the PLA96 stent degraded with minimal tissue response within 24 months. PLA96 may thus be a promising stent core material for small vessels in the future, although further investigation is needed to establish its final biocompatibility.

Cholesterol efflux capacity in vitro predicts the severity and extent of coronary artery disease in patients with and without type 2 diabetes.

OBJECTIVE: To investigate the relation between severity and extent of coronary artery disease (CAD) and in vitro cholesterol efflux capacity. DESIGN: This study consisted of 46 type 2 diabetic, and 42 nondiabetic men undergoing coronary angiography. Quantitative coronary angiography was used to estimate the severity, extent, and overall "atheroma burden" of CAD. The capacity of patient plasma to induce cholesterol efflux from cultured Fu5AH rat hepatoma cells was measured in vitro. RESULTS: In the combined study population (n = 88), there was a significant inverse correlation between efflux and global atheroma burden (r = -0.23, p < 0.05). In the diabetic group, the global atheroma burden index was independently associated both with cholesterol efflux and with LpA-I levels. However, in the nondiabetic CAD group this association was lost when efflux and LpA-I levels were included in the same model. CONCLUSION: The present study demonstrated that efflux capacity was inversely associated with the severity and extent of CAD. In the diabetic group this association was independent of LpA-I levels, suggesting impaired antiatherogenic potential of these particles in type 2 diabetic patients.

Determinants of the severity and extent of coronary artery disease in patients with type-2 diabetes and in nondiabetic subjects.

BACKGROUND: Factors predicting the anatomic distribution and the severity and extent of coronary atherosclerosis in patients with clinically manifest coronary artery disease (CAD) for type-2 diabetic patients could be different than those for nondiabetic patients. OBJECTIVE: To study the determinants of severity and extent of CAD in consecutive patients with type 2 diabetes mellitus, compared with those for matched nondiabetic patients, undergoing clinically indicated coronary angiography. METHODS: Coronary angiograms of 48 men and seven women with type-2 diabetes and an equal number of nondiabetic subjects were analyzed quantitatively. Scores reflecting severity and extent of CAD were compared with potential risk factors using univariate correlation analyses and multivariate regression models. RESULTS: For the diabetics, a global coronary atheroma burden index was independently and directly related to age (P = 0.022) and to level of intermediate-density lipoprotein cholesterol (P = 0.055), and inversely to level of particles of a subtype of high-density lipoprotein (P = 0.022). Several angiographic indexes were related to the duration of diabetes and control of glycemia. For the nondiabetic group, global atheroma burden was independently related to age (P = 0.028), a history of hypertension (P = 0.028), and concentration of low-density lipoprotein (P = 0.013), and inversely to level of apolipoprotein A-I (P = 0.008). The duration of coronary disease and a history of smoking were also predictive of severe coronary atherosclerosis among nondiabetic patients. CONCLUSIONS: Classical risk factors are strong predictors of the severity and extent of coronary atherosclerosis in nondiabetic patients, but the most important determinants for type-2 diabetic patients are levels of triglyceride-rich lipoproteins and apolipoprotein A-I-containing particles of high-density lipoprotein, and factors directly related to diabetes.

Randomized comparison between orally and transdermally administered hormone replacement therapy regimens of long-term effects on 24-hour ambulatory blood pressure in postmenopausal women.

OBJECTIVE: The aim of this study was to assess whether oral delivery and transdermal delivery of sequential combined hormone replacement therapy have similar effects on systemic blood pressure, as measured by 24-hour automated ambulatory recordings. STUDY DESIGN: Eighty-two healthy postmenopausal women, of whom 73 completed the study, were randomly assigned to start hormone replacement therapy with either orally (n = 38) or transdermally (n = 35) administered medication. Ambulatory blood pressure was recorded for a 24-hour period before the start of hormone replacement therapy and again 2 and 6 months later. Analysis of variance was used for data analysis. RESULTS: Hormone replacement therapy by both oral and transdermal routes was associated with slight but nonsignificant drops in mean 24-hour systolic and diastolic ambulatory blood pressure. Daytime systolic ambulatory blood pressure (mean +/- SE) fell significantly (P <.05) and similarly at 2 months in the oral (3.8 +/- 0.2 mm Hg) and transdermal (4.0 +/- 0.3 mm Hg) treatment groups. The daytime ambulatory blood pressure remained significantly lower than baseline at 6 months in the oral treatment group (-3.6 +/- 0.3 mm Hg), whereas the fall at 6 months in the transdermal group (-3.1 +/- 0.3 mm Hg) was not significant. Mean daytime diastolic ambulatory blood pressure was reduced in both the oral (-1.8 +/- 0.8 mm Hg) and transdermal (-3.5 +/- 0.7 mm Hg; P <.05) treatment groups at 2 months but not at 6 months. Nighttime ambulatory blood pressures in both groups remained unaffected by hormone replacement therapy. CONCLUSION: Sequential combined hormone replacement therapy delivered by both oral and transdermal routes caused significant falls in the daytime ambulatory blood pressure of normotensive postmenopausal women at 2 months of treatment. This fall persisted as long as 6 months of treatment in the oral treatment group but not in the transdermal treatment group.

Heart rate variability and progression of coronary atherosclerosis.

Low heart rate (HR) variability is associated with increased risk of cardiovascular morbidity and mortality, but the causes and mechanisms of this association are not well known. This prospective study was designed to test the hypothesis that reduced HR variability is related to progression of coronary atherosclerosis. Average HR and HR variability were analyzed in 12-hour ambulatory ECG recordings from 265 qualified patients participating in a multicenter study to evaluate the angiographic progression of coronary artery disease in patients with prior coronary artery bypass surgery and low high-density lipoprotein cholesterol concentrations (<1.1 mmol/L). Participants were randomized to receive a placebo or gemfibrozil therapy. The progression of coronary atherosclerosis was estimated by quantitative, computer-assisted analysis of coronary artery stenoses from the baseline angiograms and from repeated angiograms performed an average of 32 months later. The progression of focal coronary atherosclerosis of the patients randomized to placebo therapy was more marked in the tertile with the lowest standard deviation of all normal to normal R-R intervals (SDNN, 74+/-13 ms; mean decrease in the per-patient minimum luminal diameter -0.17 mm; 95% confidence interval [CI], -0.23 to -0.12 mm) than in the middle tertile (SDNN, 107+/-7 ms; mean decrease -0.05 mm; 95% CI, -0.08 to -0.01 mm) or highest tertile (SDNN, 145+/-25 ms; mean change 0.01 mm; 95% CI, -0. 04 to 0.02 mm) (P<0.001 between the tertiles). This association was abolished by gemfibrozil. SDNN was lower (P<0.001) and minimum HR was faster (P<0.01) in the patients with marked progression than in those with regression of focal coronary atherosclerosis. In multiple regression analysis including HR variability, minimum HR, demographic and clinical variables, smoking, blood pressure, glucose, lipid measurements and lipid-modifying therapy, progression of focal coronary atherosclerosis was independently predicted by the SDNN (beta=0.24; P=0.0001). Low HR variability analyzed from ambulatory ECG predicts rapid progression of coronary artery disease. HR variability provided information on progression of focal coronary atherosclerosis beyond that obtained by traditional risk markers of atherosclerosis.

Cardiomyocyte apoptosis and progression of heart failure to transplantation.

BACKGROUND: Cardiomyocyte apoptosis has been found in congestive heart failure, but its clinical significance has been difficult to study. We compared the occurrence of cardiomyocyte apoptosis in explanted hearts with the progression of severe heart failure until the need for transplantation. DESIGN: Using the TUNEL assay, apoptotic cardiomyocytes were quantified in explanted failing hearts from patients with either idiopathic dilated cardiomyopathy (n = 21) or ischaemic heart disease (n = 14). The percentage was compared with the clinical severity and progression of endstage heart failure. Samples obtained at autopsy and during open heart surgery served as controls. RESULTS: The number of apoptotic cardiomyocytes was significantly increased in failing hearts regardless of aetiology (medians 0.075% in ischaemic heart disease and 0.119% in dilated cardiomyopathy) compared with control myocardium. In patients with dilated cardiomyopathy, apoptotic cardiomyocytes were more numerous in subjects with a rapidly deteriorating clinical course (0.192%, n = 10) than in patients with intermediate (0.093%, n = 6, P = 0.03) or slow (0.026%, n = 5, P = 0.003) progression. No such association was observed in patients with ischaemic heart disease, in whom we found significantly increased cardiomyocyte apoptosis adjacent to scars of previous infarctions (0.576%) in contrast to the diffuse distribution seen in dilated cardiomyopathy. Expression of Bcl-2, an antiapoptotic protein, was increased in all failing hearts by immunohistochemistry. CONCLUSION: Cardiomyocyte apoptosis is a consistent feature of end-stage heart failure in man and appears to be quantitatively related to the clinical severity of deterioration in dilated cardiomyopathy. Increased expression of Bcl-2 in cardiomyocytes indicates activation of an antiapoptotic response. These observations suggest that cardiomyocyte apoptosis is a clinically relevant and potentially modifiable pathophysiological phenomenon in severe heart failure.

Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol.

BACKGROUND: Lipid-lowering secondary-prevention trials of coronary artery disease (CAD) have implicated triglyceride-rich lipoproteins as the main determinants of angiographic progression after elevated LDL cholesterol levels have been lowered with therapy. The present study focuses on the lipoprotein determinants of angiographic CAD progression in men with low HDL cholesterol concentration as their main baseline lipid abnormality who underwent 32 months of randomized therapy with gemfibrozil or placebo. METHODS AND RESULTS: Men who had undergone coronary bypass surgery (n=372) completed a randomized, placebo-controlled study with gemfibrozil 1200 mg/d. They were selected primarily for HDL cholesterol levels that corresponded to the lowest third for middle-aged men. Average baseline lipid and lipoprotein levels were serum triglyceride, 1.60; serum cholesterol, 5.17; ultracentrifugally separated LDL cholesterol, 3.43; HDL2 cholesterol, 0.41; and HDL3 cholesterol, 0. 61 mmol/L. In the gemfibrozil group, these levels were reduced on average by 40%, 9%, and 6% or increased by 5% and 9%, respectively. On-trial IDL and LDL triglyceride and cholesterol levels significantly predicted global angiographic progression, taking into account changes in native segments and in bypass grafts. HDL3 but not HDL2 cholesterol concentration was associated with protection against progression, especially focal disease in native coronary lesions. VLDL was the lipoprotein most predictive of new lesions in vein grafts; IDL was also significantly related. CONCLUSIONS: This study expands the previous evidence of the triglyceride-rich lipoproteins, especially IDL, as predictors of angiographic progression of CAD but does not negate the significance of mildly elevated LDL levels. Of the HDL subfractions, only HDL3 was protective in this group of men selected for their low initial HDL levels.

Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting.

AIMS: The aim of the study was to evaluate the effects on systemic and coronary haemodynamics and myocardial substrate utilization of a new calcium sensitizer, levosimendan, after coronary artery bypass grafting. METHODS AND RESULTS: Twenty-three low-risk patients were included in this randomized and double-blind study. They received placebo (n = 8), 8 (n = 8) or 24 (n = 7) micrograms.kg-1 of levosimendan after coronary artery bypass operation. Systemic and coronary sinus haemodynamics with thermodilution and myocardial substrate utilization were measured. The heart rate increased 11 beats.min-1 after the higher dose (P < 0.05). Cardiac output increased by 0.7 and 1.61.min-1 (P < 0.05 for both) after 8 and 24 micrograms.kg-1 of levosimendan, respectively. Systemic and pulmonary vascular resistance decreased significantly after both doses. Coronary sinus blood flow increased by 28 and 42 ml/(P = 0.054 for the combined effect) after the lower and higher dose, respectively. Myocardial oxygen consumption or substrate extractions did not change statistically significantly. CONCLUSION: Despite improved cardiac performance, levosimendan did not increase myocardial oxygen consumption or change myocardial substrate utilization. Thus levosimendan has the potential to treat low cardiac output states after cardiopulmonary bypass surgery.

Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke.

An increasing body of evidence has linked infections to atherosclerosis and thrombosis. Herpesviruses cause atherosclerosis in experimental animals. Herpesviruses can also be detected in atherosclerotic lesions in humans. Cytomegalovirus may play a role in arteriosclerosis in transplanted hearts, and this virus, together with tumor suppressor protein p53, can be found in restenosis lesions following angioplasty. Chlamydia pneumoniae and dental infections are associated with coronary heart disease in cross-sectional and longitudinal studies, and preceding respiratory infections are associated with ischemic stroke. Infections may favor formation of atherosclerosis and thrombosis by elevation of blood levels of fibrinogen, leukocytes, clotting factor, and cytokines and by alteration of the metabolism and functions of endothelial cells and monocyte macrophages. Low-grade infections may also be one of the causes of the inflammatory reaction observed in atherosclerotic lesions and acute ischemic symptoms, reflected in elevated levels of C-reactive protein. These observations warrant further studies in this field.

Amlodipine in patients with stable angina pectoris treated with beta-blockers. Double-blind comparison with placebo.

In order to assess additional anti-ischaemic effects of amlodipine (AML) on coronary artery disease (CAD) treated with beta-blockers, 32 patients with CAD, verified on angiograms, and stable angina were randomized to receive 5 mg/day of AML or placebo, increasing to 10 mg/day after 2 weeks. Baseline recording of 24-h ambulatory ECG and blood pressure, echocardiography and bicycle exercise test was repeated after treatment for 2 weeks and for 6 weeks. Reduction of ambulatory ischaemia was not significantly greater with AML than with placebo. In exercise tests the time to 0.1 mV ST segment depression and the total exercise time remained unaltered. Blood pressure was reduced by 10 mg AML. The total variability and the very low frequency component of heart rate were reduced after both doses. The clinical significance of the possible unfavourable change in autonomic modulation of the heart in CAD patients is not known.