Wilfried Dinh

Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders.

BackgroundDiabetes mellitus (DM) has reached epidemic proportions and is an important risk factor for heart failure (HF). Left ventricular diastolic dysfunction (LVDD) is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. We sought to evaluate the relationship between proinflammatory cytokine levels (TNF-alpha, IL-6) and tissue Doppler derived indices of LVDD in patients with stable coronary artery disease.MethodsWe enrolled 41 consecutive patients (mean age 65+/-10 years) submitted for coronary angiography. Echocardiographic assessment was performed in all patients. Pulsed tissue Doppler imaging was performed at the mitral annulus and was characterized by the diastolic early relaxation velocity Em. Conventional transmitral flow was measured with pw-doppler. Early (E) transmitral flow velocity was measured. LVDD was defined as E/Em ratio ≥ 15, E/Em 8-14 was classified as borderline. Plasma levels of TNF-alpha and IL-6 were determined in all patients. A standardized oral glucose tolerance test was performed in subjects without diabetes.ResultsPatients with E/Em ratio ≥ 15, classified as LVDD and those with E/Em ratio 8-14 (classified as borderline) had significantly higher IL-6 (P = 0,001), TNF-alpha (P < 0,001) and NT-pro- BNP (P = 0,001) plasma levels compared to those with normal diastolic function. TNF-alpha and IL-6 levels remains significantly elevated after adjustment for sex, age, left ventricular ejection function, body mass index, coronary heart disease, smoking, hypertension and diabetes mellitus with linear regression analysis. Furthermore, in subjects LVDD or borderline LV diastolic function, 75% had diabetes or IGT, respectively. When subjects without diabetes were excluded, both IL-6 (P = 0,006) and TNF-alpha (P = 0,002) remained significantly elevated in subjects with E/Em ratio ≥ 15.ConclusionThis study reveals that increased plasma levels of IL-6 and TNF-alpha were associated with LVDD. These findings suggest a link between low-grade inflammation and the presence of LVDD. An active proinflammatory process may be of importance in the pathogenesis of diastolic dysfunction.

Reduced global longitudinal strain in association to increased left ventricular mass in patients with aortic valve stenosis and normal ejection fraction: a hybrid study combining echocardiography and magnetic resonance imaging

BackgroundIncreased muscle mass index of the left ventricle (LVMi) is an independent predictor for the development of symptoms in patients with asymptomatic aortic stenosis (AS). While the onset of clinical symptoms and left ventricular systolic dysfunction determines a poor prognosis, the standard echocardiographic evaluation of LV dysfunction, only based on measurements of the LV ejection fraction (EF), may be insufficient for an early assessment of imminent heart failure. Contrary, 2-dimensional speckle tracking (2DS) seems to be superior in detecting subtle changes in myocardial function. The aim of the study was to assess these LV function deteriorations with global longitudinal strain (GLS) analysis and the relations to LVMi in patients with AS and normal EF.Methods50 patients with moderate to severe AS and 31 controls were enrolled. All patients underwent echocardiography, including 2DS imaging. LVMi measures were performed with magnetic resonance imaging in 38 patients with AS and indexed for body surface area.ResultsThe total group of patients with AST showed a GLS of -15,2 ± 3,6% while the control group reached -19,5 ± 2,7% (p < 0,001). By splitting the group with AS in normal, moderate and severe increased LVMi, the GLS was -17,0 ± 2,6%, -13,2 ± 3,8% and -12,4 ± 2,9%, respectively (p = 0,001), where LVMi and GLS showed a significant correlation (r = 0,6, p < 0,001).ConclusionsIn conclusion, increased LVMi is reflected in abnormalities of GLS and the proportion of GLS impairment depends on the extent of LV hypertrophy. Therefore, simultaneous measurement of LVMi and GLS might be useful to identify patients at high risk for transition into heart failure who would benefit from aortic valve replacement irrespectively of LV EF.

Metabolic syndrome with or without diabetes contributes to left ventricular diastolic dysfunction

Objective Left ventricular diastolic dysfunction (LVDD) is considered a precursor of diabetic cardiomyopathy, while the metabolic syndrome (MetS) is associated with an increased risk of cardiovascular morbidity and mortality. This study aimed to evaluate the association between LVDD, MetS and glucose metabolism disturbances classifi ed by oral glucose tolerance testing (oGTT). Methods and results The presence of LVDD was evaluated in 166 subjects with normal ejection fraction, 43 (26%) of whom had type 2 diabetes at inclusion. In subjects without diabetes, an oGTT was performed. The MetS was diagnosed as indentifi ed by the NCEPIII-criteria, while LVDD was verifi ed and graded according to the current guidelines. MetS was diagnosed in 97 (59%) patients, 44% of whom had known diabetes. The prevalence of LVDD was 68% in subjects with MetS vs. 19% in patients without MetS, respectively (P < 0.001). A severe form of LVDD was observed in 34% and 15% of patients with and without MetS, respectively (P= 0.001), whereupon the prevalence of mild and severe diastolic dysfunction increased with the number of MetS criteria (P= 0.001). In the MetS group, early diastolic tissue relaxation velocity (E´) was signifi cantly reduced (6.9 ± 1.8 cm/s vs. 7.7 ± 2.1 cm/s; P= 0.009) and the E/E´ ratio was signifi cantly higher (10.5 ± 3.9 vs. 9.1 ± 3.0 cm/s, P= 0.015) as compared to the group without MetS (n = 69). Conclusion MetS was associated with a higher prevalence and severity of LVDD, whereupon coexisting diabetes aggravates these fi nding. Patients displaying MetS with concomitant LVDD might represent a target population in which appropriate medical care for early heart failure prevention should be initiated

Six sequence variants on chromosome 9p21.3 are associated with a positive family history of myocardial infarction: a multicenter registry

BackgroundRecent genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) and myocardial infarction (MI). The 9p21.3 locus was verified by numerous replication studies to be the first common locus for CAD and MI. In the present study, we investigated whether six single nucleotide polymorphisms (SNP) rs1333049, rs1333040, rs10757274, rs2383206, rs10757278, and rs2383207 representing the 9p21.3 locus were associated with the incidence of an acute MI in patients with the main focus on the familial aggregation of the disease.MethodsThe overall cohort consisted of 976 unrelated male patients presenting with an acute coronary syndrome (ACS) with ST-elevated (STEMI) as well as non-ST-elevated myocardial infarction (NSTEMI). Genotyping data of the investigated SNPs were generated and statistically analyzed in comparison to previously published findings of matchable control cohorts.ResultsStatistical evaluation confirmed a highly significant association of all analyzed SNPs with the occurrence of MI (p < 0.0001; OR: 1.621-2.039). When only MI patients with a positive family disposition were comprised in the analysis a much stronger association of the accordant risk alleles with incident disease was found with odds ratios up to 2.769.ConclusionsThe findings in the present study confirmed a strong association of the 9p21.3 locus with MI particularly in patients with a positive family history thereby, emphasizing the pathogenic relevance of this locus as a common genetic cardiovascular risk factor.

Limiting esophageal temperature in radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal lesions

BackgroundAtrio-esophageal fistula formation following radiofrequency ablation of left atrial tachyarrhythmias is a rare but devastating complication. Esophageal injuries are believed to be precursors of fistula formation and reported to occur in up to 47% of patients. This study investigates the incidence of esophageal lesions when real time esophageal temperature monitoring and temperature limitation is used.Methods184 consecutive patients underwent open irrigated radiofrequency ablation of left atrial tachyarrhythmias. An esophageal temperature probe consisting of three independent thermocouples was used for temperature monitoring. A temperature limit of 40°C was defined to interrupt energy delivery. All patients underwent esophageal endoscopy the next day.ResultsEndoscopy revealed ulcer formation in 3/184 patients (1.6%). No patient developed atrio-esophageal fistula. Patient and disease characteristics had no influence on ulcer formation. The temperature threshold of 40°C was reached in 157/184 patients. A temperature overshoot after cessation of energy delivery was observed frequently. The mean maximal temperature was 40.8°C. Using a multiple regression analysis creating a box lesion that implies superior- and inferior lines at the posterior wall connecting the right and left encircling was an independent predictor of temperature. Six month follow-up showed an overall success rate of 78% documented as sinus rhythm in seven-day holter ECG.ConclusionLimitation of esophageal temperature to 40°C is associated with the lowest incidence of esophageal lesion formation published so far. This approach may contribute to increase the safety profile of radiofrequency ablation in the left atrium.

Gender-based differences in long-term outcome after ST-elevation myocardial infarction in patients treated with percutaneous coronary intervention.

BACKGROUND In the era of fibrinolysis, women suffered from higher early and late mortality rates than men after acute ST-elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) has been determined to be the most effective therapy strategy in STEMI. It is not clear if female gender is an independent predictor of a worse long-term prognosis among patients who were systematically treated with PCI. We, therefore, examined the effect of PCI on long-term outcome between women and men. METHODS Between 1999 and 2001, 500 consecutive patients at the Wuppertal Heart Centre were treated with PCI after acute STEMI. A long-term follow-up (up to 7 years) was achieved in 97% of the patients. RESULTS In comparison to men, women were 7 years older (65 +/- 12 vs. 58 +/- 11) and had significantly more diabetes mellitus. The time between onset of symptoms and intervention tended to be longer in women than men. There was no difference in 30-day mortality (8.9% vs. 6.6%), cardiac late mortality (3.6% vs. 3.2%), and long-term cardiac overall mortality up to 7 years (12.1% vs. 9.6%). Stepwise regression analysis did not identify female gender as an independent predictor of late mortality. The quality of life was comparable. CONCLUSIONS There was no gender-related difference in the long-term outcome if patients were sytematically treated with PCI in STEMI. PCI in STEMI has a long-lasting positive effect in women and should, therefore, be considered the treatment of choice for women with acute myocardial infarction.

Improving cardiovascular clinical trials conduct in the United States: Recommendation from clinicians, researchers, sponsors, and regulators

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Developing New Treatments for Heart Failure: Focus on the Heart

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting.

Increased levels of laminin and collagen type VI may reflect early remodelling in patients with acute myocardial infarction.

Objective — The development of left ventricular remodelling (LVR) after acute myocardial infarction (AMI) is a predictor of heart failure and mortality.The extracellular matrix (ECM) is highly susceptible to ischaemic injury. Laminin and collagen type VI (CVI) contribute to ECM formation in the infarct zone.To determine whether these markers can be detected in blood samples, we measured laminin and CVI in patients with AMI and control subjects. Methods — A total of 60patients scheduled for coronary angiography and 31patients with AMI were included.We subdivided the patients into three groups: (1) AMI, (2) stable coronary artery disease (CAD) and (3) exclusion of CAD. Laminin and CVI serum concentrations were recorded using the ELISA-technique. Results — Laminin was significantly higher in patients with AMI than in subjects with stable CAD (36.5 vs. 23.9, P<0.01) or without CAD (36.5 vs. 24.6ng/ml, P<0.05). CVI-levels were significantly elevated in patients with AMI compared to subjects without CAD (7.5ng/ml vs. 5.4ng/ml, P<0.05) or stable CAD (7.5ng/ml vs. 5.7ng/ml, P=0.01). Laminin and CVI were significantly higher in patients with severely reduced left ventricular function. Laminin and CVI values were significantly correlated (r=0.6). Conclusion — Our data suggest that laminin and CVI serum levels can be potential surrogate parameters of ECM remodelling after AMI.We hypothesize that serum laminin reflects early ECMremodelling involved in the process of postischaemic tissue degradation and repair, and CVI may be a marker of collagen denaturation and shifts in the collagen phenotype ratios.

Exploring New Endpoints for Patients With Heart Failure With Preserved Ejection Fraction

The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting.