An arrhythmogenic metabolite in atrial fibrillation.

BACKGROUND: Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. METHODS AND RESULTS: Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. CONCLUSION: Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

[Intraaortic Ballon-pump: Physiology, Indication, Management]. / Intraaortale Ballonpumpe: Physiologie, Indikationen, Management.

The intraaortic ballon-pump (IABP) is a percutaneous mechanical circulatory support device, which is used in patients either with insufficient cardiac output or in patients with high-risk situation before cardiac intervention, like surgical revascularisation or percutaneous coronary intervention (PCI). Due to electrocardiographic or arterial pressure pulse the IABP augments diastolic coronary perfusion pressure and reduces systolic afterload. Thereby, myocardial oxygen supply-demand ratio is improved and cardiac output is increased. Many national and international cardiology, cardiothoracic and intensive care medicine societies and associations worked together in order to develop evidence-based recommendations and guidelines for the preoperative, intraoperative and postoperative management of the IABP. This manuscript is mainly based on the S3 guideline "Use of intraaortic balloon-pump in cardiac surgery" from the German Society for Thoracic and Cardiovascular Surgery (DGTHG).

Cellular and mitochondrial mechanisms of atrial fibrillation.

The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation-contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Atrial contractility and fibrotic biomarkers are associated with atrial fibrillation after elective coronary artery bypass grafting.

OBJECTIVE: New-onset postoperative atrial fibrillation is common after cardiac surgery. Less has been reported about the relationship among fibrosis, inflammation, calcium-induced left atrial and right atrial contractile forces, and postoperative atrial fibrillation. We sought to identify predictors of postoperative atrial fibrillation. METHODS: From August 2016 to February 2018, we evaluated 229 patients who had preoperative sinus rhythm before elective primary coronary artery bypass grafting. Of 229 patients, 191 maintained sinus rhythm postoperatively, whereas 38 patients developed atrial fibrillation. Preoperative tissue inhibitor of metalloproteinase-1, pentraxin-3, matrix metallopeptidase-9, galectin-3, high-sensitivity C-reactive protein, growth differentiation factor 15, and transforming growth factor-ß were measured. Clinical and echocardiographic findings (tricuspid annular plane systolic excursion for right heart function) and calcium-induced force measurements from left atrial and right atrial-derived skinned myocardial fibers were recorded. RESULTS: Patients with atrial fibrillation were older (P = .001), had enlarged left atrial (P = .0001) and right atrial areas (P = .0001), and had decreased tricuspid annular plane systolic excursion (P = .001). Levels of matrix metallopeptidase-9 and pentraxin-3 were decreased (P < .05), whereas growth differentiation factor 15 was increased (P = .001). We detected lower left atrial force values at calcium-induced force measurements 5.5 (P < .05), 5.4 (P < .01), and 5.3 to 4.52 (P = .0001) and right atrial force values at calcium-induced force measurements 5.0 to 4.52 (P < .05) in patients with postoperative atrial fibrillation. Multivariable analysis showed that advanced age (P = .033), decreased left atrial force value at calcium-induced force measurement of 5.5 (P = .033), enlarged left atrial (P = .013) and right atrial (P = .081) areas, and reduced tricuspid annular plane systolic excursion (P = .010) independently predicted postoperative atrial fibrillation. CONCLUSIONS: Advanced age, decreased left atrial force value at calcium-induced force measurement of 5.5, enlarged left atrial and right atrial areas, and reduced tricuspid annular plane systolic excursion were identified as independent predictors for postoperative atrial fibrillation.

Impact of diabetes mellitus on the contractile properties of the left and right atrial myofilaments.

OBJECTIVES: The incidence of diabetes mellitus in patients with ischaemic cardiomyopathy is increasing. To evaluate the impact of diabetes mellitus on contractility, we examined the calcium-induced force in left and right atrial myofilaments of patients with and without diabetes. METHODS: We included 149 patients (106 without diabetes, 43 with diabetes), scheduled for elective coronary artery bypass grafting from August 2016 to June 2017. The left and right atria were excised and prepared for skinned fibre measurements (pCa-force curve). The unit for the force measurements is Millinewton (mN). Comprehensive demographic data as well as echocardiographic findings of the patients were collected. RESULTS: We observed a significant decrease of left atrial force values in patients with diabetes, averaged over all calcium concentrations (patients with diabetes 0.50 ± 0.19 mN vs 0.68 ± 0.23 mN in patients without diabetes, P = 0.002) as well as in right atrial fibres (patients with diabetes 0.35 ± 0.17 mN vs 0.47 ± 0.21 mN in patients without diabetes, P = 0.005). There was a significant influence of repeated measurements (of the calcium concentrations) on force in left atrial myofilaments (P < 0.001). There was also a significant impact of diabetes on the force values of the different calcium concentrations in left atrial myofilaments (P 0.002). In right atrial myofilaments we also found a significant influence of repeated measurements (of the calcium concentrations) on force (P < 0.001). Additionally the impact of diabetes on the force values was significant (P = 0.005). CONCLUSIONS: We demonstrated that diabetes mellitus has a significantly negative impact on calcium-induced force development in left and right atrial myofilaments.

Impact of levosimendan and ischaemia-reperfusion injury on myocardial subsarcolemmal mitochondrial respiratory chain, mitochondrial membrane potential, Ca2+ cycling and ATP synthesis.

OBJECTIVES: Levosimendan (LS) is increasingly used in case of myocardial failure after cardiac surgery. The impact of LS on myocardial mitochondrial functions, such as respiratory chain function (RCF), mitochondrial membrane potential (ΔΨm), Ca(2+) handling, mitochondrial permeability transition pore (mPTP) opening and ATP during ongoing ischaemia/reperfusion (IR) injury, is not well understood. Depending on LS, I/R injury or the combination of both, we analysed myocardial functions in a retrograde Langendorff-model followed by the analysis of subsarcolemmal mitochondrial (SSM) functions. METHODS: Rat hearts were divided into four study groups; two were subjected to 30 min of perfusion without (control) or with the application of 1.4 µmol/20 min LS (Levo). Experiments were repeated with hearts being subjected to 40 min of normothermic stop-flow ischaemia and 30 min of reperfusion without (IR) or with LS application (Levo-IR). Systolic left ventricular pressure (LVPsys), left ventricular contractility (LVdp/dtmax) and coronary flow were determined. SSM were analysed regarding RCF, ΔΨm, ATP, and Ca(2+) retention capacity (CRC), Ca(2+)-induced swelling and Ca(2+) fluxes after (re)perfusion. RESULTS: I/R injury suppressed LVdp/dtmax (1381 ± 927 vs 2464 ± 913 mmHg/s; P = 0.01 at 30 min (re-)perfusion time). IR revealed complex I-V state3 (19.1 ± 7.4 vs 27.6 ± 11.0 nmolO2/min; P < 0.044) and II-V state3 (20.6 ± 6.8 vs 37.3 ± 9.10 molO2/min; P < 0.0001) suppression and Levo limited I-V (14.8 ± 11.1 vs 27.6 ± 11.0 nmolO2/min; P < 0.001) and II-V (24.1 ± 6.4 vs 37.3 ± 9.10 molO2/min; P < 0.0001) function. After energizing, ΔΨm hypopolarization was observed in Levo (0.76 ± 0.04 vs 0.84 ± 0.04; P = 0.02), IR (0.75 ± 0.06 vs 0.84 ± 0.04; P = 0.007) and Levo-IR (0.75 ± 0.06 vs 0.06 ± 0.04; P = 0.01). IR (AUC: 626 vs 292; P = 0.023) and Levo-IR (AUC: 683 vs 292, P = 0.003) increased Ca(2+)-induced mPTP-opening susceptibility. CRC declined in IR (6.4 ± 2.1 vs 10.5 ± 2.6; P = 0.04) or Levo (6.5 ± 2.0 vs 10.5 ± 2.6; P = 0.023). Ca(2+) uptake was delayed in IR and Levo-IR without LS impact (P < 0.0001). Ca(2+) liberation was increased in Levo-IR. ATP synthesis was reduced in Levo (0.49 ± 0.14 vs 0.74 ± 0.14; P = 0.002) and Levo-I/R (0.34 ± 0.18 vs 0.74 ± 0.14; P < 0.002). CONCLUSION: LS limited RCF at complex IV and V with ΔΨm hypopolarization suggesting a specific [Formula: see text]-dependent pathway. Ca(2+) redistribution from SSM by LS during I/R injury possibly prevents from Ca(2+) overload due to mPTP flickering. LS-induced mPTP flickering did not promote permanent Ca(2+)-induced mPTP opening. LS-dependent inhibition of ATP generation presumably resulted from complex IV and V limitations and lowered ΔΨm. However, a resulting impact of limited ATP synthesis on myocardial recovery remains arguable.