Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation.

BACKGROUND: Alterations in the buffering of intracellular Ca2+, for which myofilament proteins play a key role, have been shown to promote cardiac arrhythmia. It is interesting that although studies report atrial myofibrillar degradation in patients with persistent atrial fibrillation (persAF), the intracellular Ca2+ buffering profile in persAF remains obscure. Therefore, we aimed to investigate the intracellular buffering of Ca2+ and its potential arrhythmogenic role in persAF. METHODS: Transmembrane Ca2+ fluxes (patch-clamp) and intracellular Ca2+ signaling (fluo-3-acetoxymethyl ester) were recorded simultaneously in myocytes from right atrial biopsies of sinus rhythm (Ctrl) and patients with persAF, alongside human atrial subtype induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Protein levels were quantified by immunoblotting of human atrial tissue and induced pluripotent stem cell-derived cardiac myocytes. Mouse whole heart and atrial electrophysiology were measured on a Langendorff system. RESULTS: Cytosolic Ca2+ buffering was decreased in atrial myocytes of patients with persAF because of a depleted amount of Ca2+ buffers. In agreement, protein levels of selected Ca2+ binding myofilament proteins, including cTnC (cardiac troponin C), a major cytosolic Ca2+ buffer, were significantly lower in patients with persAF. Small interfering RNA (siRNA)-mediated knockdown of cTnC (si-cTNC) in atrial iPSC-CM phenocopied the reduced cytosolic Ca2+ buffering observed in persAF. Si-cTnC treated atrial iPSC-CM exhibited a higher predisposition to spontaneous Ca2+ release events and developed action potential alternans at low stimulation frequencies. Last, indirect reduction of cytosolic Ca2+ buffering using blebbistatin in an ex vivo mouse whole heart model increased vulnerability to tachypacing-induced atrial arrhythmia, validating the direct mechanistic link between impaired cytosolic Ca2+ buffering and atrial arrhythmogenesis. CONCLUSIONS: Our findings suggest that loss of myofilament proteins, particularly reduced cTnC protein levels, causes diminished cytosolic Ca2+ buffering in persAF, thereby potentiating the occurrence of spontaneous Ca2+ release events and atrial fibrillation susceptibility. Strategies targeting intracellular buffering may represent a promising therapeutic lead in persAF management.

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.

The completeness of the left atrial appendage amputation during routine cardiac surgery.

BACKGROUND: Left atrial appendage (LAA) is the origin of most heart thrombi which can lead to stroke or other cerebrovascular event in patients with non-valvular atrial fibrillation (AF). This study aimed to prove safety and low complication rate of surgical LAA amputation using cut and sew technique with control of its effectiveness. METHODS: 303 patients who have undergone selective LAA amputation were enrolled in the study in a period from 10/17 to 08/20. The LAA amputation was performed concomitant to routine cardiac surgery on cardiopulmonary bypass with cardiac arrest with or without previous history of AF. The operative and clinical data were evaluated. Extent of LAA amputation was examined intraoperatively by transoesophageal echocardiography (TEE). Six months in follow up, the patients were controlled regarding clinical status and episodes of strokes. RESULTS: Average age of study population was 69.9 ± 19.2 and 81.9% of patients were male. In only three patients was residual stump after LAA amputation larger than 1 cm with average stump size 0.28 ± 0.34 cm. 3 patients (1%) developed postoperative bleeding. Postoperatively 77 (25.4%) patients developed postoperative AF (POAF), of which 29 (9.6%) still had AF at discharge. On 6 months follow up only 5 patients had NYHA class III and 1 NYHA class IV. Seven patients reported with leg oedema and no patient experienced any cerebrovascular event in early postoperative follow up. CONCLUSION: LAA amputation can be performed safely and completely leaving minimal to no LAA residual stump.

Decellularized Pulmonary Xenograft Matrix PplusN versus Cryopreserved Homograft for RVOT Reconstruction during Ross Procedure in Adults.

BACKGROUND: Decellularized pulmonary homografts are being increasingly adopted for right ventricular outflow tract reconstruction in adult patients undergoing the Ross procedure. Few reports presented Matrix PplusN xenograft (Matrix) in a negative light. The objective of this study was to compare our midterm outcomes of Matrix xenograft versus standard cryopreserved pulmonary homograft (CPHG). METHODS: Eighteen patients received Matrix xenograft between January 2012 and June 2016, whereas 66 patients received CPHG. Using nonparametric statistical tests and survival analysis, we compared midterm echocardiographic and clinical outcomes between the groups. RESULTS: Except for significant age difference (the Matrix group was significantly older with 57 ± 8 years than the CPHG group, 48 ± 9 years, p = 0.02), the groups were similar in all other baseline characteristics. There were no significant differences in cardiopulmonary bypass times (208.3 ± 32.1 vs. 202.8 ± 34.8) or in cross-clamp times (174 ± 33.9 vs. 184.4 ± 31.1) for Matrix and CPHG, respectively. The Matrix group had significantly inferior freedom from reintervention than the CPHG group with 77.8 versus 98.5% (p = 0.02). Freedom from pulmonary valve regurgitation ≥ 2 was not significantly different between the groups with 82.4 versus 90.5% for Matrix versus CPHG, respectively. After median follow-up of 4.9 years, Matrix xenograft developed significantly higher peak pressure gradients compared with CPHG (20.4 ± 15.5 vs. 12.2 ± 9.0 mm Hg; p = 0.04). CONCLUSION: After 5 years of clinical and echocardiographic follow-up, the decellularized Matrix xenograft had inferior freedom from reintervention compared with the standard CPHG. Closer follow-up is necessary to avoid progression of valve failure into right ventricular deterioration.

TIMP-2*IGFBP7 (Nephrocheck®) Measurements at Intensive Care Unit Admission After Cardiac Surgery are Predictive for Acute Kidney Injury Within 48 Hours.

BACKGROUND/AIMS: Acute kidney injury (AKI) is a postoperative complication after cardiac surgery with a high impact on mortality and morbidity. Nephrocheck® [TIMP-2*IGFBP7] determines markers of tubular stress, which occurs prior to tubular damage. It is unknown at which time-point [TIMP-2*IGFBP7] measurement should be performed to ideally predict AKI. We investigated the association of [TIMP-2*IGFBP7] at various time-points with the incidence of AKI in patients undergoing elective cardiac surgery including cardio-pulmonary bypass. METHODS: In a prospective cohort study, serial blood and urine samples were collected from 150 patients: pre-operative, at ICU-admission, 24h and 48h post-surgery. AKI was defined as Serum-Creatinine rise >0.3 mg/dl within 48hrs. Urinary [TIMP-2*IGFBP7] was measured at pre-operative, ICU-admission and 24h post-surgery; medical staff was kept blinded to these results. RESULTS: A total of 35 patients (23.5%) experienced AKI, with a higher incidence in those with high [TIMP-2*IGFBP7] values at ICU admission (57.1% vs. 10.1%, p<0.001). In logistic regression [TIMP-2*IGFBP7] at ICU admission was independently associated with the occurrence of AKI (Odds Ratio 11.83; p<0.001, C-statistic= 0.74) after adjustment for EuroSCORE II and CBP-time. CONCLUSIONS: Early detection of elevated [TIMP-2*IGFBP7] at ICU admission was strongly predictive for postoperative AKI and appeared to be more precise as compared to subsequent measurements.

Contractile properties of the right atrial myofilaments in patients with myxomatous mitral valve degeneration.

BACKGROUND: Myxomatous degeneration of the mitral valve is a common pathological finding in mitral valve surgery and the most common reason for severe mitral valve regurgitation. Considering the importance of right ventricular remodeling and global function after mitral valve surgery we tried to elucidate a possible association of myxomatous mitral valve and impairment of right atrial and ventricular function, which might have an impact on global ventricular performance after mitral valve surgery. METHODS: Right atrial tissue was harvested from 47 patients undergoing mitral valve surgery. We took the trabeculae from the right auricle, which was resected at the right auricle for implementation of extracorporal circulation. The tissue was skinned and prepared in a 24 h-lasting procedure to create small fibers for hinging them in the "muscle machine", an experimental set-up, created for pCa-force measurements. RESULTS: Patients without myxomatous mitral valve developed significantly more force (4.0 mN ± 0.8 mN) at the highest step of calcium concentration compared to 2.7 mN ± 0.4 mN in group of patients with myxomatous valve degeneration (p 0.03). Calcium sensitivity in the myxomatous valve group was at pCa 6.0 and in the non-myxomatous group at pCa 5. Furthermore we observed a significant difference in ejection fraction (EF) among the groups: 49% in the non-myxomatous group versus 57% in the myxomatous group (p 0.03). In the non-myxomatous group 5 patients had diastolic dysfunction grade I-II (22,7%), in group I 10 patients (40%). This was also significant (p 0.04). CONCLUSIONS: Patients with myxomatous mitral valve degeneration seem to have reduced force capacities. Calcium sensitivity is higher compared to the non-myxomatous group, which might be a compensatory mechanism to cover the physiological demand. Furthermore we suggest a higher incidence of diastolic dysfunction in patients with myxomatous mitral valve degeneration, which might have an impact on ventricular remodeling after mitral valve surgery.

Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model.

BACKGROUND: Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4-6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an "out-of-hospital" sudden unexpected death with subsequent "in-hospital" cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin-streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V-A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia-reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem. RESULTS: BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, - 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice. CONCLUSIONS: Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.

Recruited macrophages elicit atrial fibrillation.

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2-∕- HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.

Benefits of Intra-Aortic Balloon Pump Support in Patients with Postcardiotomy Shock Requiring Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: The benefit of the combined use of an intra-aortic balloon pump (IABP) and venoarterial extracorporeal membrane oxygenation (VA-ECMO) for postcardiotomy shock remains unclear. We aimed to analyse the potential benefits and safety of combining these two devices. METHODS: We enrolled 200 patients treated with either VA-ECMO only or in combination with IABP (ECMO-I group) between January 2012 and January 2021. To adjust the patients' backgrounds, we used propensity score matching for additional analyses, resulting in 57 pairs. The primary endpoint was 30-day survival. Secondary endpoints included successful weaning and complication rates. We also analysed hemodynamic parameters in both groups. RESULTS: After propensity score matching, 30-day survival was better in the ECMO-I group (log-rank p = 0.004). The ECMO-I and ECMO-only groups differed regarding the secondary endpoints, including successful weaning (50.9% and 26.3%, respectively; p = 0.012) and the need for continuous renal replacement therapy (28.1% and 50.9%, p = 0.021). Complication rates were not statistically different between the two groups. CONCLUSION: Compared to VA-ECMO alone, the combined use of VA-ECMO and IABP is beneficial regarding 30-day survival in selected patients with postcardiotomy shock; successful ECMO weaning and freedom from renal replacement therapy is more common in patients supported with VA-ECMO plus IABP.

Central Versus Peripheral Arterial Cannulation for Veno-Arterial Extracorporeal Membrane Oxygenation in Post-Cardiotomy Patients.

Different arterial cannulation strategies are feasible for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in postcardiotomy shock. We aimed to analyze potential benefits and safety of different arterial cannulation strategies. We identified 158 patients with postcardiotomy cardiogenic shock requiring VA-ECMO between 01/10 and 01/19. Eighty-eight patients were cannulated via axillary or femoral artery (group P), and 70 centrally via the ascending aorta directly or through an 8 mm vascular graft anastomosed to the ascending aorta (group C). Demographics and operative parameters were similar. Change of cannulation site for Harlequin's syndrome or hyperperfusion of an extremity occurred in 13 patients in group P but never in group C (p = 0.001). Surgical revision of cannulation site was also encountered more often in group P than C. The need for left ventricular (LV) unloading was similar between groups, whereas surgical venting was more often implemented in group C (11.4% vs. 2.3, p = 0.023). Stroke rates, renal failure, and peripheral ischemia were similar. Weaning rate from ECMO (52.9% vs. 52.3%, p = NS) was similar. The 30 day mortality was higher in group P (60% vs. 76.1%, p = 0.029). Central cannulation for VA-ECMO provides antegrade flow without Harlequin's syndrome, changes of arterial cannula site, and better 30 day survival. Complication rates regarding need for reexploration and transfusion requirements were similar.

Long-Term Outcomes of Patients Undergoing the Ross Procedure.

BACKGROUND: Treatment of aortic-valve disease in young patients still poses challenges. The Ross procedure offers several potential advantages that may translate to improved long-term outcomes. OBJECTIVES: This study reports long-term outcomes after the Ross procedure. METHODS: Adult patients who were included in the Ross Registry between 1988 and 2018 were analyzed. Endpoints were overall survival, reintervention, and major adverse events at maximum follow-up. Multivariable regression analyses were performed to identify risk factors for survival and the need of Ross-related reintervention. RESULTS: There were 2,444 adult patients with a mean age of 44.1 ± 11.7 years identified. Early mortality was 1.0%. Estimated survival after 25 years was 75.8% and did not statistically differ from the general population (p = 0.189). The risk for autograft reintervention was 0.69% per patient-year and 0.62% per patient-year for right-ventricular outflow tract (RVOT) reintervention. Larger aortic annulus diameter (hazard ratio [HR]: 1.12/mm; 95% confidence interval [CI]: 1.05 to 1.19/mm; p < 0.001) and pre-operative presence of pure aortic insufficiency (HR: 1.74; 95% CI: 1.13 to 2.68; p = 0.01) were independent predictors for autograft reintervention, whereas the use of a biological valve (HR: 8.09; 95% CI: 5.01 to 13.08; p < 0.001) and patient age (HR: 0.97 per year; 95% CI: 0.96 to 0.99; p = 0.001) were independent predictors for RVOT reintervention. Major bleeding, valve thrombosis, permanent stroke, and endocarditis occurred with an incidence of 0.15% per patient-year, 0.07% per patient-year, 0.13%, and 0.36% per patient-year, respectively. CONCLUSIONS: The Ross procedure provides excellent survival over a follow-up period of up to 25 years. The rates of reintervention, anticoagulation-related morbidity, and endocarditis were very low. This procedure should therefore be considered as a very suitable treatment option in young patients suffering from aortic-valve disease. (Long-Term Follow-up After the Autograft Aortic Valve Procedure [Ross Operation]; NCT00708409).

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.

First clinical experience with the novel cold storage SherpaPak™ system for donor heart transportation.

BACKGROUND: The current gold standard for donor heart preservation is a three-bag-technique and storage in a cooler filled with slush ice. This technique can cause freezing injury with protein denaturation. We report our early experience with a single-use disposable device (SherpaPak™, Paragonix Technologies, MA, USA) specifically designed for sterile permanent temperature-controlled transportation of donor hearts. METHODS: In this case control study with 2:1 matching we identified 21 patients after heart transplantation depending on type of organ transport (standard three-bag-technique vs. SherpaPak™). The outcome after donor heart storage in the SherpaPak™ was compared with donor heart transportation with the standard technique. RESULTS: Since July 2018 seven patients (5 males; mean age 50.3±13.2years) underwent heart transplantation with the SherpaPak™ system. Cold ischemic time was longer in the SherpaPak™ group (207.7±23.3 vs. 181.6±21.9, P=0.027). SherpaPak™ kept the organ temperature at 5.1±0.8 °C, with an average outside temperature of 21.4±3.6 °C. Among all 21 transplanted patients four developed fatal early graft failure (28.6% vs. 21.4%, P=0.432). Over the first hours we noticed no difference in hemodynamic parameters, CK-MB levels or vasoactive-inotropic score. During first follow-up we noticed slightly better right heart function in the SherpaPak™ group (TAPSE 17.83±2.71 vs. 14.52±2.61 mm, P=0.020). We identified no positive blood cultures in the SherpaPak™ group within the first 30 days after heart transplantation. CONCLUSIONS: The SherpaPak™ provides a constant temperature during transportation with permanent monitoring, never dropping below 4 °C. Organs transported with this novel device showed a normal perioperative function.

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.

Myocardial Fibrosis Predicts 10-Year Survival in Patients Undergoing Aortic Valve Replacement.

Background Long-term data on evolution and clinical impact of myocardial fibrosis in valvular heart disease are scarce. Methods and Results In this 10 years' extension of a prospective study in patients undergoing conventional aortic valve replacement because of symptomatic severe aortic valve stenosis, the impact of myocardial replacement fibrosis (MRF) on long-term outcome was assessed. Endomyocardial biopsies were acquired during aortic valve replacement in 58 consecutive patients. MRF was graded using the calculated percentage area of fibrosis and patients categorized as severe (n=21), mild (n=15), and no fibrosis (n=22). Echocardiography including strain imaging, as well as cardiovascular magnetic resonance, to assess late gadolinium enhancement was performed at baseline, 1, and 10 years after aortic valve replacement. Death of any cause occurred in 21 patients (38.9%): 3 (14.3%) in the group without MRF, 6 (42.9%) in the mild MRF group, and 12 (63.2%) in the severe MRF group ( P=0.006), resulting in the lowest cumulative survival for patients with severe MRF (log-rank P=0.003). In the group without MRF, none died of cardiovascular cause. MRF was found to be an independent predictor of survival (hazard ratio, 1.271; 95% CI, 1.032-1.564; P=0.024). Conclusions This 10-year follow-up study underlines the profound impact of replacement fibrosis with regard to cardiac and all-cause mortality in patients undergoing aortic valve replacement for severe aortic valve stenosis. Integrating cardiovascular magnetic resonance and echocardiographic functional imaging beyond ejection fraction quantification could help in clinical decision making to stratify patient prognosis with regard to myocardial longitudinal function and prevalence of replacement fibrosis.

Myofilament function and body mass index.

Body mass is reported to influence myocardial performance. Recent studies have emphasised the importance of negative inotropic adipocyte-derived factors and their impact on cardiac contractile function. However, the underlying mechanisms remain unclear. We aimed to determine whether body mass impacts cardiac force development on the level of the contractile apparatus. We examined the influence of body mass index (BMI) (3 groups: group I >25, group II 25-30, group III >30) on the myocardial performance of skinned muscle fibres. Right atrial tissue preparations of 70 patients undergoing aortocoronary bypass operation (CABG, 48 patients, group a) and aortic valve replacement (AVR, 22 patients, group b) were obtained. The fibres were exposed to a gradual increase in the calcium concentration, and the force values were recorded. The statistical analysis was performed using Pearson's correlation (P<0.05 significant). A BMI >30 (group III) was associated with less force (mean force 1.58±0.1 mN, P=0.02, max force 2.24±0.17 mN, P=0.02 vs. group II (mean force 1.8±0.3 mN, P=0.04, max force 2.59±0.2 mN, P=0.03) and group I (mean force 1.8±0.1 mN, P=0,03, max force 2.62±0.3 mN, P=0.03). Dividing the groups in the post-surgical procedure, the impact of BMI on force development in group III was more intense in the CABG group compared to the AVR group: 2.0±0.2 mN vs. 2.4±0.1 mN, P=0.04. In accordance with the literature, a BMI >30 is associated with reduced force capacities. Additionally, the underlying cardiac disease may aggravate the impact of weight on cardiac force. Further studies are needed to evaluate the clinical relevance of this experimental observation and the potential consequences for the treatment of cardiac function.

Reduced right atrial contractile force in patients with left ventricular diastolic dysfunction: A study in human atrial fibers-contractile force and diastolic dysfunction.

BACKGROUND/OBJECTIVE: The aim of our study was to evaluate right heart contractile force in patients with diastolic dysfunction (DD) with preserved left heart ejection fraction undergoing cardiac surgery. We examined the contractile properties of skinned human fibers obtained from the right auricle in two groups (DD and controls). METHODS: Right atrial tissue from 64 patients, who were undergoing cardiac surgery, were collected before extracorporal circulation. Tissue was conserved and prepared as "skinned fibers". We exposed the dissected fibers to increasing calcium concentrations and recorded the force values. RESULTS: Patients with DD develop significantly less force at middle and higher calcium concentrations pCa 4.0: DD 2.58 ± 0.4 mN, controls 5.32 ± 0.4 mN, p = 0.02; pCa 5.5: DD 1.14 ± 0.3 mN, controls 1.45 ± 0.3 mN, p = 0.03. DD significantly correlates with left ventricular hypertrophy (LVH; p = 0.03). DD did not significantly occur more often in patients with mitral valve insufficiency, aortic insufficiency or stenosis, or coronary heart disease (all p > 0.10). LVH, which was associated with DD, correlated significantly with mitral valve prolapse (p = 0.05), aortic valve stenosis (p = 0.02), and mitral valve insufficiency (p = 0.03). CONCLUSION: Contractile force is significantly reduced in right atrial skinned human fibers with DD. DD is significantly associated with LVH, but emerges independently from underlying pathologies like valve diseases or coronary heart disease. This underlines the hypothesis that impairment of contractile capacity directly results from DD-independent from volume or pressure overload due to valvular or ischemic heart disease.

Rapid deployment valve system shortens operative times for aortic valve replacement through right anterior minithoracotomy.

BACKGROUND: There is growing evidence from the literature that right anterior minithoracotomy aortic valve replacement (RAT-AVR) improves clinical outcome. However, increased cross clamp time is the strongest argument for surgeons not performing RAT-AVR. Rapid deployment aortic valve systems have the potential to decrease cross-clamp time and ease this procedure. We assessed clinical outcome of rapid deployment and conventional valves through RAT. METHODS: Sixty-eight patients (mean age 76 ± 6 years, 32% females) underwent RAT-AVR between 9/2013 and 7/2015. According to the valve type implanted the patients were divided into two groups. In 43 patients (R-group; mean age 74.1 ± 6.6 years) a rapid deployment valve system (Edwards Intuity, Edwards Lifesciences Corp; Irvine, Calif) and in 25 patients (C-group; mean age 74.2 ± 6.6 years) a conventional stented biological aortic valve was implanted. RESULTS: Aortic cross-clamp (42.1 ± 12 min vs. 68.3 ± 20.3 min; p < 0.001) and bypass time (80.4 ± 39.3 min vs. 106.6 ± 23.2 min; p = 0.001) were shorter in the rapid deployment group (R-group). We observed no differences in clinical outcome. Postoperative gradients (R-group: max gradient, 14.3 ± 8 mmHg vs. 15.5 ± 5 mmHg (C-group), mean gradient, 9.2 ± 1.7 mmHg (R-group) vs. 9.1 ± 2.3 mmHg (C-group) revealed no differences. However, larger prostheses were implanted in C-group (25 mm; IQR 23-27 mm vs. 23 mm; IQR 21-25; p = 0.009). CONCLUSIONS: Our data suggest that the rapid deployment aortic valve system reduced cross clamp and bypass time in patients undergoing RAT-AVR with similar hemodynamics as with larger size stented prosthesis. However, larger studies and long-term follow-up are mandatory to confirm our findings.

Right atrial contractile dynamics are impaired in patients with postcapillary pulmonary hypertension.

Left ventricular (LV) dysfunction in conjunction with postcapillary pulmonary hypertension (PH) is frequently associated with right ventricular (RV) dysfunction, determining the patient prognosis. Compensatory mechanisms for RV dysfunction have not been previously evaluated in detail. Since calcium dependent right atrial (RA) dynamics are a surrogate for RA contractile properties, the present study examined the calcium dependency of RA tissue obtained from patients with or without postcapillary PH. In total, 15 patients with PH (PH group; mean age, 70.7±7.2 years) and 10 patients without postcapillary PH (non-PH group; mean age, 55.7±11.8 years) who were scheduled to undergo elective left heart valve surgery were included in the current study. Calcium concentration (pCa; shown as the negative log10) against force curves were generated, while LV and RV function was evaluated by echocardiography. Echocardiography data revealed a significantly reduced LV function in the PH group, while the RV function was preserved in the two groups, precluding overt RV dysfunction. In the PH group, significantly reduced force values were detected at high pCa values when compared with the non-PH group force, indicating impaired RA function. Furthermore, reduced calcium sensitivity was observed (which was determined as the pCa at half maximal activation) in the PH group, and the presence of a compensatory mechanism for reduced force capacity was hypothesized. In conclusion, the preliminary results of the current study showed impaired RA contractile properties in postcapillary hypertension with preserved RV function. The diminished RA compensatory mechanisms may lead to accelerated RV dysfunction in the clinical course of postcapillary PH.

Effects of gender, ejection fraction and weight on cardiac force development in patients undergoing cardiac surgery--an experimental examination.

BACKGROUND: It has long been recognized that differences exist between men and women in the impact of risc factors, symptoms, development and outcome of special diseases like the cardiovascular disease. Gender determines the cardiac baseline parameters like the number of cardiac myocyte, size and demand and may suggest differences in myofilament function among genders, which might be pronounced under pathological conditions. Does gender impact and maybe impair the contractile apparatus? Are the differences more prominent when other factors like weight, age, ejection fraction are added?Therefore we performed a study on 36 patients (21 male, 15 female) undergoing aortic valve replacement (AVR) or aortocoronary bypass operation (CABG) to examine the influence of gender, ejection fraction, surgical procedure and body mass index (BMI) on cardiac force development. METHODS: Tissue was obtained from the right auricle and was stored in a special solution to prevent any stretching of the fibers. We used the skinned muscle fiber model and single muscle stripes, which were mounted on the "muscle machine" and exposed to a gradual increase of calcium concentration calculated by an attached computer program. RESULTS: 1.) In general female fibers show more force than male fibers: 3.9 mN vs. 2.0 mN (p = 0.03) 2.) Female fibers undergoing AVR achieved more force than those undergoing CABG operation: 5.7 mN vs. 2.8 mN (p = 0.02) as well as male fibers with AVR showed more force values compared to those undergoing CABG: 2.0 mN vs. 0.5 mN (p = 0.01). 3.) Male and female fibers of patients with EF > 55% developed significantly more force than from those with less ejection fraction than 30%: p = 0.002 for the male fibers (1.6 vs. 2.8 mN) and p = 0.04 for the female fibers (5.7 vs. 2.8 mN). 4.) Patients with a BMI between 18 till 25 develop significant more force than those with a BMI > 30: Females 5.1 vs. 2.6 mN; p 0.03, Males 3.8 vs. 0.8 mN; p 0.04). CONCLUSION: Our data suggest that female patients undergoing AVR or CABG develop significantly more force than male fibers. Additionally we could image the clinical impression of negative impact of overweight and obesity as well as low ejection fraction on cardiac function on level of the myofilaments and observed a reduced force capacity, which is more prominent in male fibers.