Treatment of heart failure with preserved ejection fraction with SGLT2 inhibitors: new therapy standard?

Heart failure with preserved ejection fraction (HFpEF) is a common and difficult-to-treat heart disease. Approximately half of patients with heart failure suffer from this form, and mortality is between 5% and 7% per year. Previous therapeutic trials for the treatment of HFpEF have been disappointing. However, recent data on therapy with sodium-glucose cotransporter­2 (SGLT2) inhibitors in HFpEF are encouraging. In addition to numerous experimental studies showing improvement in diastolic dysfunction parameters, the EMPEROR-Preserved study demonstrated for the first time clinically that therapy with the SGLT2 inhibitor empagliflozin significantly reduced hospitalization for heart failure. By contrast, cardiovascular mortality was not affected. Differences for patients with and without type 2 diabetes mellitus were not observed. Thus, for the first time, there is an evidence-based treatment option to reduce hospitalization and improve quality of life in these patients. Further studies will show to what extent these beneficial effects will also lead to an improvement in the prognosis of these patients.

Laparoscopic-Assisted Ventriculoperitoneal Shunt Placement in Children Younger Than the Age of 1 Year.

OBJECTIVES: To analyze the safety and feasibility of laparoscopic-assisted ventriculoperitoneal shunt (VPS) insertion in children younger than the age of 1 year and weighing less than 5 kg. METHODS: We performed a retrospective review of children receiving laparoscopic-assisted VPS. Patient characteristics, complications, operation and hospitalization time, blood loss, and conversion to the standard approach were noted and analyzed. RESULTS: Laparoscopic-assisted VPS was performed in 25 children. Mean age was 32 months (range 19 days to 18 years); 16 patients (64%) were younger than the age of 1 year and 10 patients (38%) weighed less than 5 kg at the time of surgery. In all cases laparoscopic insertion was possible without the need to convert to the standard approach. No intraoperative laparoscopy-associated complications occurred. Mean estimated blood volume lost was 4.52%, showing no significant difference between patients younger and older than 1 year. Mean operation time was 75.44 minutes (range 45-121 minutes), and mean hospitalization time was 37.1 days (range 4-142 days, median: 22 days). Patients younger than the age of 1 year showed significant shorter operation time (P < 0.001) and longer hospitalization time (P = 0.04). Complication rate within 30 days was 24% (n = 6), and overall complication rate was 36% (n = 9), whereas none were related to the abdominal placement of the catheter, and showed no difference between the 2 age groups. CONCLUSIONS: Laparoscopic-assisted VPS insertion in children seems to be safe and feasible leading to very good results even in patients under the age of 1 and weighing less than 5 kg.

[Treatment of stable coronary artery disease in type II diabetes mellitus: drugs, coronary intervention and bypass surgery]. / Therapie der stabilen Angina pectoris bei Diabetes mellitus Typ 2: Medikamente, Koronarintervention und Bypass.

The prognosis of patients with type 2 diabetes is reduced by coronary artery disease. The aim of treatment is therefore not only to treat angina symptoms but also improve the prognosis by medical and interventional treatment. LDL-lowering and coronary revascularisation have the largest beneficial impact on prognosis.

A clinical risk score for heart failure in patients with type 2 diabetes and macrovascular disease: an analysis of the PROactive study.

BACKGROUND: Diabetes mellitus is associated with a high risk for heart failure, which is further increased in the presence of coronary heart disease. So far no clinical risk score for development of heart failure exists for patients with type 2 diabetes and macrovascular disease. METHODS: Independent clinical predictors for heart failure events were identified by Cox regression in a post-hoc analysis of the PROactive trial and were used for calculating a risk prediction score. RESULTS: 233 of 4951 patients with available baseline data suffered a serious adverse heart failure event during a mean follow-up of 34.5 (±2.3) months. Age, renal dysfunction, diuretic use, HbA1c, duration of diabetes, LDL-cholesterol, heart rate, right and left bundle branch block, microalbuminuria, previous myocardial infarction and pioglitazone treatment were independent predictors of heart failure. The risk score showed a good calibration and moderate discrimination (AUC 0.75). Patients were accurately stratified with an actual risk of 1.0%, 3.2% and 9.7% in the bottom, middle and top tertile of the score, respectively, with corresponding hazard ratios of 3.5 (95% CI 2.0-6.2) and 10.5 (95% CI 6.3-17.6) for the middle and top tertile compared to the bottom tertile (both p<0.0001). The score stratified well in subgroups defined by pioglitazone treatment, prior myocardial infarction, obesity, poor glycemic control and microalbuminuria. CONCLUSION: A risk score based on routinely assessed clinical variables proved a good stratification for future heart failure events in diabetic patients with macrovascular disease. Strategies targeting specific interventions and monitoring of high risk patients need further evaluation.

NT-pro-BNP for diagnostic and prognostic evaluation in patients hospitalized for syncope.

BACKGROUND: Single clinical parameters are inaccurate for diagnostic and prognostic estimation in patients with syncope. The cardiac marker NT-pro-BNP has not thoroughly been evaluated for this application. METHODS: NT-pro-BNP was assessed in 161 consecutive patients (median age 69 years, 58% male) hospitalized for syncope in a cardiological university department and association (odds ratio: OR, 95% confidence interval: CI) with diagnosis of cardiac cause and 6-months outcome was analyzed. RESULTS: NT-pro-BNP levels were significantly higher in patients with cardiac (n=78) compared to non-cardiac syncope (n=83). At a cutoff of 156 pg/ml, NT-pro-BNP showed a sensitivity of 89.7%, a specificity of 51.8% and a negative predictive value of 84.3% for the diagnosis of cardiac syncope. Increasing NT-pro-BNP was a significant predictor of cardiac syncope (OR 3.7, 95% CI 2.3-5.8 per standard deviation of Log NT-pro-BNP, p<0.001) and addition of NT-pro-BNP significantly improved a predictive model including heart rate, history of structural heart disease and abnormal ECG. Adding left-ventricular ejection fraction to the model did not change results. Sixty-three patients had an adverse event during hospitalization or 6-months follow-up. NT-pro-BNP>156 pg/ml significantly predicted an adverse outcome (OR 2.7, 95% CI 1.04-6.9, p=0.04) after multivariate adjustment. CONCLUSIONS: In patients hospitalized for syncope, NT-pro-BNP was a strong and independent diagnostic and prognostic marker and addition to conventional criteria of history and examination improved the discriminatory performance. Randomized trials must clarify the benefit and position of NT-pro-BNP in the management algorithm of patients with syncope.

[Diabetes and heart failure]. / Diabetes und Herzinsuffizienz.

Heart failure is a common complication of type 2 diabetes and bears a poor prognosis. For patients with diabetes and heart failure the commonly accepted standards for diagnosis and treatment of heart failure are to be applied, although prospective diabetes- specific trials are lacking. The optimum HbA(1c) target value as well as the optimum blood glucoselowering treatment are not known. Due to an absence of prospective randomized trials the treatment should follow general therapeutic principles (low incidence of side effects, combination therapy, patient-friendly dosage, costs).

The relationship and prognostic impact of low-T3 syndrome and NT-pro-BNP in cardiovascular patients.

OBJECTIVES: Low-T3 syndrome is highly prevalent and independently prognostic in cardiovascular patients. The relationship and prognostic impact with the cardiac marker NT-pro-BNP have not been thoroughly investigated. METHODS: Thyroid hormone levels and NT-pro-BNP were assessed in 615 consecutive patients hospitalized for cardiovascular disease. Patients with primary overt or latent thyroid disorder, hormone replacement, thyreostatic and amiodarone therapy were excluded. The association with and predictive impact on mortality were examined. RESULTS: 36 (7.1%) patients had low-T3 syndrome. After adjustment for known confounders, NT-pro-BNP was significantly associated with fT3 and low-T3 syndrome. fT3 (HR 0.58, 95%CI 0.34-0.98) and low-T3 syndrome (HR 3.0, 95%CI 1.4-6.3) were predictive for mortality after adjustment for NT-pro-BNP levels and other cardiovascular prognostic variables. In patients with fT3 levels within the normal range, fT3 and NT-pro-BNP stratified by median values showed complementary prognostic information with the highest risk for mortality in patients with low normal fT3 and high NT-pro-BNP (HR 10.5, 95%CI 3.2-34.6). CONCLUSIONS: fT3 and low-T3 syndrome are significantly related to NT-pro-BNP in patients with cardiovascular disease, but are predictors of mortality independently of NT-pro-BNP and other known cardiovascular risk parameters.

NT-pro-BNP for differential diagnosis in patients with syncope.

BACKGROUND: Syncope is a frequent diagnosis and establishing the etiology is often elaborate. Aim of this study was to evaluate the diagnostic value of NT-pro-BNP in patients with syncope. METHODS: NT-pro-BNP was assessed in 61 patients admitted for syncope to our cardiological department of the University hospital Cologne, Germany. RESULTS: 16 patients (26.2%) had neurally-mediated syncope, 9 (14.8%) had orthostatic syncope, 12 (19.7%) had cardiac arrhythmias, 8 (13.1%) had structural cardiac/cardiopulmonary disease, 2 patients (3.3%) had cerebrovascular disease, 3 (4.9%) had non-syncopal attack and in 11 (18%) patients the cause remained unknown. Patients with cardiac syncope had significantly higher NT-pro-BNP values (514 IQR 286-1154 pg/ml) than patients with non-cardiac cause (182 IQR 70-378 pg/ml, p=0.001). NT-pro-BNP at a cut-off of 164 pg/ml identified patients with cardiac syncope and patients requiring interventional cardiological therapy with a sensitivity of 90% and 93.8%, a specificity of 48.8% and 46.7% and a negative predictive value of 91% and 95.5%. NT-pro-BNP pre-testing could save 45% of the Holter ECGs, 83% of the telemetry monitoring, 47% of stress tests, 49% of echocardiographies, 67% of coronary angiographies and 43% of electrophysiological examinations. CONCLUSIONS: NT-pro-BNP assessment was helpful in differentiating cardiac from non-cardiac syncope. Further studies are needed to define the role of NT-pro-BNP in the diagnostic algorithm of syncope.

Inefficacy of different strategies to improve guideline awareness - 5-year follow-up of the hypertension evaluation project (HEP).

BACKGROUND: In spite of numerous guidelines for evidence based diagnostic and therapy adequate knowledge of current recommendations is disappointingly low. In the Hypertension Evaluation Project (HEP I) we showed that awareness of national hypertension guidelines under German practitioners was less than 25% in the year 2000. This indicates the need for efficient strategies to relevantly improve guideline awareness. METHODS: To asses different tools for amending guideline knowledge we used three strategies (guideline in print, interactive guideline, expert seminars) to train 8325 randomised physicians, who had participated in the HEP I trial. Guideline knowledge of the trained physicians was again tested with the HEP questionnaire and compared to a control group of HEP I physicians. RESULTS: The return rate of questionnaires was 57.9% without a significant distinction between the groups. Overall guideline awareness was still low but remarkably improved compared to the results of HEP I (37.1% vs. 23.7%, p < 0.0001). There was no difference between the trained physicians and the control group (35.8% and 35.9% vs. 39.7%, p = n.s.). CONCLUSION: We investigated the influence of different strategies to improve guideline awareness among German physicians. None of our interventions (guideline in print, interactive guideline, expert seminars) brought a notable benefit compared to control group. However, overall knowledge of guideline contents increased from 23.7% to 37.1% over five years. Therefore, other probably multimodal interventions are necessary to significantly improve guideline awareness beyond spontaneous advancement. TRIAL REGISTRATION: ISRCTN53383289.

Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.

Patients with diabetes and chronic kidney disease (CKD) are at particularly high risk for cardiovascular disease (CVD). This post hoc analysis from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. CKD, defined as an estimated GFR <60 ml/min per 1.73m(2), was present in 597 (11.6%) of 5154 patients. More patients with CKD reached the primary composite end point (all-cause mortality, myocardial infarction (MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle) than patients without CKD (27.5 versus 19.6%; P < 0.0001). Patients with CKD were also more likely to reach a secondary composite end point (all-cause mortality, MI, and stroke). Patients who had CKD and were treated with pioglitazone were less likely to reach the secondary end point (hazard ratio 0.66; 95% confidence interval 0.45 to 0.98), but this association was not observed among those with better renal function. In addition, there was a greater decline in estimated GFR with pioglitazone (between-group difference 0.8 ml/min per 1.73 m(2)/yr) than with placebo. In conclusion, CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and preexisting macrovascular disease. Patients who had CKD and were treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke, independent of the severity of renal impairment.

Increased functional importance of the Na,Ca-exchanger in contracting failing human myocardium but unchanged activity in isolated vesicles.

The present study aimed to investigate the hypothesis that the function of the Na,Ca-exchanger (NCX) is of higher importance for contractility and Ca(2+)-homeostasis in left ventricle from terminally failing than from nonfailing human hearts. The effect of decreasing extracellular [Na](e) (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na](e) has previously been shown to increase contractility in vitro secondary to a decreased Ca(2+)-extrusion by the NCX. In addition, the NCX activity was measured as Na(+)-dependent (45)Ca(2+)-uptake into isolated myocardial vesicles as a function of time and Ca(2+)-concentration (DCM n = 8, NF n = 8). Decreasing [Na](e) enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na](e) than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T(1/2): DCM 2.4 +/- 0.3 s versus NF 2.5 +/- 0.3 s) and as a function of Ca(2+) (DCM 0.99 +/- 0.08 versus NF 0.96 +/- 0.07 nmol/mg protein x 3 s, K(1/2): DCM 39.2 microM versus NF 38.3 microM). These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca(2+)-ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca (2+)-affinity of the Na,Ca-exchanger in isolated vesicles was unchanged, we propose that alterations in Ca(2+)-and Na(+)-homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na(+), K(+)-ATPase) or the prolonged action potential are the reason for this observation.

Prevalence of cardiovascular risk factors in middle-aged type 2 diabetic automobile employees assessed at the workplace--the Praeford study.

OBJECTIVE: The purpose of this study was to provide contemporary data on the prevalence of cardiovascular risk factors in middle-aged diabetic employees in Germany. METHODS: Cardiovascular risk factors were assessed at the workplace in employees of the automobile industry who identified themselves as having type 2 diabetes mellitus. The proportion of subjects reaching the target values for hemoglobin A1c (HbA1c), systolic blood pressure, and low-density lipoprotein (LDL) cholesterol was analyzed. RESULTS: Among 4234 employees, 91 employees with diabetes were identified (mean age, 52 years). Only 7 of 91 (8%) diabetic employees achieved all three recommended target values. Blood pressure targets were achieved by 26%, HbA1c target value by 54%, and LDL target value by 31% of employees. CONCLUSION: Only a negligible proportion of working people with diabetes achieve the recommended target values. This sobering result questions current management modalities and calls for new treatment and monitoring strategies for working people with diabetes.

Improving macrovascular outcomes in type 2 diabetes: Outcome studies in cardiovascular risk and metabolic control.

BACKGROUND: Type 2 diabetes is accompanied by a host of potentially modifiable cardiovascular disease risk factors. Consequently, people with type 2 diabetes have a higher risk of macrovascular disease than the non-diabetic population, and a poor prognosis following an event. Several large-scale primary and secondary outcome studies have included large diabetes subgroups for post-hoc analysis, and a limited number of studies have focused specifically on type 2 diabetes. SCOPE: This review provides an overview of macrovascular outcome studies in type 2 diabetes and discusses potential new targets for therapy based upon a MEDLINE literature search from January 1990 to April 2006. FINDINGS: Large cardiovascular outcome studies show that treating cardiovascular disease risk factors significantly reduces the risk of primary and secondary macrovascular events in patients with type 2 diabetes. The evidence for targeting hypertension (using renin-angiotensin system inhibitors), dyslipidemia (statins), and coagulation factors (aspirin) appears robust. However, the macrovascular benefits of improved glucose control remain to be proven definitively, although metformin may have advantages over other glucose-lowering agents. Nevertheless, these studies reveal that significant excess residual risk remains, highlighting the need for new therapies. It is also apparent that some agents (e.g. metformin, statins, renin-angiotensin system inhibitors) may also have pleiotropic mechanisms. Newer strategies are investigating other lipid targets (especially HDL cholesterol) or using agents, such as thiazolidinediones, that address multiple established and emerging risk factors. A recent study with pioglitazone suggests that macrovascular risk can be reduced in very high-risk patients with type 2 diabetes who are already receiving contemporary lipid, anti-hypertensive, and anti-platelet therapy. CONCLUSION: The core therapeutic paradigm targeting glycemia, hypertension, dyslipidemia, and coagulation factors has failed to remove excess residual risk in patients with type 2 diabetes completely. Emerging data, and on-going trials, should provide better guidance on new therapeutic opportunities in this high-risk patient group.

Pioglitazone: an antidiabetic drug with cardiovascular therapeutic effects.

The antidiabetic compound pioglitazone, an activator of the intracellular peroxisome proliferator-activated receptor-gamma, and decreases metabolic and vascular insulin resistance. The drug is well tolerated, and its metabolic effects include improvements in blood glucose and lipid control. Vascular effects consist of improvements in endothelial function and hypertension, and a reduction in surrogate markers of artherosclerosis. In a large, placebo-controlled, outcome study in secondary prevention, PROactive study, the use of pioglitazone in addition to an existing optimized macrovascular risk management resulted in a significant reduction of macrovascular endpoints within a short observation period that was comparable to the effect of statins and angiotensin converting enzyme inhibitors in other trials. These results underline the value of pioglitazone for managing the increased cardiovascular risk of patients with a metabolic syndrome or Type 2 diabetes mellitus.

F-18-FDG uptake is a reliable predictory of functional recovery of akinetic but viable infarct regions as defined by magnetic resonance imaging before and after revascularization.

Identification of akinetic but viable myocardium is important for the selection of patients for coronary revascularization. In order to assess predictive values of end-diastolic wall thickness and dobutamine induced wall thickening obtained by magnetic resonance imaging (MRI) and [18F]Fluorodeoxyglucose uptake assessed by positron emission tomography (F-18-FDG-PET), these parameters were compared to recovery of left ventricular function after successful revascularization. Forty patients with chronic myocardial infarction and regional a- or dyskinesia by ventriculography underwent rest- and dobutamine-MRI studies (10 microg dobutamine/kg body weight/min) and F-18-FDG-PET. Viability of the infarct region was considered to be present if; 1) end-diastolic wall thickness was > or =5.5 mm; 2) dobutamine induced wall thickening > or =2 mm could be measured; and 3) normalized F-18-FDG-uptake was > or =50% in > or =50% of akinetic segments. Preserved end-diastolic wall thickness was found in 32/40 patients, functional improvement during dobutamine infusion in 26/40 patients and preserved F-18-FDG-uptake in 29/40 patients. After revascularization regional left ventricular function improved in 25/40 patients. Positive and negative predictive values and diagnostic accuracy were 78%, 100%, and 83% for preserved end-diastolic wall thickness, 92%, 93%, and 93% for dobutamine inducible contraction reserve and 86%, 100%, and 90% for preserved F-18-FDG-uptake. Quantitative assessment of dobutamine induced systolic wall thickening by MRI and F-18-FDG-uptake by PET are highly accurate techniques for the identification of viable myocardium and prediction of functional recovery after successful revascularization. Preserved end-diastolic wall thickness results in an overestimation of viable myocardium compared to functional improvement, but wall thickness <5.5 mm excludes recovery of regional function.

[Physicians and the internet--a cross-sectional study against the background of guideline implementation]. / Arzte und Internet--eine Querschnittsuntersuchung vor dem Hintergrund der Leitlinienimplementierung.

The internet is an innovative medium for the implementation of current recommendations for diagnosis and therapy, e.g. by means of guidelines. In this context, evaluation of the internet is very important because traditional ways of implementation have been proved less effective. Therefore, we investigated the frequency of online access and individual utilisation of the internet among 13,547 family practitioners, internists and general practitioners using a questionnaire procedure. Furthermore, we asked for a personal grading of its current relevance in their daily practice. Out of 2,786 responders (20.6% response rate) 79% reported personal online access. 40% had online computer access in their office and 71% at home. 45% of the internists had online access in their office compared to 34% of general practitioners. Almost all physicians under the age of 40 years (94%) had personal online access in comparison to only 49% of those over 60 years. The average daily duration of internet usage was up to ten minutes in 61%, and 1.5% use the internet more than one hour per day. 46% of responders believe that the internet is an appropriate source for professional education, whereas it has little professional relevance for 38%. We conclude that the internet appears to be a useful medium for the implementation of guidelines. However, in subgroups with the most urgent need for current medical information the internet seems to be unsuitable as an implementation tool.