Thomas Kaier

Intracellular signaling pathways control mitochondrial events associated with the development of ischemia/ reperfusion-associated damage.

Ischemia (I) and reperfusion (R) trigger a series of events, which culminate in severe injury to the transplanted organ. Cell death resulting from the formation of mitochondrial reactive oxygen species (ROS) coupled with the perturbation of mitochondrial Ca2+ homeostasis is central to the development of IR‐associated tissue damage. We and others have shown recently that intracellular signaling pathways critically control these mitochondrial changes, making them potential targets for therapeutic intervention. Using a heterotopic murine heart transplant model as well as primary and immortalized cardiomyocyte cells we established the activity patterns of mitogen‐activated protein kinases (MAPKs) ERK, JNK, and p38 during IR, and probed into their role in the perturbation of mitochondrial ROS and Ca2+ homeostasis, which are necessary for cardiomyocyte death. Our results showed a strong activation of all three MAPKs as well as a rise in mitochondrial ROS and Ca2+ during early reoxygenation. Inhibiting p38 kinase most efficiently prevented ROS production, Ca2+ overload and cell death, suggesting that targeting this signaling molecule may provide a possible strategy to limit the effects of IR.

The effect of bariatric surgery on echocardiographic indices: a review of the literature

Obesity is the new epidemic and is associated with an increased risk of diastolic and systolic heart failure. Effective treatment options with drastic results such as bariatric surgery have raised interest in the possible reversal of some of the cardiovascular sequelae. Many studies have assessed individually the effect of weight loss on specific echocardiographic indices, mostly employing nonhomogeneous groups. The purpose of this narrative review is to summarise the effect of bariatric surgery on echocardiographic indices of biventricular function and to help in the understanding of the expected echocardiographic changes in bariatric patients after weight‐loss surgery

Ventricular remodelling post-bariatric surgery: is the type of surgery relevant? A prospective study with 3D speckle tracking

AIMS The aim of the study was to examine ventricular remodelling in patients free of cardiac risk factors, before, and 6 months post-bariatric surgery with the new imaging modality of three-dimensional (3D) strain and the comparison of two surgical techniques: sleeve gastrectomy vs. gastric bypass. METHODS AND RESULTS Fifty-two consecutive patients referred to the Bariatric Services of Imperial College NHS Trust were examined with conventional 2D and 3D strain echocardiography, prior to and 6 months after bariatric surgery. They were all free from cardiac disease. The study cohorts mean age was 44.2 ± 8.7 years and body mass index of 42.4 ± 4.6 g/m(2) prior to surgery. Eighteen patients (34.6%) underwent laparoscopic sleeve gastrectomy, and 34 laparoscopic gastric bypass. On 3D speckle tracking, there was significant reverse remodelling post-bariatric surgery [left ventricular (LV) ejection fraction (EF): pre-surgery: 59 ± 8% vs. post-surgery: 67 ± 7%, P < 0.001 and right ventricular (RV) EF: pre-surgery: 60 ± 9% vs. post-surgery: 68 ± 8.2%, P = 0.0001]. Furthermore, there was significant regression of mass (LV mass: pre-surgery: 111 ± 23.5 g vs. post-surgery: 92.8 ± 15.5 g and RV mass: pre-surgery: 95.2 ± 19.8 vs. post-surgery: 67.3 ± 16.3, P < 0.001). RV and LV global strain improved 6 months post-bariatric surgery: global RV strain: pre-surgery -11.7 ± 4 vs. post-surgery -17.52 ± 3.7, P < 0.001; global LV strain: pre-surgery: -20.2 ± 1.7 vs. post-surgery: -26.5 ± 1.86, P < 0.001. Sleeve gastrectomy and gastric bypass had comparable effects. CONCLUSION Bariatric surgery has an important effect in reverse LV and RV remodelling and it substantially improves RV longitudinal strain.

Quantifying the Release of Biomarkers of Myocardial Necrosis from Cardiac Myocytes and Intact Myocardium

BACKGROUND Myocardial infarction is diagnosed when biomarkers of cardiac necrosis exceed the 99th centile, although guidelines advocate even lower concentrations for early rule-out. We examined how many myocytes and how much myocardium these concentrations represent. We also examined if dietary troponin can confound the rule-out algorithm. METHODS Individual rat cardiac myocytes, rat myocardium, ovine myocardium, or human myocardium were spiked into 400-μL aliquots of human serum. Blood was drawn from a volunteer after ingestion of ovine myocardium. High-sensitivity assays were used to measure cardiac troponin T (cTnT; Roche, Elecsys), cTnI (Abbott, Architect), and cardiac myosin-binding protein C (cMyC; EMD Millipore, Erenna®). RESULTS The cMyC assay could only detect the human protein. For each rat cardiac myocyte added to 400 μL of human serum, cTnT and cTnI increased by 19.0 ng/L (95% CI, 16.8-21.2) and 18.9 ng/L (95% CI, 14.7-23.1), respectively. Under identical conditions cTnT, cTnI, and cMyC increased by 3.9 ng/L (95% CI, 3.6-4.3), 4.3 ng/L (95% CI, 3.8-4.7), and 41.0 ng/L (95% CI, 38.0-44.0) per μg of human myocardium. There was no detectable change in cTnI or cTnT concentration after ingestion of sufficient ovine myocardium to increase cTnT and cTnI to approximately 1 × 108 times their lower limits of quantification. CONCLUSIONS Based on pragmatic assumptions regarding cTn and cMyC release efficiency, circulating species, and volume of distribution, 99th centile concentrations may be exceeded by necrosis of 40 mg of myocardium. This volume is much too small to detect by noninvasive imaging.

The development and application of a high-sensitivity immunoassay for cardiac myosin–binding protein C

Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin–binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery (107.1 ± 3.7%; mean ± standard deviation), dilutional linearity (101.0 ± 7.7%), and intraseries precision (CV, 11 ± 3%) and interseries precision (CV, 13 ± 3%). In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration (median, 12.2 ng/L; interquartile range [IQR], 7.9–21.2 ng/L) was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0–4.9 ng/L; R = 0.56, P < 0.01) and cTnI (median, 2.10 ng/L; IQR, 1.3–4.2 ng/L; R = 0.77, P < 0.01) and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability.

Direct Comparison of Cardiac Myosin-Binding Protein C with Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction

Background: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI. Methods: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality. Results: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (P<0.0001) and 0.926 (P=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (P<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (P<0.05 for both) and similar to hs-cTnT at predicting death at 3 years. Conclusions: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Temporal Relationship between Cardiac Myosin-Binding Protein C and Cardiac Troponin I in Type 1 Myocardial Infarction

To the Editor: Although acute chest pain is a common presenting symptom, the proportion of patients with acute myocardial infarction (AMI)1 who have diagnostic electrocardiographic changes on presentation is dwindling. Consequently, early triage of chest pain patients is becoming ever more reliant on assessment of the release of cardiac troponin I (cTnI) or cTnT into the systemic circulation. However, these biomarkers are released relatively slowly, reaching their peak many hours after symptom onset (1). To achieve rapid triage, the latest guidelines recommend the use of assays for cTnI and cTnT that have very high analytical sensitivity to rule-in and rule-out AMI based on concentrations markedly above and markedly below the population-defined 99th percentiles, respectively. The use of these widely spaced decision limits improves the specificity of rule-in and the sensitivity of rule-out. However, the majority of patients presenting with chest pain have cardiac troponin concentrations that place them between these decision limits, in an indeterminate zone. These patients require repeat testing and subsequent second or third rounds of triage based on rates of change of cardiac troponin concentration over time (2). This introduces systematic delays in allocation of evidence-based treatments and prolongs stay in the pressured and precious environment of the emergency department. We have described a new biomarker of …

Troponins and other biomarkers in the early diagnosis of acute myocardial infarction.

Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early rule-out protocols for AMI, when measured at presentation and again at 3–6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.

A single centre prospective cohort study addressing the effect of a rule-in/rule-out troponin algorithm on routine clinical practice:

Aims: In 2015, the European Society of Cardiology introduced new guidelines for the diagnosis of acute coronary syndromes in patients presenting without persistent ST-segment elevation. These guidelines included the use of high-sensitivity troponin assays for ‘rule-in’ and ‘rule-out’ of acute myocardial injury at presentation (using a ‘0 hour’ blood test). Whilst these algorithms have been extensively validated in prospective diagnostic studies, the outcome of their implementation in routine clinical practice has not been described. The present study describes the change in the patient journey resulting from implementation of such an algorithm in a busy innercity Emergency Department. Methods and results: Data were prospectively collected from electronic records at a large Central London hospital over seven months spanning the periods before, during and after the introduction of a new high-sensitivity troponin rapid diagnostic algorithm modelled on the European Society of Cardiology guideline. Over 213 days, 4644 patients had high-sensitivity troponin T measured in the Emergency Department. Of these patients, 40.4% could be ‘ruled-out’ based on the high-sensitivity troponin T concentration at presentation, whilst 7.6% could be ‘ruled-in’. Adoption of the algorithm into clinical practice was associated with a 37.5% increase of repeat high-sensitivity troponin T measurements within 1.5 h for those patients classified as ‘intermediate risk’ on presentation. Conclusions: Introduction of a 0 hour ‘rule-in’ and ‘rule-out’ algorithm in routine clinical practice enables rapid triage of 48% of patients, and is associated with more rapid repeat testing in intermediate risk patients.

Cardiac myosin-binding protein C is a novel marker of myocardial injury and fibrosis in aortic stenosis

Objective Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis. Methods cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11.3 years. Results In the mechanism cohort, cMyC concentration correlated with left ventricular mass (adjusted β=11.0 g/m2 per log unit increase in cMyC, P<0.001), fibrosis volume (adjusted β=8.0 g, P<0.001) and extracellular volume (adjusted β=1.3%, P=0.01) in patients with aortic stenosis but not in controls. In those with late gadolinium enhancement (LGE) indicative of myocardial fibrosis, cMyC concentrations were higher (32 (21–56) ng/L vs 17 (12–24) ng/L without LGE, P<0.001). cMyC was unrelated to coronary calcium scores. Unadjusted Cox proportional hazards analysis in the outcome cohort showed greater all-cause mortality (HR 1.49 per unit increase in log cMyC, 95% CI 1.11 to 2.01, P=0.009). Conclusions Serum cMyC concentration is associated with myocardial hypertrophy, fibrosis and an increased risk of mortality in aortic stenosis. The quantification of serum sarcomeric protein concentrations provides objective measures of disease severity and their clinical utility to monitor the progression of aortic stenosis merits further study. Clinical trial registration NCT1755936; Post-results.