Optimizing fibrosis detection: a comparison of electroanatomical mapping and late enhancement gadolinium magnetic resonance imaging.

BACKGROUND: Fibrotic atrial cardiomyopathy plays an important role in determining the outcome of ablation in patients with atrial fibrillation (AF). Two main methods are being used for the evaluation of fibrosis: voltage-based high-density (HD) electroanatomical mapping (EAM) and late gadolinium enhancement MRI (LGE-MRI). The comparability between both methods in detecting fibrosis has not been systematically investigated. METHODS: LGE-MRIs of the left atrium (LA) were performed in 21 patients. LA-fibrosis was evaluated using a custom-designed software generating a 3D-model of the LA. HD-electroanatomical maps were recorded in each patient. After processing the maps and the MRI models by excluding the mitral valve, pulmonary veins, and the left atrial appendage, the LGE areas were measured and compared to the low voltage areas (LVA) in the HD maps using three different cutoff values of 0.5 mV, 0.7 mV, and 1.0 mV. RESULTS: The analysis revealed significant differences between EAM and LGE-MRI in assessing LA-fibrosis at 0.5-mV (for anterior and posterior walls) and 1.0-mV cutoffs (for anterior and posterior wall and septum). However, no significant differences were found between EAM and LGE-MRI when using a 0.7-mV cutoff for all the investigated areas. CONCLUSIONS: A voltage cutoff of 0.7 mV provided the best correlation between EAM and LGE MRI for detecting left atrial fibrosis. It supports the idea that a 0.5-mV cutoff may underestimate fibrosis, as areas with local signal voltages between 0.6 and 0.8 mV could also show LGE on MRI. Further research is needed to determine the ideal voltage cutoff for detecting left atrial fibrosis.

Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice.

BACKGROUND: Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p.R350P. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WT-TAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 µl/min, HET sham: 10391 ± 1349µl/min, WT-TAC: 8097 ± 1903µl/min, HET-TAC: 5793 ± 2517µl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. CONCLUSION: Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

Increased mortality and ICD therapies in ischemic versus non-ischemic dilated cardiomyopathy patients with cardiac resynchronization having survived until first device replacement.

INTRODUCTION: Cardiac resynchronization therapy combined with an implantable cardioverter defibrillator (CRT-D) is widely applied in heart failure patients. Sufficient data on arrhythmia and defibrillator therapies during long-term follow-up of more than 4 years are lacking and data on mortality are conflicting. We aimed to characterize the occurrence of ventricular arrhythmia, respective defibrillator therapies and mortality for several years following CRT-D implantation or upgrade. MATERIAL AND METHODS: Eighty-eight patients with ischemic (ICM) or non-ischemic dilated cardiomyopathy (DCM) and at least one CRT-D replacement were included in this study and analyzed for incidence of non-sustained ventricular tachycardia (NSVT), defibrillator shocks, anti-tachycardia pacing (ATP) and mortality. RESULTS: ICM was the underlying disease in 59%, DCM in 41% of patients. During a mean follow-up of 76.4 ±24.8 months the incidence of appropriate defibrillator therapies (shock or ATP) was 46.6% and was elevated in ICM compared to DCM patients (57.7% vs. 30.6%, respectively; p = 0.017). Kaplan-Meier analysis revealed significantly higher ICD therapy-free survival rates in DCM patients (p = 0.031). Left ventricular ejection fraction, NSVT per year and ICM (vs. DCM) were independent predictors of device intervention. The ICM patients showed increased mortality compared to DCM patients, with cumulative all-cause mortality at 9 years of follow-up of 45.4% and 10.6%, respectively. Chronic renal failure, peripheral artery disease and chronic obstructive pulmonary disease were independent predictors of mortality. CONCLUSIONS: The clinical course of patients with ICM and DCM treated with CRT-D differs significantly during long-term follow-up, with increased mortality and incidence of ICD therapies in ICM patients.

Treatment with mononuclear cell populations improves post-infarction cardiac function but does not reduce arrhythmia susceptibility.

BACKGROUND: Clinical and experimental data give evidence that transplantation of stem and progenitor cells in myocardial infarction could be beneficial, although the underlying mechanism has remained elusive. Ventricular tachyarrhythmia is the most frequent and potentially lethal complication of myocardial infarction, but the impact of mono nuclear cells on the incidence of ventricular arrhythmia is still not clear. OBJECTIVE: We aimed to characterize the influence of splenic mononuclear cell populations on ventricular arrhythmia after myocardial infarction. METHODS: We assessed electrical vulnerability in vivo in mice with left ventricular cryoinfarction 14 days after injury and intramyocardial injection of specific subpopulations of mononuclear cells (MNCs) (CD11b-positive cells, Sca-1-positive cells, early endothelial progenitor cells (eEPCs)). As positive control group we used embryonic cardiomyocytes (eCMs). Epicardial mapping was performed for analysing conduction velocities in the border zone. Left ventricular function was quantified by echocardiography and left heart catheterization. RESULTS: In vivo pacing protocols induced ventricular tachycardia (VT) in 30% of non-infarcted mice. In contrast, monomorphic or polymorphic VT could be evoked in 94% of infarcted and vehicle-injected mice (p<0.01). Only transplantation of eCMs prevented post-infarction VT and improved conduction velocities in the border zone in accordance to increased expression of connexin 43. Cryoinfarction resulted in a broad aggravation of left ventricular function. All transplanted cell types augmented left ventricular function to a similar extent. CONCLUSIONS: Transplantation of different MNC populations after myocardial infarction improves left ventricular function similar to effects of eCMs. Prevention of inducible ventricular arrhythmia is only seen after transplantation of eCMs.

Cardiac magnetic resonance using late gadolinium enhancement and atrial T1 mapping predicts poor outcome in patients with atrial fibrillation after catheter ablation therapy.

To determine the pre-procedural value of different fibrotic biomarkers and comprehensive cardiac magnetic resonance (CMR) for the prediction of poor response to ablation therapy in patients with atrial fibrillation (AF). Left atrial (LA) late gadolinium enhancement (LGE) and native LA T1 relaxation times were assessed using CMR. Plasma levels of relaxin, myeloperoxidase and serum levels of matrix metalloproteinase (MMP)-mediated cardiac specific titin fragmentation and MMP-mediated type IV collagen degradation were obtained. Poor outcome was defined by the recurrence of AF during 1-year follow-up. 61 patients were included in final analysis. Twenty (32.8%) patients had recurrence of AF. Patients with a recurrence of AF had a higher percentage of LA LGE (26.7 ± 12.5% vs. 17.0 ± 7.7%; P < 0.001), higher LA T1 relaxation times (856.7 ± 112.2 ms vs. 746.8 ± 91.0 ms; P < 0.001) and higher plasma levels of relaxin (0.69 ± 1.34 pg/ml vs. 0.37 ± 0.88 pg/ml; P = 0.035). In the multivariate Cox regression analysis, poor ablation outcome was best predicted by advanced LGE stage (hazard ratio (HR):5.487; P = 0.001) and T1 relaxation times (HR:1.007; P = 0.001). Pre-procedural CMR is a valuable tool for prediction of poor response to catheter ablation therapy in patients with AF. It offers various imaging techniques for outcome prediction and might be valuable for a better patient selection prior to ablation therapy.

A Closed-chest Model to Induce Transverse Aortic Constriction in Mice.

Research on cardiac hypertrophy and heart failure is frequently based on pressure overload mouse models induced by TAC. The standard procedure is to perform a partial thoracotomy to visualize the transverse aortic arch. However, the surgical trauma caused by the thoracotomy in open-chest models changes the respiratory physiology as the ribs are dissected and left unattached after chest closure. To prevent this, we established a minimally invasive, closed chest approach via lateral thoracotomy. Herein we approach the aortic arch via the 2nd intercostal space without entering the chest cavities, leaving the mouse with a less traumatic injury to recover from. We perform this operation using standard laboratory settings for open chest TAC procedures with equal survival rates. Apart from maintaining physiological breathing patterns due to the closed chest approach, the mice seem to benefit by showing rapid recovery, as the less invasive technique appears to facilitate a fast healing process and to reduce immune response after trauma.

High rate of persistent iatrogenic atrial septal defect after single transseptal puncture for cryoballoon pulmonary vein isolation.

PURPOSE: Congenital atrial septal defect (ASD) is associated with increased morbidity, whereas little is known about the rate of spontaneous closure, associated clinical and echocardiographic parameters, or complications of iatrogenic atrial septal defect (iASD) beyond 1 year of follow-up. Persistent iASD after transseptal puncture for PVI has been described in up to 38% of small cohorts of patients in short-term follow-up after transseptal puncture. We sought to investigate the course of iASD after single transseptal puncture for first pulmonary vein isolation (PVI) with cryoballoon, along with possible risk factors for persistent iASD. METHODS: After a first PVI with cryoballoon, 102 patients (64 ± 10 years, 64% male) underwent long-term clinical follow-up and comprehensive transthoracic and transesophageal echocardiographic study. RESULTS: Prevalence of iASD after PVI was 37% after 2.9 (1.6-4.9) years. No clinical complications or deterioration of echocardiographic parameters were associated with iASD. Lower left atrial appendage flow velocity was associated with higher risk of persistence of iASD (3.5% for every 1 cm/s decrease, p = 0.002). CONCLUSIONS: Despite a high rate of iASD after cryoballoon PVI in long-term follow-up, this was not associated with increased clinical complications. Lower LAA velocity was associated with higher risk of persistent iASD. Repeated routine echocardiographic follow-up may not be necessary in these patients.

Outcome in patients with left common pulmonary vein after cryoablation with second-generation cryoballoon.

BACKGROUND: Pulmonary vein isolation (PVI) has become a widely accepted therapy in patients suffering from symptomatic atrial fibrillation (AF). HYPOTHESIS: AF-free survival differs in patients with left common pulmonary vein (LCPV) after PVI with second-generation cryoballoon. METHODS: We included patients scheduled for first PVI for paroxysmal or persistent AF. Symptomatic and/or documented arrhythmia episodes (>30 seconds) were defined as AF recurrence, excluding a 3-month blanking period. RESULTS: We observed a LCPV in 37 of 270 consecutive patients (13.7%). Analyses were performed in a 1:1 propensity score matched cohort of 68 patients. During a median follow-up of 77.0 weeks, 37 patients (54.4%) had recurrent AF. The prevalence of LCPV was numerically higher in patients with AF recurrence (62.2% vs 35.5%, P  =  0.051) and Kaplan-Meier analysis showed lower AF-free survival in patients with existence of a LCPV (P  =  0.028). At 1-year follow-up, 70.6% of patients without versus 55.1% of patients with LCPV were free of AF. Multivariate Cox regression analysis revealed presence of a LCPV (hazard ratio [HR]: 2.996), chronic heart failure (HR: 3.423), and mitral regurgitation > I° (HR: 2.571) as predictors of AF recurrence. CONCLUSION: Patients with LCPV had significantly reduced AF-free survival after ablation with the second-generation cryoballoon, despite similar acutely successful PVIs.

Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties.

BACKGROUND: The peptide hormone relaxin-2 (RLX) exerts beneficial effects during myocardial ischemia, but functional data on lower-dose RLX in myocardial infarction (MI) is lacking. Therefore, we investigated the impact of 75µg/kg/d RLX treatment on electrical vulnerability and left ventricular function in a mouse model of MI. METHODS AND RESULTS: Standardized cryoinfarction of the left anterior ventricular wall was performed in mice. A two week treatment period with vehicle or RLX via subcutaneously implanted osmotic minipumps was started immediately after MI. The relaxin receptor RXFP1 was expressed on ventricular/atrial cardiomyocytes, myofibroblasts, macrophages and endothelial but not vascular smooth muscle cells of small coronary vessels. RLX treatment resulted in a significant reduction of ventricular tachycardia inducibility (vehicle: 91%, RLX: 18%, p<0.0001) and increased epicardial conduction velocity in the left ventricle and borderzone. Furthermore, left ventricular function following MI was improved in RLX treated mice (left ventricular ejection fraction; vehicle: 41.1±1.9%, RLX: 50.5±3.5%, p=0.04). Interestingly, scar formation was attenuated by RLX with decreased transcript expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1ß were upregulated in hearts of vehicle treated animals compared to mice without MI. Application of RLX attenuated this inflammatory response. In addition, macrophage infiltration was reduced in the borderzone of RLX treated mice. CONCLUSION: Treatment with lower-dose RLX in mice prevents post-infarction ventricular tachycardia due to attenuation of scar formation and cardiac inflammation. Therefore, RLX could be evaluated as new therapeutic option in the treatment of MI.

Aging-related mitochondrial dysfunction facilitates the occurrence of serious arrhythmia after myocardial infarction.

BACKGROUND: During aging a mosaic of normal cells and cells with mitochondrial deficiency develops in various tissues including the heart. Whether this contributes to higher susceptibility for arrhythmia following myocardial infarction (MI) is unknown. METHODS AND RESULTS: Myocardial cryoinfarction was performed in 12-month-old transgenic mice with accelerated accumulation of deletions in mitochondrial DNA. Occurrence and pathogenesis of arrhythmia was investigated after two weeks. Holter-ECG recordings revealed higher rates of premature ventricular complexes (incidence > 10/24 h: 100% vs. 20%; p = 0.048) and more severe spontaneous arrhythmia during stress test in mutant mice with MI as compared to control mice with MI. Mice with mitochondrial dysfunction exhibited longer spontaneous AV-blocks (467 ± 26 ms vs. 377 ± 24 ms; p = 0.013), an increased probability for induction of ventricular tachycardia during in vivo electrophysiological investigation (22% vs. 9%; p = 0.044), and a reduced conduction velocity in the infarct borderzone (38.5 ± 0.5 cm/s vs. 55.3 ± 0.9 cm/s; p = 0.001). Furthermore, mutant mice exhibited a significant reduction of the phospho-Cx43/Cx43 ratio in right (0.59 ± 0.04 vs. 0.85 ± 0.01; p = 0.027) and left ventricular myocardium (0.72 ± 0.01 vs. 0.86 ± 0.02; p = 0.023). CONCLUSIONS: Aging-related cardiac mosaic respiratory chain dysfunction facilitates the occurrence of spontaneous and inducible cardiac arrhythmia after myocardial infarction and is associated with slowing of electrical impulse propagation in the infarct borderzone.

Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.

BACKGROUND: Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). METHODS: Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 µg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. RESULTS: RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1ß were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. CONCLUSION: Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI.

A real world wearable cardioverter defibrillator experience - Very high appropriate shock rate in ischemic cardiomyopathy patients at a European single-center.

BACKGROUND: The wearable cardioverter defibrillator (WCD) has emerged as a valuable tool to protect patients with increased risk of sudden cardiac death (SCD). We sought to characterize WCD patients and to analyze predictors of ventricular arrhythmia (VA) occurrence and WCD shock delivery. METHODS AND RESULTS: One hundred fourteen patients with WCD use were included in the study. Indications were mainly ischemic cardiomyopathy (ICM; 31.6%), non-ICM (45.6%) and explantation of implantable cardioverter defibrillator due to device infection (11.4%). We observed sustained VA in 9.6% of the study population and 6.1% received an appropriate shock. VA occurred in 16.7% of ICM, 3.8% of non-ICM and 15.4% of patients with device infection. CONCLUSIONS: Our data demonstrate a very high rate of sustained VA in patients at risk for SCD during WCD use. ICM patients, including those with recent MI, bore the highest risk.

Laserballoon and Cryoballoon Pulmonary Vein Isolation in Persistent and Longstanding Persistent Atrial Fibrillation.

BACKGROUND: Visually guided laserballoon (LB) ablation has recently been introduced for pulmonary vein (PV) isolation (PVI). We analyzed efficacy and safety results of the newly introduced LB ablation technique in patients with persistent and longstanding persistent atrial fibrillation (AF), and compared this with an established standard method using the cryoballoon (CB). METHODS: A total of 35 patients with symptomatic persistent AF underwent LB ablation and were followed-up for 1 year. Results were compared to 35 patients who underwent CB ablation at the same institution and case matched for age, sex, CHA2 DS2 -VASc score, and left atrial volume. RESULTS: Complete isolation of all PVs was achieved in 68.6% in the LB and 97.1% in the CB group (P < 0.01). No significant differences were found for AF-free survival after 12 months in the complete cohort of all patients (LB: 53.3% vs CB: 70.4%; P = n.s.) and after excluding patients without complete PVI (LB: 57.8% vs CB: 72.5%; P = n.s.). LB ablation resulted in longer procedure (158.5 ± 37.9 minutes vs 110.9 ± 26.5 minutes; P < 0.01) and fluoroscopy durations (28.4 ± 11.1 minutes vs 23.5 ± 9.4 minutes; P = 0.04.), and a trend toward more major complications (14.3% vs 2.9%; P = n.s.). Procedure durations and complications declined over time and were level with CB-treated patients when reaching the last quartile of the LB patients. CONCLUSION: PVI in patients with persistent AF using the LB or the CB resulted in comparable success rates. Initial prolongations in procedure and safety parameters as a result of a learning curve effect for the LB have to be considered before starting to use this technique.

AMP-activated protein kinase α1-sensitive activation of AP-1 in cardiomyocytes.

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampkα1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampkα1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampkα1 increased the phosphorylation of Pkcζ. Constitutively active Ampkα1 further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkcζ silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampkα1 and Pkcζ, but not of Ampkα2. In wild-type mice, angiotensin-II infusion increased cardiac Ampkα1 and cardiac Pkcζ protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampkα1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampkα1 and Pkcζ abundance as well as c-Fos, Il6 and Ncx1 mRNA expression, effects again blunted in Ampkα1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampkα1 increased Pkcζ protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampkα1 promotes myocardial AP-1 activation in a Pkcζ-dependent manner and thus contributes to cardiac stress signaling.

Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis.

INTRODUCTION: Cyclase-associated protein 2 (CAP2) plays a major role in regulating the actin cytoskeleton. Since inactivation of CAP2 in a mouse model by a gene trap approach (Cap2 (gt/gt) ) results in cardiomyopathy and increased mortality, we hypothesized that CAP2 has a major impact on arrhythmias and electrophysiological parameters. MATERIAL AND METHODS: We performed long-term-ECG recordings in transgenic CAP2 deficient mice (C57BL/6) to detect spontaneous arrhythmias. In vivo electrophysiological studies by right heart catheterization and ex vivo epicardial mapping were used to analyze electrophysiological parameters, the inducibility of arrhythmias, and conduction velocities. Expression and distribution of cardiac connexins and the amount of cardiac fibrosis were evaluated. RESULTS: Spontaneous ventricular arrhythmias could be detected in Cap2 (gt/gt) during the long-term-ECG recording. Cap2 (gt/gt) showed marked conduction delays at atrial and ventricular levels, including a reduced heart rate (421.0 ±40.6 bpm vs. 450.8 ±27.9 bpm; p < 0.01), and prolongations of PQ (46.3 ±4.1 ms vs. 38.6 ±6.5 ms; p < 0.01), QRS (16.2 ±2.6 ms vs. 12.6 ±1.4 ms; p < 0.01), and QTc interval (55.8 ±6.0 ms vs. 45.2 ±3.3 ms; p = 0.02) in comparison to wild type mice. The PQ prolongation was due to an infra-Hisian conduction delay (HV: 9.7 ±2.1 ms vs. 6.5 ±3.1 ms; p = 0.02). The inducibility of ventricular tachycardias during the electrophysiological studies was significantly elevated in the mutant mice (inducible animals: 88% vs. 33%; p = 0.04). Cap2 (gt/gt) showed more abnormal distribution of connexin43 compared to WT (23.0 ±4.7% vs. 2.9 ±0.8%; p < 0.01). Myocardial fibrosis was elevated in Cap2 (gt/gt) hearts (9.1 ±6.7% vs. 5.5 ±3.3%; p < 0.01). CONCLUSIONS: Loss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias. Structural changes in Cap2 (gt/gt) are associated with alterations in myocardial connexins and fibrosis.

Association of Heart Rate Turbulence With Arrhythmia Susceptibility and Heart Disease in Mice.

INTRODUCTION: Recent studies have demonstrated the feasibility of measuring heart rate turbulence (HRT) as a marker of baroreflex function in healthy mice. The aim of this investigation was to measure HRT in a mouse model with induced structural heart defects and to determine if there were threshold values of HRT for inducible ventricular tachycardias (VTs). METHODS AND RESULTS: HRT was measured during electrophysiological investigations 2 weeks after transverse aortic constriction (TAC, n = 13) or myocardial cryoinfarction (MCI, n = 14). Sham-operated mice served as controls (n = 8 for TAC controls and n = 9 for MCI controls). Mice with heart disease lacked an early acceleration (turbulence onset [TO]) in heart rate after extrastimulus pacing (heart disease: 0.39% [0.19%-0.59%] vs. all controls: -0.04% [-0.25-0.19%]; P < 0.01). At a cutoff value of >0.25%, TO could be used to classify mice with induced heart disease with a sensitivity of 64.0% and specificity of 88.2% (P < 0.01) but did not identify mice at higher risk of induced VTs. Animals that were susceptible to VTs (n = 8) had lower values for turbulence slope (TS) compared with noninducible mice (6.2 milliseconds/beat [3.1-9.5 milliseconds/beat] vs. 10.1 milliseconds/beat [7.2-14.2 milliseconds/beat]; P = 0.03). TS <7.8 milliseconds/beat identified mice with inducible VTs with a sensitivity of 75.0% and specificity of 75.8% (P = 0.02). CONCLUSION: Measurement of HRT is feasible in mouse models with induced structural heart disease. More abnormal values for TO were found in the presence of structural heart disease but did not predict susceptibility to VTs. Decreased TS was associated with VTs induced by programmed stimulation.