Markus Resch

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.

Background: Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. Objectives: Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. Methods: Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3–10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). Results: Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend toward shortening of the QRS complex after tVNS. Conclusion: To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.

High-sensitive troponin T in chronic heart failure correlates with severity of symptoms, left ventricular dysfunction and prognosis independently from N-terminal pro-b-type natriuretic peptide.

Abstract Background: Troponin T is an established marker of myocardial ischemia. We speculated that the role of the new high-sensitive troponin T (hs-cTnT) might expand towards non-ischemic myocardial disease, indicate disease severity and allow for prognostication in chronic heart failure. Methods: Hs-cTnT (Roche Diagnostics, Mannheim, Germany) was assessed in 233 individuals with chronic heart failure (n=149) or healthy controls (n=84). Results: Hs-cTnT was significantly elevated in patients with chronic heart failure [0.018 ng/mL, interquartile range (IQR) 0.009–0.036 ng/mL, vs. controls 0.003 ng/mL, 0.003–0.003 ng/mL, p<0.001] and positively correlated with N-terminal pro-b-type natriuretic peptide (NT-proBNP) (r=0.79, p<0.001). Hs-cTnT increased stepwise and signitificantly according to clinical (NYHA stage) as well as functional (LV ejection fraction, fluid retention) severity (each p<0.001). At a binary cutpoint of 0.014 ng/mL, hs-TropT was a significant predictor of all-cause mortality and all-cause mortality or rehospitalization for congestive heart failure (each p≤0.01). Of note, the prognostic value of hs-TropT was independent and additive to that of NT-proBNP. Conclusions: Hs-cTnT increases stepwise with the severity of symptoms and LV dysfunction and offers important prognostic information in chronic heart failure, independently from and additive to NT-proBNP. The utility of hs-cTnT expands beyond acute myocardial ischemia and towards chronic heart failure.

Prosthesis sizing for transcatheter aortic valve implantation — Comparison of three dimensional transesophageal echocardiography with multislice computed tomography

BACKGROUND The complex anatomy of the aortic annulus warrants the use of three dimensional (3D) modalities for prosthesis sizing in transcatheter aortic valve implantation (TAVI). Multislice computed tomography (MSCT) has been used for this purpose, but its use may be restricted because of contrast administration. 3D transesophageal echocardiography (3D-TEE) lacks this limitation and data on comparison with MSCT is scarce. We compared 3D-TEE with MSCT for prosthesis sizing in TAVI. METHODS Aortic annulus diameters in the sagittal and coronal plane and annulus areas in 3D-TEE and MSCT were compared in 57 patients undergoing TAVI. Final prosthesis size was left at the operators discretion and the agreement with 3D-TEE and MSCT was calculated. RESULTS Sagittal diameters on 3D-TEE and MSCT correlated well (r=.754, p<.0001) and means were comparable (22.3±2.1 vs. 22.5±2.3 mm; p=0.2; mean difference: -0.3 mm [-3.3-2.8]). On 3D-TEE, coronal diameter and annulus area were significantly smaller (p<.0001 for both) with moderate correlation (r=0.454 and r=0.592). Interobserver variability was comparable for both modalities. TAVI was successful in all patients with no severe post-procedural insufficiency. Final prosthesis size was best predicted by sagittal annulus diameters in 84% and 79% by 3D-TEE and MSCT, respectively. Agreement between both modalities was 77%. CONCLUSIONS Annulus diameters and areas for pre-procedural TAVI assessment by 3D-TEE are significantly smaller than MSCT with exception of sagittal diameters. Using sagittal diameters, both modalities predicted well final prosthesis size and excellent procedural results were obtained. 3D-TEE can thus be a useful alternative in patients with contraindications to MSCT.

Globular and full-length adiponectin induce NO-dependent vasodilation in resistance arteries of Zucker lean but not Zucker diabetic fatty rats.

BACKGROUND Adiponectin increases nitric oxide (NO) production in endothelial cell cultures and is reduced in the circulation of obese and diabetic patients, but its functional effect on resistance arteries is not yet studied in detail. METHODS We assessed the direct vasodilatory response of isolated mesenteric resistance arteries of Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats to globular adiponectin (gAd) and full-length adiponectin (fAd) and tested the effect of additional reactive oxygen species (ROS) inhibitors in vitro. Serum adiponectin and insulin levels were measured by ELISA. The mRNA expressions of the adiponectin receptors and the downstream signaling molecules adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1), adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2), and endothelial NO synthase (eNOS) in mesenteric resistance arteries were quantified by real-time reverse transcriptase PCR. RESULTS Both gAd and fAd induced a relevant dose-dependent vasodilation in ZL, but not in hypoadiponectinemic ZDF rats. This effect was totally blunted by L-nitroarginine-methyl-ester indicating NO dependency. The addition of ROS inhibitors could not improve the vasodilatory effect of adiponectin. Vasodilatory response to acetylcholine was reduced in ZDF rats, which could not be enhanced by low-dose adiponectin. Adiponectin receptor 1 (AdipoR1) was higher expressed than adiponectin receptor 2 (AdipoR2) with no significant differences between both animal groups, but APPL1 was significantly decreased in ZDF rats. The eNOS expression was not significantly different between ZL and ZDF rats. CONCLUSIONS Adiponectin exerts a NO-dependent vasodilation in resistance arteries of normoglycemic ZL rats, but not diabetic ZDF rats. This may contribute to endothelial dysfunction in ZDF rats. Alterations in the expression of APPL1 may be involved in the observed insensitivity to adiponectin in ZDF rats.

Expression of fourteen novel obesity-related genes in zucker diabetic fatty rats

BackgroundGenome-wide association studies (GWAS) are useful to reveal an association between single nucleotide polymorphisms and different measures of obesity. A multitude of new loci has recently been reported, but the exact function of most of the according genes is not known. The aim of our study was to start elucidating the function of some of these genes.MethodsWe performed an expression analysis of fourteen genes, namely BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MCR4, MTCH2, NEGR1, NRXN3, TMEM18, SEC16B and TFAP2B, via real-time RT-PCR in adipose tissue of the kidney capsule, the mesenterium and subcutaneum as well as the hypothalamus of obese Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats at an age of 22 weeks.ResultsAll of our target genes except for SEC16B showed the highest expression in the hypothalamus. This suggests a critical role of these obesity-related genes in the central regulation of energy balance. Interestingly, the expression pattern in the hypothalamus showed no differences between obese ZDF and lean ZL rats. However, LYPLAL1, TFAP2B, SEC16B and FAIM2 were significantly lower expressed in the kidney fat of ZDF than ZL rats. NEGR1 was even lower expressed in subcutaneous and mesenterial fat, while MTCH2 was higher expressed in the subcutaneous and mesenterial fat of ZDF rats.ConclusionThe expression pattern of the investigated obesity genes implies for most of them a role in the central regulation of energy balance, but for some also a role in the adipose tissue itself. For the development of the ZDF phenotype peripheral rather than central mechanisms of the investigated genes seem to be relevant.

Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus: An Open Pilot Study

OBJECTIVES Vagus nerve stimulation represents an established treatment strategy for epilepsy and affective disorders. Recently, positive effects were also shown in animals and humans with tinnitus. Here we report the results of an open pilot study exploring feasibility, safety and efficacy of tVNS in the treatment of chronic tinnitus. STUDY DESIGN Fifty patients with chronic tinnitus underwent tVNS in an open single-armed pilot study which was conducted in two phases applying two different stimulating devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as change in TQ (baseline vs. final visit in week 24). The study has been registered with clinicaltrials.gov (NCT01176734). RESULTS Primary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8 points (phase 2) significant for the first study phase. Secondary analyses indicated a significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further systematic or significant effects. Adverse events included twitching and pressure at electrode placement site. The occurrence of one hospitalization because of palpations and the development of a left bundle branch block were considered as unrelated to the intervention. Cognitive testing revealed no significant changes. CONCLUSION Our data demonstrate the feasibility of tVNS over a period of 6 months. There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS to be considered safe in patients without a history of cardiac disease.

Increased Aldosterone Levels in a Model of Type 2 Diabetes Mellitus

BACKGROUND Aldosterone is an important mediator of cardiovascular and renal remodeling. Type II diabetes mellitus leads to renal and cardiac end organ damage. We investigated the renin-angiotensin-aldosterone system in a model of type 2 diabetes mellitus with known diabetic nephropathy and cardiac remodeling, the Zucker Diabetic Fatty rat with and without ACE-inhibition (ZDF and ZDF+ACE-I) and its control, the Zucker Lean (ZDL) rat. METHODS Male animals were studied from an age of 7-24 weeks. At ages 7, 14, 17, 20, and 23 weeks, urinary excretion of aldosterone-glucuronide and potassium was assessed. ACE-inhibition with ramipril was started orally at week 13 (1 mg/kg/d). At the end of the study rats were sacrificed and plasma aldosterone concentration and plasma renin activity were measured. Aldosterone synthase (CYP11B2) mRNA expression in the adrenals, kidney, heart and adipose tissue was assessed by real-time PCR. Urinary albumin excretion as marker for diabetic nephropathy was measured in metabolic cages and correlated to aldosterone. RESULTS Plasma aldosterone concentration and aldosterone-glucuronide was significantly elevated in ZDF rats, and significantly reduced by ACE-inhibiton. In contrast, plasma renin activity was significantly reduced in ZDF rats and normalized by ACE-inhibition. The urinary aldosterone correlated significantly to albuminuria. Adrenal CYP11B2 expression was not significantly higher in ZDF rats. CYP11B2 mRNA was not detected in the kidney, heart and adipose tissue. CONCLUSION In ZDF rats, urinary and plasma aldosterone levels were elevated despite reduced plasma renin activity. The reversible effect of ACE-inhibition shows that the up-regulation of aldosterone must be dependent of the renin-angiotensin-system in this type II diabetes model. The correlation between aldosterone and diabetic nephropathy suggests a clinical relevance of this observation.

High-sensitive Troponin I in acute cardiac conditions: Implications of baseline and sequential measurements for diagnosis of myocardial infarction

BACKGROUND High-sensitive Troponin I (hsTnI) facilitates the early diagnosis of myocardial infarction (MI). However, since hsTnI has not been well characterized in non-ischemic cardiac conditions, the predictive value of hsTnI for MI remains unclear. METHODS hsTnI (ADVIA Centaur, Siemens) on admission was analyzed in 929 patients with acute cardiac condition and invasive ascertainment of coronary status by catheterization. RESULTS Hs-TnI upon presentation was higher in patients with STEMI (median 1.27 ng/mL, IQR 0.13-14.5 ng/mL) as compared to patients with Non-STEMI (0.66 ng/mL, IQR 0.10-4.0 ng/mL, p<0.001) whereas it did not differ from STEMI in Tako-Tsubo cardiomyopathy (2.57 ng/mL, IQR 0.17-8.4 ng/mL) and myocarditis (9.76 ng/mL, IQR 2.0-27.0 ng/mL). In patients with resuscitation of non-ischemic cause (0.31 ng/mL, IQR 0.06-1.3 ng/mL), acute heart failure (0.088 ng/mL, IQR 0.035-0.30 ng/mL) and hypertensive emergency (0.066 ng/mL, IQR 0.032-0.34 ng/mL), hs-TnI was elevated above the recommended threshold of 0.04 ng/mL. At this cutpoint of 0.04 ng/mL, hsTnI indicated acute MI (STEMI or Non-STEMI) with a sensitivity of 88% and a specificity of 45% (ROC-AUC 0.748). When patients with STEMI were excluded, hsTnI indicated Non-STEMI with a sensitivity of 87% and a specificity of 45% (ROC-AUC 0.725). When sequential measurements were taken into account in a restricted cohort, a maximum hsTnI of ≥0.40 ng/mL provided a sensitivity of 89% and a specificity of 85% (ROC-AUC 0.909) for Non-STEMI. CONCLUSIONS HsTnI is a sensitive, albeit unspecific marker of MI. In patients with mildly elevated hsTnI and without evidence for STEMI, we suggest serial assessment of hsTnI and a 10-fold higher cutpoint of 0.40 ng/mL before Non-STEMI is assumed.

Alterations in mechanical properties of mesenteric resistance arteries in experimental portal hypertension

Splanchnic vasodilation is the pathophysiological hallmark in the development of the hyperdynamic circulatory syndrome in liver cirrhosis and portal hypertension. This has been attributed so far mainly to a marked vascular hyporeactivity to endogenous vasoconstrictors. However, myogenic tone and vessel stiffness have not been addressed in mesenteric arteries in liver cirrhosis. CCl(4)(-)-induced ascitic cirrhotic (LC) and age-matched control rats, portal vein-ligated (PVL) rats, and sham-operated rats were investigated. Third-order mesenteric resistance arteries were studied under no-flow conditions using a pressure myograph measuring media thickness and lumen diameter in response to incremental increases in intramural pressure, from which wall mechanics were calculated. Electron microscopy was used for investigation of wall ultrastructure, especially the fenestrae in internal elastic lamina (IEL). In PVL animals, no significant change in passive vessel strain, stress, media-to-lumen ratio, or cross-sectional area was noted. In contrast, in LC rats, vessel strain was markedly elevated compared with healthy control rats, indicating a marked reduction in vessel stiffness. In addition, the strain-stress curve was shifted to the right, and the elastic modulus in dependency on vessel stress decreased, demonstrating predominantly structure-dependent factors to be involved. The media-to-lumen quotient was not significantly altered, but cross-sectional area was highly increased in LC rats, indicating hypertrophic outward remodeling. These findings were paralleled by enlarged fenestrae in the IEL but no change in thickness of IEL or proportion of extracellular matrix or vascular smooth muscle in LC rats. We concluded that, in long-standing severe portal hypertension such as ascitic LC but not in short-term conditions such as PVL, mesenteric resistance arteries exhibit vascular remodeling and markedly less resistant mechanical properties, leading to decreased vessel stiffness accompanied by structural changes in the IEL. This may well contribute to the maintenance and severity of splanchnic arterial vasodilation in LC.

Direct Visualization of Regurgitant Orifice by CMR Reveals Differential Asymmetry According to Etiology of Mitral Regurgitation

OBJECTIVES This study sought to characterize the shape of regurgitant orifice area (ROA) and mitral apparatus in various forms of mitral regurgitation (MR) by cardiac magnetic resonance (CMR). BACKGROUND ROA is an accepted parameter of MR severity. However, there are little data on the shape of the ROA in various forms of MR. METHODS Direct assessment of ROA was performed with a 1.5-T CMR scanner using a breath-hold fast imaging with steady-state free precession. The regurgitant orifice shape and the anatomy of the mitral valve apparatus including mitral annulus, mitral leaflet angles, and mitral valve tenting area were assessed. RESULTS We studied 74 patients. MR severity was mild in 39%, moderate in 27%, and moderate-to-severe or severe in 34%. Mitral valve pathology was degenerative in 26%, prolapse in 22%, flail in 33%, and functional in 19%. For all patients, ROA correlated significantly with regurgitant fraction (r = 0.80, p < 0.001). The ROA shape index as expressed by the ratio of the larger length to the smaller length was a median of 2.04 (interquartile range [IQR]: 1.49 to 3.08) over all patients. CMR revealed significant asymmetry of the ROA geometry in functional MR 3.91 (IQR: 2.79 to 4.84) compared with prolapse 2.14 (IQR: 1.80 to 3.04), flail 2.20 (IQR: 1.69 to 2.91), and degenerative MR 1.24 (IQR: 1.09 to 1.57), all p < 0.01. The assessment of mitral valve geometry demonstrated that patients with functional MR had significantly increased leaflet angles, mitral valve tenting area, and mitral annulus area (all p < 0.05). Of note, the orifice shape index correlated with increasing leaflet angles in patients with functional MR (r = 0.68, p = 0.005). CONCLUSIONS Direct assessment of ROA by CMR revealed significant asymmetry of ROA in various forms of MR, particularly in patients with functional MR. The slitlike appearance in functional MR correlates with a distended mitral apparatus.