Oliver Dörr

Release Kinetics of Circulating Muscle-Enriched MicroRNAs in Patients Undergoing Transcoronary Ablation of Septal Hypertrophy

OBJECTIVES This study sought to evaluate exact release kinetics of microRNAs (miRNAs) in acute myocardial infarction (AMI). BACKGROUND miRNAs may be useful as novel biomarkers in patients with cardiovascular disease, although it is difficult to establish the detailed release kinetics of miRNAs in patients with AMI. METHODS We analyzed the release kinetics of circulating cardiac-specific (miR-21, miR-208a) and muscle-enriched (miR-1, miR-133a) miRNAs using the TaqMan polymerase chain reaction in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n = 21) undergoing TASH were included. Serum samples were collected prior to and at 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. RESULTS Circulating concentrations of miR-1 were significantly increased (>3-fold; p = 0.01) after 15 min, with a peak after 75 min (>60-fold; p < 0.001). The miR-21 concentrations were not increased at any time point. Concentrations of miR-133a were significantly increased at 15 min (2.9-fold; p < 0.001) and reached a plateau between 75 and 480 min (>50-fold change). The miR-208a concentrations were elevated at 105 min (>2-fold; p = 0.01), without a further increase. CONCLUSIONS miR-1, miR-133a, and miR-208a were continuously increased during the first 4 h after the induction of MI. In particular, miR-1 and miR-133a were significantly increased at early time points. These results demonstrate the release kinetics of miRNAs, which are helpful for developing their potential use as biomarkers in patients with acute coronary syndromes.

Soluble fms-like tyrosine kinase-1 and endothelial adhesion molecules (intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1) as predictive markers for blood pressure reduction after renal sympathetic denervation.

Renal sympathetic denervation (RSD) is a treatment option for patients with resistant arterial hypertension, but in some patients it is not successful. Predictive parameters on the success of RSD remain unknown. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are known to be associated with endothelial dysfunction, vascular remodeling, and hypertension. We evaluated whether sFLT-1, ICAM-1, and VCAM-1 are predictive markers for blood pressure reduction after RSD. Consecutive patients (n=55) undergoing renal denervation were included. Venous serum samples for measurement of sFlt-1, ICAM-1, and VCAM-1 were collected before and 6 months after RSD. A therapeutic response was defined as an office systolic blood pressure reduction of >10 mm Hg 6 months after RSD. A significant mean office systolic blood pressure reduction of 31.2 mm Hg was observed in 46 patients 6 months after RSD. Nine patients were classified as nonresponders, with a mean systolic blood pressure reduction of 4.6 mm Hg. At baseline, sFLT-1 levels were significantly higher in responders than in nonresponders (P<0.001) as were ICAM-1 (P<0.001) and VCAM-1 levels (P<0.01). The areas under the curve for sFLT-1, ICAM-1, and VCAM-1 were 0.82 (interquartile range, 0.718–0.921; P<0.001), 0.754 (0.654–0.854; P<0.001), and 0.684 (0.564–804; P=0.01), respectively, demonstrating prediction of an RSD response. Responders showed significantly higher serum levels of sFLT-1, ICAM-1, and VCAM-1 at baseline compared with nonresponders. Thus, this study identified for the first time potential biomarkers with a predictive value indicating a responder or nonresponder before renal denervation.

Release Kinetics of Copeptin in Patients Undergoing Transcoronary Ablation of Septal Hypertrophy

BACKGROUND The release kinetics of copeptin in patients with acute myocardial infarction (AMI) have been difficult to establish. METHODS We analyzed the release kinetics of copeptin in patients with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH) as a model of AMI. We included 21 consecutive patients who underwent TASH. Blood samples were collected before and at 15, 30, 45, 60, 75, 90, and 105 min, and at 2, 4, 8, and 24 h after TASH. Serum copeptin was quantified by a sandwich immunoluminometric assay. RESULTS All patients had copeptin concentrations below the 99th percentile at baseline. The median copeptin concentration was significantly increased at 30 min [16.0 pmol/L; interquartile range (IQR), 13.4-20.2 pmol/L], compared with the median baseline concentration (6.6 pmol/L; IQR, 5.3-8.3 pmol/L; P = 0.002). The copeptin concentration peaked 90 min after induction of myocardial infarction and returned to baseline concentrations (median, 8.2 pmol/L; IQR, 6.3-10.1) after 24 h, compared with the above baseline values (P = 0.06). Serum creatine kinase (CK) activities were significantly increased above baseline values by 1 day after TASH [median maximal postprocedural CK activity, 935.0 U/L (IQR, 545.5-1115.0 U/L); median baseline CK activity, 80.0 U/L (IQR, 63.5-109.0 U/L); P < 0.001]. CONCLUSIONS Our results provide additional evidence that early rule-out of suspected AMI is possible by using the copeptin concentration in combination with cardiac troponin T.

Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of cardiac surgery associated acute kidney injury

Abstract Background. Acute kidney injury (AKI) is a common complication after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) may be an early biomarker for cardiac surgery–associated (CSA) AKI. We investigated whether increased urinary NGAL concentrations were predictive of AKI within 4 days after surgery and of mortality within 9 months. Methods. Consecutive patients (n = 141) undergoing major cardiac surgery were included. Creatinine, blood urea nitrogen, cystatin C and urinary NGAL were measured before, 4 hours and 4 days after extracorporeal circulation. Results. AKI was observed in 47 (33.3%) patients. The 4-hour urinary NGAL measurement was an independent predictor of stage 2 and 3 AKI (AUC 0.901; 95% CI 0.81–0.99). Patients with AKI had a higher 9-month mortality rate (19.1% vs. 3.2%; logrank 10.9; P = 0.001; HR 19.8; 95% CI 3.7–107.1). Urinary NGAL was not predictive of mortality within 9 months after surgery. Conclusion. Urinary NGAL is a biomarker for very early risk stratification of AKI after cardiac surgery and may be useful as a basis for early interventional strategies to prevent CSA-AKI.

Mechanisms involved in postconditioning protection of cardiomyocytes against acute reperfusion injury

Experimental and clinical studies demonstrated that postconditioning confers protection against myocardial ischemia/reperfusion injury. However the underlying cellular mechanisms responsible for the beneficial effect of postconditioning are still poorly understood. The aim of the present study was to examine the role of cytosolic and mitochondrial Ca(2+)-handling. For this purpose adult rat cardiomyocytes were subjected to simulated in vitro ischemia (glucose-free hypoxia at pH6.4) followed by simulated reperfusion with a normoxic buffer (pH7.4; 2.5 mmol/L glucose). Postconditioning, i.e., 2 repetitive cycles of normoxic (5s) and hypoxic (2.5 min) superfusion, was applied during the first 5 min of reoxygenation. Mitochondrial membrane potential (ΔΨm), cytosolic and mitochondrial Ca(2+) concentrations, cytosolic pH and necrosis were analysed applying JC-1, fura-2, fura-2/manganese, BCECF and propidium iodide, respectively. Mitochondrial permeability transition pore (MPTP) opening was detected by calcein release. Hypoxic treatment led to a reduction of ΔΨm, an increase in cytosolic and mitochondrial Ca(2+) concentration, and acidification of cardiomyocytes. During the first minutes of reoxygenation, ΔΨm transiently recovered, but irreversibly collapsed after 7 min of reoxygenation, which was accompanied by MPTP opening. Simultaneously, mitochondrial Ca(2+) increased during reperfusion and cardiomyocytes developed spontaneous cytosolic Ca(2+) oscillations and severe contracture followed by necrosis after 25 min of reoxygenation. In postconditioned cells, the collapse in ΔΨm as well as the leak of calcein, the increase in mitochondrial Ca(2+), cytosolic Ca(2+) oscillations, contracture and necrosis were significantly reduced. Furthermore postconditioning delayed cardiomyocyte pH recovery. Postconditioning by hypoxia/reoxygenation was as protective as treatment with cyclosporine A. Combining cyclosporine A and postconditioning had no additive effect. The data of the present study demonstrate that postconditioning by hypoxia/reoxygenation prevents reperfusion injury by limiting mitochondrial Ca(2+) load and thus opening of the MPTP in isolated cardiomyocytes. These effects seem to be supported by postconditioning-induced delay in pH recovery and suppression of Ca(2+) oscillations.

Trends in aortic valve replacement in Germany in 2015: transcatheter versus isolated surgical aortic valve repair

AimsWe analysed the number of procedures, indications, and in-hospital mortality rates of all patients undergoing isolated surgical aortic valve replacement (sAVR) or transvascular (TV-) and transapical (TA-) transcatheter aortic valve implantation (TAVI) from 2012 to 2015 in Germany.Methods and resultsMore than 31,000 aortic valve procedures were performed in 2015 in Germany, representing a total increase of 4.5% over 2014. TV-TAVI accounts for 13,108 of these procedures, with an increase of 21%, whereas the numbers of isolated sAVR and TA-TAVI decreased slightly. Age, frailty, high risk, and patients’ choice were the main reasons for a catheter-based intervention. In 2015, the in-hospital mortality rate after TV-TAVI decreased to 3.4%, approaching that of sAVR (2.9%), despite a considerably higher baseline risk. A stratified analysis according to the German aortic valve (AKL) score demonstrated a further decrease of the in-hospital mortality for TV-TAVI, showing a lower in-hospital mortality rate than expected in all risk groups. Importantly, this also accounts for the lowest risk group with an AKL score <3% showing an in-hospital mortality rate of 1.7%, which is now comparable to that of sAVR (1.5%). In all other risk groups, the in-hospital mortality in patients undergoing TV-TAVI was lower than in patients undergoing sAVR.ConclusionsMortality after TV-TAVI keeps decreasing over the last years and equals that of SAVR in the lowest risk cohort in the meanwhile. All TV-TAVI patients have significantly lower observed than expected mortality, which will further lead to a redefinition of standard of care.

Renal sympathetic denervation does not aggravate functional or structural renal damage.

To the Editor: Renal sympathetic denervation (RSD) is an interventional treatment option for resistant arterial hypertension (HT) ([1][1]). Previous investigations of RSD excluded patients with progressive chronic kidney disease because of potential RSD-related kidney damage ([1,2][1]). Diagnosis

Feasibility of everolimus-eluting bioresorbable vascular scaffolds in patients with chronic total occlusion

OBJECTIVE This study evaluates the feasibility of percutaneous coronary intervention with bioresorbable vascular scaffolds (BVSs) in chronic total occlusion (CTO) lesions. BACKGROUND Everolimus-eluting BVSs represent a new approach to treating coronary artery disease, but experience with CTO is limited. METHODS Patients with a previously diagnosed CTO who had been treated with BVS were included. Patients with unsuccessful CTO procedures and patients treated with drug-eluting stents were excluded. Difficulty of the CTO procedure was assessed by the J-score. RESULTS A total of 23 patients were included. Mean age was 60.4 ± 9.0 years, 17.4% were female, 91.3% suffered from hypertension and 34.8% from diabetes. Mean J-score was 1.7 ± 1.0. Median procedure time was 70 min (54-85), mean contrast volume was 213.5 mL (±94.2) and median fluoroscopy time was 19.1 min (13.1-30.0). A total of 64 BVSs were implanted with a mean number of 2.8 ± 1.0 BVSs per patient, a mean total BVS length of 64.8 ± 24.2 mm per lesion, and a mean BVS diameter of 3.1 ± 0.2 mm. Neither a scaffold-related dissection nor any other intra-procedural complication occurred. During a follow-up of 108 (79.5-214.5) days one in-scaffold thrombosis was noted 4 days after the CTO procedure due to a lack of dual antiplatelet therapy. No further major adverse cardiac events occurred. CONCLUSION These results suggest that BVS implantation in CTO lesions can be performed with good procedural success and reasonable clinical short-term outcome in highly selected cases.

Release Kinetics of Inflammatory Biomarkers in a Clinical Model of Acute Myocardial Infarction

RATIONALE Inflammation in the setting of acute myocardial infarction (MI) has been linked to risk stratification; however, the release kinetics of inflammatory biomarkers in patients with acute MI has been difficult to establish. OBJECTIVE The aim of this study was to determine the kinetics of changes in the levels of several biomarkers specifically linked to inflammation after transcoronary ablation of septal hypertrophy, a procedure that mimics acute MI. METHODS AND RESULTS We analyzed release kinetics of C-reactive protein, high-sensitivity C-reactive protein, interleukin-6, soluble CD40 ligand, and peripheral blood leukocyte subsets in patients (n=21) undergoing transcoronary ablation of septal hypertrophy. Blood samples were collected before transcoronary ablation of septal hypertrophy and at various times after transcoronary ablation of septal hypertrophy. Serum levels of C-reactive protein were increased at 24 hours (1.0 mg/dL [interquartile range [IQR], 0.7-1.75] versus 0.2 mg/dL [IQR, 0.1-1.05] at baseline [BL]; P<0.001), whereas high-sensitivity C-reactive protein increased as early as 8 hours (2.68 mg/L [IQR, 1.23-11.80] versus 2.17 mg/L [IQR, 1.15-5.06] at BL; P=0.002). Interleukin-6 was significantly increased at 45 minutes (2.59 pg/mL [IQR, 1.69-5.0] versus 1.5 pg/mL [IQR, 1.5-2.21] at BL; P=0.002), and soluble CD40 ligand was significantly decreased at 60 minutes (801.6 pg/mL [IQR, 675.0-1653.5] versus 1750.0 pg/mL [IQR, 1151.0-2783.0] at BL; P=0.016). Elevated counts of polymorphonuclear neutrophils were detectable at 15 minutes, with a significant increase at 2 hours (6415 cells/μL [IQR, 5288-7827] versus 4697 cells/μL [IQR, 2892-5620] at BL; P=0.004). Significant monocytosis was observed at 24 hours (729 cells/μL [IQR, 584-1344] versus 523 cells/μL [IQR, 369-701] at BL; P=0.015). CONCLUSIONS Interleukin-6 and neutrophil granulocytes showed a continuous rise at all prespecified time points after induction of MI. Our results provide valuable additional evidence of the diagnostic value of inflammatory biomarkers in the setting of early acute MI.

Release kinetics of early ischaemic biomarkers in a clinical model of acute myocardial infarction

Objective To determine the release kinetics of different biomarkers with potential as novel early ischaemic biomarkers in patients with acute coronary syndrome (ACS); it is difficult to establish the detailed release kinetics in patients with acute myocardial infarction (AMI). Methods We analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischaemia modified albumin (IMA), and heart-type fatty acid binding protein (hFABP) in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n=21) undergoing TASH were included. Blood samples were collected before TASH and 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. sFlt-1 and hFABP were quantified in serum, and IMA was quantified in plasma using immunoassays. Results sFLT-1 and hFABP increased significantly 15 min after induction of AMI vs baseline as follows: sFlt-1, 3657.5 ng/L (IQR 2302.3–4475.0) vs 76.0 ng/L (IQR 71.2–88.8) (p<0.001); hFABP, 9.0 ng/mL (IQR 7.0–15.4) vs 4.6 ng/mL (IQR 3.4–7.1) (p<0.001). sFlt-1 demonstrated a continuous decrease after the 15th min. hFABP showed a continuous increase until the 8th hour with a decline afterwards. The IMA concentrations increased significantly 30 min after induction of AMI vs baseline, with values of 26.0 U/mL (IQR 21.8–38.6) vs 15.6 U/mL (IQR 10.1–24.7) (p=0.02), and then decreased after 75 min. Conclusions sFlt-1 and hFABP increased very early after induction of myocardial ischaemia, showing different release kinetics. The additional information provided by these findings is helpful for developing their potential combined use with cardiac troponins in patients with suspected AMI.