Predictive value of the PRAETORIAN score for defibrillation test success in patients with subcutaneous ICD: A subanalysis of the PRAETORIAN-DFT trial.

BACKGROUND: The PRAETORIAN score estimates the risk of failure of subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy by using generator and lead positioning on bidirectional chest radiographs. The PRospective randomized compArative trial of subcutanEous implanTable cardiOverter-defibrillatoR ImplANtation with and without DeFibrillation Testing (PRAETORIAN-DFT) investigates whether PRAETORIAN score calculation is noninferior to defibrillation testing (DFT) with regard to first shock efficacy in spontaneous events. OBJECTIVE: This prespecified subanalysis assessed the predictive value of the PRAETORIAN score for defibrillation success in induced ventricular arrhythmias. METHODS: This multicenter investigator-initiated trial randomized 965 patients between DFT and PRAETORIAN score calculation after de novo S-ICD implantation. Successful DFT was defined as conversion of induced ventricular arrhythmia in <5 seconds from shock delivery within 2 attempts. Bidirectional chest radiographs were obtained after implantation. The predictive value of the PRAETORIAN score for DFT success was calculated for patients in the DFT arm. RESULTS: In total, 482 patients were randomized to undergo DFT. Of these patients, 457 (95%) underwent DFT according to protocol, of whom 445 (97%) had successful DFT and 12 (3%) had failed DFT. A PRAETORIAN score of ≥90 had a positive predictive value of 25% for failed DFT, and a PRAETORIAN score of <90 had a negative predictive value of 99% for successful DFT. A PRAETORIAN score of ≥90 was the strongest independent predictor for failed DFT (odds ratio 33.77; confidence interval 6.13-279.95; P < .001). CONCLUSION: A PRAETORIAN score of <90 serves as a reliable indicator for DFT success in patients with S-ICD, and a PRAETORIAN score of ≥90 is a strong predictor for DFT failure.

Is it safe to give birth with an activated implantable cardioverter-defibrillator: A multicentre observational study.

OBJECTIVE: Data and guidelines are lacking, so implantable cardioverter-defibrillators (ICDs) are often deactivated during labour to prevent inappropriate shocks. This study aimed to ascertain the safety of an activated ICD during labour. DESIGN: An observational study was performed. SETTING: Dutch hospitals. POPULATION OR SAMPLE: A total of 41 childbirths were included of 26 patients who gave birth between February 2009 and November 2018 after receiving an ICD in our tertiary hospital. Five of these childbirths were attended by the research team between December 2018 and August 2020, during which the ICD remained active. METHODS: Groups were made based on ICD status during labour. Patients who gave birth with an activated ICD at least once were stratified to the activated ICD group. Patients' files were checked and patients received a questionnaire about childbirth perceptions and treatment preferences. The differences in ordinal data resulting from the questionnaire were calculated using a chi-square or Fisher's exact test. MAIN OUTCOME MEASURES: Primary outcome was inappropriate ICD therapy and occurrence of ventricular arrhythmias requiring treatment. RESULTS: During the 41 childbirths, no inappropriate shocks or ventricular arrhythmias occurred during labour. All patients in the activated ICD group (n = 13) preferred this setting, while 8 of the 13 patients in the deactivated ICD group preferred activation (p = 0.002). Reasons included avoiding hemodynamic monitoring, magnet placement, or labour induction to facilitate technician availability. CONCLUSIONS: This study shows no evidence that labour and birth in women with an activated ICD are unsafe, as there were no ventricular arrhythmias or inappropriate therapy. In addition, most patients prefer an activated ICD during labour.

Successful defibrillation testing in patients undergoing elective subcutaneous implantable cardioverter-defibrillator generator replacement.

AIMS: After implantation of a subcutaneous implantable cardioverter-defibrillator (S-ICD), a defibrillation test (DFT) is performed to ensure that the device can effectively detect and terminate the induced ventricular arrhythmia. Data on DFT efficacy at generator replacement are scarce with a limited number of patients and conflicting results. This study evaluates conversion efficacy during DFT at elective S-ICD generator replacement in a large cohort from our tertiary centre. METHODS AND RESULTS: Retrospective data of patients who underwent an S-ICD generator replacement for battery depletion with subsequent DFT between February 2015 and June 2022 were collected. Defibrillation test data were collected from both implant and replacement procedures. PRAETORIAN scores at implant were calculated. Defibrillation test was defined unsuccessful when two conversions at 65 J failed. A total of 121 patients were included. The defibrillation test was successful in 95% after the first and 98% after two consecutive tests. This was comparable with success rates at implant, despite a significant rise in shock impedance (73 ± 23 vs. 83 ± 24 Ω, P < 0.001). Both patients with an unsuccessful DFT at 65 J successfully converted with 80 J. CONCLUSION: This study shows a high DFT conversion rate at elective S-ICD generator replacement, which is comparable to conversion rates at implant, despite a rise in shock impedance. Evaluating device position before generator replacement may be recommended to optimize defibrillation success at generator replacement.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

Accuracy and clinical relevance of the single-lead Apple Watch electrocardiogram to identify atrial fibrillation.

Background: The Apple Watch (AW) is the first commercially available wearable device with built-in electrocardiogram (ECG) electrodes to perform a single-lead ECG to detect atrial fibrillation (AF). Methods: Patients with AF who were scheduled for electrical cardioversion (ECV) were included in this study. The AW ECGs were obtained pre-ECV and post-ECV. In case of an unclassified recording, the AW ECG was obtained up to 3 times. The 12-lead ECG was used as the reference standard. Sensitivity, specificity, and kappa coefficient were calculated. Results: In total, 74 patients were included. Mean age was 67.1 ± 12.3 years and 20.3% were female. In total 65 AF and 64 sinus rhythm measurements were obtained. The first measurement with the AW showed a sensitivity of 93.5% and specificity of 100% (κ = 0.94). A second measurement resulted in a sensitivity of 94.6% and specificity of 100% (κ = 0.95). A third measurement resulted in a sensitivity of 93% and a specificity of 96.5% (κ = 0.90). Adjudication of unclassified recordings by a physician reduced the total unclassified recordings from 27.9% to 1.6%, but also reduced the accuracy. The kappa coefficient for unclassified single-lead ECGs was 0.58. Conclusion: The single-lead ECG of the AW shows a high accuracy for identifying AF in a clinical setting. Repeating the recording once decreases the total of unclassified recordings; however, a third recording resulted in a lower accuracy and the occurrence of false-positive measurements. Unclassified results of the AW can be reduced by physicians' interpretation of the single-lead ECG; however, the interrater agreement is only moderate.

Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial.

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks. METHODS: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population. RESULTS: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05). CONCLUSIONS: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

Subcutaneous or Transvenous Defibrillator Therapy.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies. METHODS: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks. RESULTS: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12). CONCLUSIONS: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).

Rationale and design of the PRAETORIAN-DFT trial: A prospective randomized CompArative trial of SubcutanEous ImplanTable CardiOverter-DefibrillatoR ImplANtation with and without DeFibrillation testing.

In transvenous implantable cardioverter-defibrillator (TV-ICD) implants, routine defibrillation testing (DFT) does not improve shock efficacy or reduce arrhythmic death but patients are exposed to the risk of complications related to DFT. The conversion rate of DFT in subcutaneous ICD (S-ICD) is high and first shock efficacy is similar to TV-ICD efficacy rates. STUDY DESIGN: The PRAETORIAN-DFT trial is an investigator-initiated, randomized, controlled, multicenter, prospective two-arm trial designed to demonstrate non-inferiority of omitting DFT in patients undergoing S-ICD implantation in which the S-ICD system components are optimally positioned. Positioning of the S-ICD will be assessed with the PRAETORIAN score. The PRAETORIAN score is developed to systematically evaluate implant position of the S-ICD system components which determine the defibrillation threshold on post-operative chest X-ray. A total of 965 patients, scheduled to undergo a de novo S-ICD implantation without contra-indications for either DFT strategy, will be randomized to either standard of care S-ICD implantation with DFT, or S-ICD implantation without DFT but with evaluation of the implant position using the PRAETORIAN score. The study is powered to claim non-inferiority of S-ICD implantation without DFT in de novo S-ICD patients in respect to the primary endpoint of first shock efficacy in spontaneous arrhythmia episodes. Patients with a high PRAETORIAN score (≥90) in the interventional arm of this study will undergo DFT according to the same DFT protocol as in the control arm. CONCLUSION: The PRAETORIAN-DFT trial is a randomized trial that aims to gain scientific evidence to safely omit a routine DFT after S-ICD implantation in patients with correct device positioning.

A novel tool to evaluate the implant position and predict defibrillation success of the subcutaneous implantable cardioverter-defibrillator: The PRAETORIAN score.

BACKGROUND: Suboptimal positioning of the subcutaneous implantable cardioverter-defibrillator (S-ICD) increases the defibrillation threshold and risk of conversion failure. OBJECTIVE: Our objective is to develop a tool to evaluate the implant position and predict defibrillation success of the S-ICD: the PRAETORIAN score. METHODS: The PRAETORIAN score is based on clinical and computer modeling knowledge of determinants affecting the defibrillation threshold: subcoil fat, subgenerator fat, and anterior positioning of the S-ICD generator. The score evaluates these determinants on the postoperative anterior-posterior and lateral chest radiographs and has 3 categories: 30-<90 points representing a low risk, 90-<150 points representing an intermediate risk, and ≥150 points representing a high risk of conversion failure. The score was developed using 2 separate S-ICD data sets for derivation and validation. The performance metrics are the positive and negative predictive values. RESULTS: The development data set consisted of 181 patients with S-ICD, and the validation cohort consisted of 321 patients from the S-ICD Investigational Device Exemption trial. The distribution of scores was 93%-98% low risk (<90 points), 2%-5% intermediate risk (90-<150 points), and 1% high risk (≥150 points). The positive predictive value for an intermediate or high PRAETORIAN score for a failed conversion test was 51%, while a low PRAETORIAN score predicted a successful conversion in 99.8% of patients. CONCLUSION: The PRAETORIAN score allows the identification of patients with high defibrillation thresholds by using the routine chest radiograph and provides feedback to implanters on S-ICD positioning. The PRAETORIAN-DFT trial will prospectively validate the score by randomizing to standard conversion testing vs using the score without conversion testing.

Assessment of the Extravascular Implantable Defibrillator: Feasibility of Substernal Ventricular Pacing.

INTRODUCTION: The objective of this study was to assess feasibility of ventricular pacing and thresholds from within the substernal space to examine a new extravascular ICD configuration with pacing capabilities. METHODS: In patients undergoing midline sternotomy, a duodecapolar diagnostic pacing catheter was positioned in the substernal space anterior to the pericardium, and a cutaneous patch in left lateral position. Different unipolar and bipolar pacing configurations were assessed. Strength-duration curves were performed to identify the optimal output, starting at 25 mA with a pulse width of 10 milliseconds. RESULTS: Eight patients with mean age 69 ± 9 years were included. In 5, ventricular capture was achieved in ≥1 configuration. The mean bipolar pacing thresholds at PW 10, 5, 3, 1 milliseconds were 12.4 ± 3.7 mA (5 patients), 13.3 ± 5.8 mA (3 patients), 18.3 ± 5.7 mA (3 patients), and 25 ± 0 mA (2 patients), respectively. The 60-mm electrode spacing was the most successful bipolar configuration. Unipolar pacing was successful in 3 out of 4 patients with mean thresholds of 10 ± 0 mA at 10 milliseconds (3 patients), 15 ± 0 mA at 5 milliseconds (3 patients), 16.7 ± 2.9 mA at 3 milliseconds (3 patients), and 20 ± 7.1 mA at 1 milliseconds (2 patients). CONCLUSION: Ventricular pacing from the substernal space in patients with midline sternotomy is feasible. Closed sternum studies are needed to determine pacing thresholds more accurately.

Low tidal volume ventilation ameliorates left ventricular dysfunction in mechanically ventilated rats following LPS-induced lung injury.

BACKGROUND: High tidal volume ventilation has shown to cause ventilator-induced lung injury (VILI), possibly contributing to concomitant extrapulmonary organ dysfunction. The present study examined whether left ventricular (LV) function is dependent on tidal volume size and whether this effect is augmented during lipopolysaccharide(LPS)-induced lung injury. METHODS: Twenty male Wistar rats were sedated, paralyzed and then randomized in four groups receiving mechanical ventilation with tidal volumes of 6 ml/kg or 19 ml/kg with or without intrapulmonary administration of LPS. A conductance catheter was placed in the left ventricle to generate pressure-volume loops, which were also obtained within a few seconds of vena cava occlusion to obtain relatively load-independent LV systolic and diastolic function parameters. The end-systolic elastance / effective arterial elastance (Ees/Ea) ratio was used as the primary parameter of LV systolic function with the end-diastolic elastance (Eed) as primary LV diastolic function. RESULTS: Ees/Ea decreased over time in rats receiving LPS (p = 0.045) and high tidal volume ventilation (p = 0.007), with a lower Ees/Ea in the rats with high tidal volume ventilation plus LPS compared to the other groups (p < 0.001). Eed increased over time in all groups except for the rats receiving low tidal volume ventilation without LPS (p = 0.223). A significant interaction (p < 0.001) was found between tidal ventilation and LPS for Ees/Ea and Eed, and all rats receiving high tidal volume ventilation plus LPS died before the end of the experiment. CONCLUSIONS: Low tidal volume ventilation ameliorated LV systolic and diastolic dysfunction while preventing death following LPS-induced lung injury in mechanically ventilated rats. Our data advocates the use of low tidal volumes, not only to avoid VILI, but to avert ventilator-induced myocardial dysfunction as well.

Injurious mechanical ventilation causes kidney apoptosis and dysfunction during sepsis but not after intra-tracheal acid instillation: an experimental study.

BACKGROUND: Intratracheal aspiration and sepsis are leading causes of acute lung injury that frequently necessitate mechanical ventilation (MV), which may aggravate lung injury thereby potentially increasing the risk of acute kidney injury (AKI). We compared the effects of ventilation strategies and underlying conditions on the development of AKI. METHODS: Spraque Dawley rats were challenged by intratracheal acid instillation or 24 h of abdominal sepsis, followed by MV with a low tidal volume (LVT) and 5 cm H2O positive end-expiratory pressure (PEEP) or a high tidal volume (HVT) and no PEEP, which is known to cause more lung injury after acid instillation than in sepsis. Rats were ventilated for 4 hrs and kidney function and plasma mediator levels were measured. Kidney injury was assessed by microscopy; apoptosis was quantified by TUNEL staining. RESULTS: During sepsis, but not after acid instillation, MV with HVT caused more renal apoptosis than MV with LVT. Increased plasma active plasminogen activator inhibitor-1 correlated to kidney apoptosis in the cortex and medulla. Increased apoptosis after HVT ventilation during sepsis was associated with a 40% decrease in creatinine clearance. CONCLUSIONS: AKI is more likely to develop after MV induced lung injury during an indirect (as in sepsis) than after a direct (as after intra-tracheal instillation) insult to the lungs, since it induces kidney apoptosis during sepsis but not after acid instillation, opposite to the lung injury it caused. Our findings thus suggest using protective ventilatory strategies in human sepsis, even in the absence of overt lung injury, to protect the kidney.

Pulse pressure variation does not reflect stroke volume variation in mechanically ventilated rats with lipopolysaccharide-induced pneumonia.

1. The present study examined the relationship between centrally measured stroke volume variation (SVV) and peripherally derived pulse pressure variation (PPV) in the setting of increased total arterial compliance (CA rt ). 2. Ten male Wistar rats were anaesthetized, paralysed and mechanically ventilated before being randomized to receive intrapulmonary lipopolysaccharide (LPS) or no LPS. Pulse pressure (PP) was derived from the left carotid artery, whereas stroke volume (SV) was measured directly in the left ventricle. Values of SVV and PPV were calculated over three breaths. Balloon inflation of a catheter positioned in the inferior vena cava was used, for a maximum of 30 s, to decrease preload while the SVV and PPV measurements were repeated. Values of CA rt were calculated as SV/PP. 3. Intrapulmonary LPS increased CA rt and SV. Values of SVV and PPV increased in both LPS-treated and untreated rats during balloon inflation. There was a correlation between SVV and PPV in untreated rats before (r = 0.55; P = 0.005) and during (r = 0.69; P < 0.001) occlusion of the vena cava. There was no such correlation in LPS-treated rats either before (r = -0.08; P = 0.70) or during (r = 0.36; P = 0.08) vena cava occlusion. 4. In conclusion, under normovolaemic and hypovolaemic conditions, PPV does not reflect SVV during an increase in CA rt following LPS-induced pneumonia in mechanically ventilated rats. Our data caution against their interchangeability in human sepsis.

Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS-induced pneumonia in rats.

BACKGROUND: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism. MATERIALS AND METHODS: N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level. RESULTS: Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses. CONCLUSIONS: Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity.