Mikael K. Poulsen

Left Ventricular Diastolic Function in Type 2 Diabetes Mellitus Prevalence and Association With Myocardial and Vascular Disease

Background—Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results—A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction (P=0.002) or LA volume index ≤32 mL/m2 (P<0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score (P<0.001) and valvulo-arterial impedance (P=0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score (P<0.001) was a predictor of LA dilation. Conclusions—Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration—The trial has been registered at www.clinicaltrial.gov with Identifier: NCT00298844.Background— Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results— A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction ( P =0.002) or LA volume index ≤32 mL/m2 ( P <0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score ( P <0.001) and valvulo-arterial impedance ( P =0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score ( P <0.001) was a predictor of LA dilation. Conclusions— Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration— The trial has been registered at www.clinicaltrial.gov with Identifier: [NCT00298844][1]. Received December 13, 2008; accepted October 20, 2009. # CLINICAL PERSPECTIVE {#article-title-2} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00298844&atom=%2Fcirccvim%2F3%2F1%2F24.atom

Global strain in severe aortic valve stenosis: relation to clinical outcome after aortic valve replacement.

Background— Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. Methods and Results— A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P =0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02–1.25), P =0.04. Comparing the overall log likelihood χ2 of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. Conclusions— In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors. Clinical Trial Registration— URL: [http://www.clinicaltrials.gov][1]. Unique identifier: [NCT00294775][2]. [1]: http://www.clinicaltrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00294775&atom=%2Fcirccvim%2F5%2F5%2F613.atomBackground—Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. Methods and Results—A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P=0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02–1.25), P=0.04. Comparing the overall log likelihood &khgr;2 of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. Conclusions—In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775.

Automated detection of hypoglycemia-induced EEG changes recorded by subcutaneous electrodes in subjects with type 1 diabetes--the brain as a biosensor

AIMS Hypoglycemia unawareness is a common condition associated with increased risk of severe hypoglycemia. We test the hypothesis that specific changes in the electroencephalogram (EEG) during hypoglycemia can be recorded by subcutaneous electrodes and processed by a general mathematical algorithm, and that hypoglycemia associated EEG changes appear before the development of severe hypoglycemia. METHODS Fifteen patients with type 1 diabetes were exposed to insulin-induced hypoglycemia and EEG was recorded. The cognitive function was evaluated by repeated cognitive testing. Insulin infusion was terminated when plasma glucose reached 1.8mmol/l or when the subjects showed obvious signs of cognitive dysfunction. EEG was analyzed by an automated mathematical algorithm with a predefined threshold of hypoglycemia. RESULTS Hypoglycemia associated EEG changes were detected by the mathematical algorithm in all subjects. Plasma glucose at the time of EEG changes above the threshold value ranged from 2.0 to 3.4mmol/l and occurred 29+/-28min (range 3-113min) before termination of insulin infusion. CONCLUSIONS Hypoglycemia associated EEG changes could be detected by an automated mathematical algorithm in all subjects exposed to insulin-induced hypoglycemia. In 12 of 15 patients, EEG changes occurred before severe hypoglycemia as evaluated by the cognitive testing.

Left Ventricular Diastolic Function Is Associated With Symptom Status in Severe Aortic Valve Stenosis

Background—In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. Methods and Results—In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P=0.002), presented less often with atrial fibrillation (13% versus 24%; P=0.05) and chronic obstructive pulmonary disease (2% versus 19%; P<0.001), and had a lower prevalence of hypertension (73% versus 40%; P<0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m2; P<0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P<0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P<0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m2; P=0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. Conclusions—The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus

BackgroundCardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.MethodsType 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.ResultsThe prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.ConclusionsIncreased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.Trial registration numberat http://www.clinicaltrial.gov: NCT00298844

Plasma fibulin-1 is linked to restrictive filling of the left ventricle and to mortality in patients with aortic valve stenosis.

Background Plasma fibulin-1 levels have been associated with N-terminal pro–B-type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. Methods and Results One hundred twenty-five patients with severe aortic stenosis who were scheduled for aortic valve replacement (AVR) were evaluated with preoperative echocardiography and their plasma fibulin-1 levels were determined with ELISA. The cohort was followed for a median of 4 years after AVR. Increased restrictive left ventricular (LV) filling pattern was observed with increased plasma fibulin-1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin-1 tertile groups, P=0.004). Likewise, reduced longitudinal systolic LV function (6.6±1.1 versus 6.1±1.3 versus 5.7±1.5 cm/s, P=0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin-1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13±4 versus 15±5 versus 16±6 in the fibulin-1 tertile groups, P=0.04). Conclusions In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin-1 is associated with restrictive filling of the LV, decreased longitudinal systolic function of the LV, and increased LV filling pressures. Clinical Trial Registration URL: http://www.clinicaltrial.gov with Identifier: NCT00294775

Coronary, Carotid, and Lower-extremity Atherosclerosis and Their Interrelationship in Danish Patients with Systemic Lupus Erythematosus

Objective. Atherosclerosis is highly prevalent among patients with systemic lupus erythematosus (SLE), but has been demonstrated predominantly in non-European SLE cohorts and few investigations have included more than 1 imaging modality. We aimed to investigate the prevalence of atherosclerosis in 3 frequently affected vascular territories, the coronary, carotid, and lower-extremity arteries, in a Danish, predominantly population-based SLE cohort. Methods. Patients with SLE without prior cardiovascular disease (CVD; n = 103) were screened for coronary artery calcification, carotid intima-media thickening and plaque, and abnormal ankle-brachial index by means of cardiac computed tomography, ultrasound of the carotid arteries, and ankle systolic blood pressure. Results. In patients with SLE, the prevalence of atherosclerosis in any vascular territory was 41%. The distribution of the atherosclerotic manifestations showed an overlap with 45% of the patients having involvement in more than 1 vascular territory. However, more than one-third of the patients with SLE with coronary, carotid, or lower-extremity atherosclerosis exclusively demonstrated this particular manifestation. Based on a multiple logistic regression model, age (p < 0.001), current smoking (p = 0.009), and the Systemic Lupus International Collaborating Clinics (SLICC; p = 0.008) were significant independent risk factors for atherosclerosis at any vascular territory. Conclusion. Atherosclerosis is highly prevalent among Danish patients with SLE without prior CVD. Screening for atherosclerosis in 1 vascular territory is insufficient in diagnosing atherosclerosis in patients with SLE. In Danish patients with SLE, the presence of atherosclerosis was not only assigned to traditional CV risk factors, but also associated with SLICC.

Plasma osteoprotegerin concentrations in peripheral sensory neuropathy in Type 1 and Type 2 diabetic patients

Diabet. Med. 27, 289–294 (2010)

Plasma copeptin as marker of cardiovascular disease in asymptomatic type 2 diabetes patients

Recently, copeptin was found associated with cardiovascular disease (CVD) and all-cause mortality in type 2 diabetes mellitus (T2DM) patients treated in primary care. This study aimed to evaluate whether plasma copeptin correlated to CVD in asymptomatic T2DM patients intensively investigated for sub-clinical CVD. A total of 302 T2DM patients referred to the Diabetes Clinic at Odense University Hospital, Denmark, entered the study. None of the patients had known or suspected CVD. As a control group, 30 healthy adults were recruited from the DanRisk study – a random sample of middle-aged Danes. A variety of clinical investigations were performed, including blood pressure measurements, carotid intima media thickness evaluation and myocardial perfusion scintigraphy. Blood sample analyses included copeptin measurements. Median plasma copeptin concentrations were similar in the T2DM group and the control group. However, men had significantly higher copeptin concentrations than women in the T2DM group (p < 0.001), and also, T2DM men had significantly higher copeptin concentrations than men without T2DM (p = 0.038). Copeptin correlated significantly with a number of variables, but the strongest correlation was with creatinine (R = 0.432, p < 0.001), and in multiple regression analysis, only this correlation remained significant. When association with clinical scores were investigated, plasma copeptin remained significantly associated with peripheral arterial disease (PAD) (p = 0.01). We found correlations between creatinine, copeptin levels and PAD in T2DM patients, and if confirmed, plasma copeptin combined with plasma creatinine could be a candidate for PAD screening in T2DM patients.

Hypoglycemia-Associated Electroencephalogram and Electrocardiogram Changes Appear Simultaneously:

Background: Tight glycemic control in type 1 diabetes mellitus (T1DM) may be accomplished only if severe hypoglycemia can be prevented. Biosensor alarms based on the bodys reactions to hypoglycemia have been suggested. In the present study, we analyzed three lead electrocardiogram (ECG) and single-channel electroencephalogram (EEG) in T1DM patients during hypoglycemia. Materials and Methods: Electrocardiogram and EEG recordings during insulin-induced hypoglycemia in nine patients were used to assess the presence of ECG changes by heart rate, and estimates of QT interval (QTc) and time from top of T wave to end of T wave corrected for heartbeat interval and EEG changes by extraction of the power of the signal in the delta, theta, and alpha bands. These six features were assessed continuously to determine the time between changes and severe hypoglycemia. Results: QT interval changes and EEG theta power changes were detected in six and eight out of nine subjects, respectively. Rate of false positive calculations was one out of nine subjects for QTc and none for EEG theta power. Detection time medians (i.e., time from significant changes to termination of experiments) was 13 and 8 min for the EEG theta power and QTc feature, respectively, with no significant difference (p = .25). Conclusions: Severe hypoglycemia is preceded by changes in both ECG and EEG features in most cases. Electroencephalogram theta power may be superior with respect to timing, sensitivity, and specificity of severe hypoglycemia detection. A multiparameter algorithm that combines data from different biosensors might be considered.