Sudden Cardiac Death Despite a Functional Cardioverter-Defibrillator: The Case for Early and Aggressive Therapy for Ventricular Tachycardia in Selected Patients.

We present three cases within 11 months at a single institution of sustained VT that fell below the programmed detection rate of the patients' implantable cardioverter-defibrillators (ICDs), two of which continued until converting to an agonal VF that did not meet criteria for detection, and a third case that could not be successfully defibrillated after a prolonged period of VT. These episodes may be under-recognized due to the dependence of device diagnostic storage on programming and the post-mortem effort that is often required to review these events. Some patients, likely those with the most advanced heart failure, may not tolerate sustained ventricular tachycardia (VT) and may even die from ventricular arrhythmias without ever having a rhythm that meets detection criteria in a ventricular fibrillation (VF) zone.

Efficacy of a Bio-Absorbable Antibacterial Envelope to Prevent Cardiac Implantable Electronic Device Infections in High-Risk Subjects.

INTRODUCTION: Cardiac implantable electronic device (CIED) infections are potentially preventable complications associated with high morbidity, mortality, and cost. A recently developed bio-absorbable antibacterial envelope (TYRX™-A) might prevent CIED infections in high-risk subjects. However, data regarding safety and efficacy have not been published. METHODS AND RESULTS: In a single-center retrospective cohort study, we compared the prevalence of CIED infections among subjects with ≥2 risk factors treated with the TYRX™-A envelope (N = 135), the nonabsorbable TYRX™ envelope (N = 353), and controls who did not receive an envelope (N = 636). Infection was ascertained by individual chart review. The mean (95% confidence interval) number of risk factors was 3.08 (2.84-3.32) for TYRX™-A, 3.20 (3.07-3.34) for TYRX™, and 3.09 (2.99-3.20) for controls, P = 0.3. After a minimum 300 days follow-up, the prevalence of CIED infection was 0 (0%) for TYRX™-A, 1 (0.3%) for TYRX™, and 20 (3.1%) for controls (P = 1 for TYRX™-A vs. TYRX™, P = 0.03 for TYRX™-A vs. controls, and P = 0.002 for TYRX™ vs. controls). In a propensity score-matched cohort of 316 recipients of either envelope and 316 controls, the prevalence of infection was 0 (0%) and 9 (2.8%), respectively, P = 0.004. When limited to 122 TYRX™-A recipients and 122 propensity-matched controls, the prevalence of CIED infections was 0 (0%) and 5 (4.1%), respectively, P = 0.024. CONCLUSIONS: Among high-risk subjects, the TYRX™-A bio-absorbable envelope was associated with a very low prevalence of CIED related infections that was comparable to that seen with the nonabsorbable envelope.

Diminishing impairments in glucose uptake, mitochondrial content, and ADP-stimulated oxygen flux by mesenchymal stem cell therapy in the infarcted heart.

A constant provision of ATP is of necessity for cardiac contraction. As the heart progresses toward failure following a myocardial infarction (MI), it undergoes metabolic alterations that have the potential to compromise the ability to meet energetic demands. This study evaluated the efficacy of mesenchymal stem cell (MSC) transplantation into the infarcted heart to minimize impairments in the metabolic processes that contribute to energy provision. Seven and twenty-eight days following the MI and MSC transplantation, MSC administration minimized cardiac systolic dysfunction. Hyperinsulinemic-euglycemic clamps, coupled with 2-[(14)C]deoxyglucose administration, were employed to assess systemic insulin sensitivity and tissue-specific, insulin-mediated glucose uptake 36 days following the MI in the conscious, unrestrained, C57BL/6 mouse. The improved systolic performance in MSC-treated mice was associated with a preservation of in vivo insulin-stimulated cardiac glucose uptake. Conserved glucose uptake in the heart was linked to the ability of the MSC treatment to diminish the decline in insulin signaling as assessed by Akt phosphorylation. The MSC treatment also sustained mitochondrial content, ADP-stimulated oxygen flux, and mitochondrial oxidative phosphorylation efficiency in the heart. Maintenance of mitochondrial function and density was accompanied by preserved peroxisome proliferator-activated receptor-γ coactivator-1α, a master regulator of mitochondrial biogenesis. These studies provide insight into mechanisms of action that lead to an enhanced energetic state in the infarcted heart following MSC transplantation that may assist in energy provision and dampen cardiac dysfunction.

Comparative outcomes of transvenous extraction of sprint fidelis and riata defibrillator leads: a single center experience.

INTRODUCTION: The FDA has issued class I advisories for Medtronic Sprint Fidelis(®) and St. Jude Medical Riata(TM) ICD lead families. Transvenous Riata(TM) ICD lead extraction is typically considered higher risk than Fidelis(®) extraction, based on longer duration from implant, presence of externalized conductors and lack of silicone backfill in the SVC and RV coils. However, published data comparing procedural outcomes between these leads are limited. METHODS: Records were reviewed for all patients undergoing transvenous extraction of Sprint Fidelis(®) or Riata(TM) ICD leads at the Vanderbilt Heart and Vascular Institute from July 2006 to April 2013 to ascertain indication for extraction, procedural details, complications, and 30-day mortality. RESULTS: There were significant differences between those undergoing extraction of a Sprint Fidelis(®) (n = 145) or Riata(TM) lead (n = 47). In the Riata(TM) group, device-related endocarditis was a more common indication for extraction, the mean duration of implant was longer, and larger excimer laser sheaths were required. Lead malfunction was a more common indication in the Fidelis(®) group. There were no statistically significant differences in median procedure duration, procedural success (97.9% vs 95.7%, P = 0.41), median length of hospital stay (1 day vs 1 day, P = 0.23), procedural complication rate (5.5% vs 10.6%, P = 0.23) or 30-day mortality (2.1% vs 2.1%, P = 0.98). Analyses excluding patients with device infection revealed similar results. CONCLUSION: Despite differences in baseline characteristics, this study indicates that Medtronic Sprint Fidelis(®) and St. Jude Riata(TM) ICD leads have similar procedural outcomes with transvenous lead extraction.

Efficacy and safety of implantable cardioverter-defibrillator implantation in the elderly-The I-70 Study: A randomized clinical trial.

Background: There is conflicting evidence on the efficacy of primary prevention implantable cardioverter-defibrillator (ICD) implantation in the elderly. Objective: The purpose of this study was to determine the efficacy and safety of ICD implantation in patients 70 years and older. Methods: Patients (n = 167) aged 70 years or older and eligible for ICD implantation were randomly assigned (1:1) to receive either optimal medical therapy (OMT) (n = 85) or OMT plus ICD (n = 82). Results: Of the 167 participants (mean age 76.4 years; 165 men), 144 completed the study protocol according to their assigned treatment. Average participant follow-up was 31.5 months. Mortality was similar between the 2 groups: 27 deaths in OMT vs 26 death in ICD (unadjusted hazard ratio 0.92; 95% confidence interval 0.53-1.57), but there was a trend favoring the ICD over the first 36 months of follow-up. Rates of sudden death (7 vs 5; P = .81) and all-cause hospitalization (2.65 events per participant in OMT vs 3.09 in ICD; P = .31) were not statistically significantly different. Eleven participants randomized to ICD received appropriate therapy. Five participants received an inappropriate therapy that included at least 1 ICD shock. Conclusion: The study did not recruit to target sample size, and accumulated data did not show benefit of ICD therapy in patients 70 years or older. Future studies similar in design might be feasible but will need to contend with patient treatment preference given the large number of patients who do not want an ICD implanted. Further research is needed to determine whether the ICD is effective in prolonging life among elderly device candidates.

Mesenchymal stem cell transplantation for the infarcted heart: therapeutic potential for insulin resistance beyond the heart.

BACKGROUND: This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance. METHODS: C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers. RESULTS: MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding. CONCLUSIONS: These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.

Mesenchymal stem cell transplantation for the infarcted heart: a role in minimizing abnormalities in cardiac-specific energy metabolism.

Intense interest has been focused on cell-based therapy for the infarcted heart given that stem cells have exhibited the ability to reduce infarct size and mitigate cardiac dysfunction. Despite this, it is unknown whether mesenchymal stem cell (MSC) therapy can prevent metabolic remodeling following a myocardial infarction (MI). This study examines the ability of MSCs to rescue the infarcted heart from perturbed substrate uptake in vivo. C57BL/6 mice underwent chronic ligation of the left anterior descending coronary artery to induce a MI. Echocardiography was performed on conscious mice at baseline as well as 7 and 23 days post-MI. Twenty-eight days following the ligation procedure, hyperinsulinemic euglycemic clamps assessed in vivo insulin sensitivity. Isotopic tracer administration evaluated whole body, peripheral tissue, and cardiac-specific glucose and fatty acid utilization. To gain insight into the mechanisms by which MSCs modulate metabolism, mitochondrial function was assessed by high-resolution respirometry using permeabilized cardiac fibers. Data show that MSC transplantation preserves insulin-stimulated fatty acid uptake in the peri-infarct region (4.25 ± 0.64 vs. 2.57 ± 0.34 vs. 3.89 ± 0.54 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05) and prevents increases in glucose uptake in the remote left ventricle (3.11 ± 0.43 vs. 3.81 ± 0.79 vs. 6.36 ± 1.08 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05). This was associated with an enhanced efficiency of mitochondrial oxidative phosphorylation with a respiratory control ratio of 3.36 ± 0.18 in MSC-treated cardiac fibers vs. 2.57 ± 0.14 in the infarct-only fibers (P < 0.05). In conclusion, MSC therapy exhibits the potential to rescue the heart from metabolic aberrations following a MI. Restoration of metabolic flexibility is important given the metabolic demands of the heart and the role of energetics in the progression to heart failure.

Familial evaluation for diagnosis of arrhythmogenic right ventricular dysplasia.

Most sudden cardiac deaths in young athletes are caused by previously undetected inherited cardiac diseases. Here, we report a case of a young male athlete in whom a presumptive diagnosis of hypertrophic cardiomyopathy (HCM) was made following a near sudden cardiac death. Although his imaging studies initially suggested HCM, a detailed clinical and genetic evaluation of the patient and his asymptomatic father led to the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in both. DNA sequencing revealed that each individual was heterozygous for two rare variants in the PKP2 and DSC2 genes, both of which were previously shown to be associated with ARVD and to encode desmosomal proteins, i.e. the previously reported splicing variant c2489 + 1A > G in the PKP2 gene and the novel p.I109M variant in the DSC2 gene. Imaging and electrophysiologic studies further supported a diagnosis of ARVD in the father. This case highlights the importance of detailed clinical evaluation and genetic testing of family members when dealing with sudden cardiac death or unexplained cardiomyopathies in the young.

Metabolic implications of reduced heart-type fatty acid binding protein in insulin resistant cardiac muscle.

Insulin resistance is characterized by elevated rates of cardiac fatty acid utilization resulting in reduced efficiency and cardiomyopathy. One potential therapeutic approach is to limit the uptake and oxidation of fatty acids. The aims of this study were to determine whether a quantitative reduction in heart-type fatty acid binding protein (FABP3) normalizes cardiac substrate utilization without altering cardiac function. Transgenic (FABP3(+/-)) and wild-type (WT) littermates were studied following low fat (LF) or high fat (HF) diets, with HF resulting in obese, insulin-resistant mice. Cardiovascular function (systolic blood pressure, % fractional shortening) and heart dimension were measured at weaning and every month afterward for 3 mo. During this period cardiovascular function was the same independent of genotype and diet. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions in mice at 4 mo of age. Following 5 d recovery, mice underwent either a saline infusion or a hyperinsulinemic-euglycemic clamp (4 mU kg(-1) min(-1)). Indices of long chain fatty acid and glucose utilization (R(f), R(g); mumol g wet weight(-1) min(-1)) were obtained using 2-deoxy[(3)H]glucose and [(125)I]-15-rho-iodophenyl)-3-R,S-methylpentadecanoic acid. FABP3(+/-) had enhanced cardiac R(g) compared with WT during saline infusion in both LF and HF. FABP3(+/-) abrogated the HF-induced decrement in insulin-stimulated cardiac R(g). On a HF diet, FABP(+/-) but not WT had an increased reliance on fatty acids (R(f)) during insulin stimulation. In conclusion, cardiac insulin resistance and glucose uptake is largely corrected by a reduction in FABP3 in vivo without contemporaneous deleterious effects on cardiac function.

Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice.

Stimulation of nitric oxide-cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat-fed mice treated with sildenafil plus L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus L-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU x kg(-1) x min(-1))-euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat-fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.

Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease.

Reovirus induces apoptosis in cultured cells and in vivo. In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-kappaB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-kappaB in this process, we tested the capacity of reovirus to induce apoptosis in mice lacking a functional nfkb1/p50 gene. The genetic defect had no apparent effect on reovirus replication in the intestine or dissemination to secondary sites of infection. In comparison to what was observed in wild-type controls, apoptosis was significantly diminished in the CNS of p50-null mice following reovirus infection. In sharp contrast, the loss of p50 was associated with massive reovirus-induced apoptosis and uncontrolled reovirus replication in the heart. Levels of IFN-beta mRNA were markedly increased in the hearts of wild-type animals but not p50-null animals infected with reovirus. Treatment of p50-null mice with IFN-beta substantially diminished reovirus replication and apoptosis, which suggests that IFN-beta induction by NF-kappaB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-kappaB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.

Long chain fatty acid uptake in vivo: comparison of [125I]-BMIPP and [3H]-bromopalmitate.

Insulin resistance is characterized by increased metabolic uptake of fatty acids. Accordingly, techniques to examine in vivo shifts in fatty acid metabolism are of value in both clinical and experimental settings. Partially metabolizable long chain fatty acid (LCFA) tracers have been recently developed and employed for this purpose: [9,10-3H]-(R)-2-bromopalmitate ([3H]-BROMO) and [125I]-15-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid ([125I]-BMIPP). These analogues are taken up like native fatty acids, but once inside the cell do not directly enter beta-oxidation. Rather, they become trapped in the slower processes of omega and alpha-oxidation. Study aims were to (1) simultaneously assess and compare [3H]-BROMO and [125I]-BMIPP and (2) determine if tracer breakdown is affected by elevated metabolic demands. Catheters were implanted in a carotid artery and jugular vein of Sprague-Dawley rats. Following 5 days recovery, fasted animals (5 h) underwent a rest (n = 8) or exercise (n = 8) (0.6 mi/h) protocol. An instantaneous bolus containing both [3H]-BROMO and [125I]-BMIPP was administered to determine LCFA uptake. No significant difference between [125I]-BMIPP and [3H]-BROMO uptake was found in cardiac or skeletal muscle during rest or exercise. In liver, rates of uptake were more than doubled with [3H]-BROMO compared to [125I]-BMIPP. Analysis of tracer conversion by TLC demonstrated no difference at rest. Exercise resulted in greater metabolism and excretion of tracers with approximately 37% and approximately 53% of [125I]-BMIPP and [3H]-BROMO present in conversion products at 40 min. In conclusion, [3H]-BROMO and [125I]-BMIPP are indistinguishable for the determination of tissue kinetics at rest in skeletal and cardiac muscle. Exercise preferentially exacerbates the breakdown of [3H]-BROMO, making [125I]-BMIPP the analogue of choice for prolonged (>30 min) experimental protocols with elevated metabolic demands.

Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance.

The aim of this study was to determine the contribution of heart-type fatty acid-binding protein (H-FABP) to glucose and long-chain fatty acid (LCFA) utilization in dietary-induced insulin resistance. We tested the hypothesis that H-FABP facilitates increases in LCFA flux present in glucose-intolerant states and that a partial reduction in the amount of this protein would compensate for all or part of the impairment. Transgenic H-FABP heterozygotes (HET) and wild-type (WT) littermates were studied following chow diet (CHD) or high-fat diet (HFD) for 12 weeks. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions, respectively. Following 5 days of recovery, mice received either a saline infusion or underwent a euglycemic insulin clamp (4 mU x kg(-1) x min(-1)) for 120 min. At 90 min, a bolus of 2-deoxyglucose and [125I]-15-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid were administered to obtain indexes of glucose and LCFA utilization. At 120 min, skeletal muscles were excised for tracer determination. All HFD mice were obese and hyperinsulinemic; however, only HFD-WT mice were hyperglycemic. Glucose infusion rates during insulin clamps were 49 +/- 4, 59 +/- 4, 16 +/- 4, and 33 +/- 4 mg x kg(-1) x min(-1) for CHD-WT, CHD-HET, HFD-WT, and HFD-HET mice, respectively, showing that HET limited the severity of whole-body insulin resistance with HFD. Insulin-stimulated muscle glucose utilization was attenuated in HFD-WT but unaffected in HFD-HET mice. Conversely, rates of LCFA clearance were increased with HFD feeding in HFD-WT but not in HFD-HET mice. In conclusion, a partial reduction in H-FABP protein normalizes fasting glucose levels and improves whole-body insulin sensitivity in HFD-fed mice despite obesity.

Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice.

Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor gamma coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.

Frequency of late recurrence of intra-atrial reentry tachycardia after radiofrequency catheter ablation in patients with congenital heart disease.

Forty-seven catheter ablation procedures for intra-atrial reentry tachycardia were performed in 40 patients with palliated congenital heart disease. The acute success rate was 87% and the recurrence rate was 34% during an average follow-up of 36 months. Of those patients who had recurrence, 88% did so within 1 year of ablation. Of the 23 patients who were free of recurrence 1 year after ablation, 21 (91%) remain free from recurrence at an average of 45 months (median 39; range 15 to 88) after ablation.

Inhibition of angiotensin II signaling and recurrence of atrial fibrillation in AFFIRM.

OBJECTIVES: We investigated whether inhibition of endogenous angiotensin II signaling reduces the recurrence rate of atrial fibrillation (AF) in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. BACKGROUND: Structural and electrical remodeling contribute to AF. Previous experimental studies have implicated the angiotensin II signaling pathway in this process, and recent clinical evidence supports a beneficial effect of inhibiting angiotensin II activity. METHODS: Using the AFFIRM database, we retrospectively identified a cohort of patients randomized to the rhythm-control arm who were in sinus rhythm. Exposure to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ANGI) was determined, and the time to first recurrence of AF was compared between ANGI users and nonusers. RESULTS: The study cohort included 732 patients not taking ANGI through the initial 2-month follow-up and 421 patients taking ANGI during this time. Patients in the ANGI group more likely had hypertension, diabetes, coronary artery disease, and congestive heart failure compared to patients not taking ANGI. Risk of AF recurrence in the ANGI treatment group did not differ from the risk observed in patients not taking the drugs (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.77-1.09). However, in patients with congestive heart failure or impaired left ventricular function, ANGI use was associated with a lower risk of AF recurrence. CONCLUSIONS: This analysis provides evidence that ANGI use may be beneficial in some patient subgroups with AF and underscores the need for randomized clinical trials defining more fully the role of angiotensin II inhibition in treating AF.

Temporal changes in ventricular function assessed echocardiographically in conscious and anesthetized mice.

The mouse is an important model system for cardiovascular biology, with echocardiography a critical tool for noninvasive measurement of cardiac morphology and function. The feasibility and short-term temporal consistency of repeated echocardiographic measurements in conscious mice has not been previously evaluated. We performed serial 2-dimensional guided M-mode transthoracic echocardiographic measurements at 5- to 10-minute intervals over 60 minutes in conscious mice and in mice treated with 1 of 3 anesthetic regimens: ketamine and acepromazine (n = 14); pentobarbital (n = 14); and ketamine and xylazine (n = 13). Unanesthetized mice received intraperitoneal saline (n = 6) or no injection (n = 7). In sequentially repeated measurements over 1 hour in conscious mice, none of the measured or derived echocardiographic parameters differed from baseline, whereas all 3 anesthetic regimens produced significant, prolonged, and temporally variable decreases in heart rate and fractional shortening. The relationship between heart rate and fractional shortening was not altered by anesthetic choice. Serial echocardiographic assessments of cardiac function, dimension, and mass can be performed with high reproducibility in conscious mice.

High prevalence of insulation failure with externalized cables in St. Jude Medical Riata family ICD leads: fluoroscopic grading scale and correlation to extracted leads.

BACKGROUND: Inside-out abrasion with externalization of sensing ring or high-voltage cables in St Jude Medical Riata implantable cardioverter-defibrillator leads has been reported. The prevalence of extruded cables, rate of electrical abnormalities, and predictors of failure in Riata leads are unknown. OBJECTIVES: To estimate the incidence of lead failure in the St Jude Medical Riata implantable cardioverter-defibrillator leads and to propose a standard for the fluoroscopic assessment of insulation breakdown. METHODS: Patients undergoing cine-fluoroscopy on Riata implantable cardioverter-defibrillator leads at our institution before January 25, 2012, were included (n = 87). Leads were graded as types 0-3 (0 = normal, 1 = abnormal conductor spacing, 2 ≤1 cm cable extrusion, 3 = >1 cm length extrusion). Comparison to extracted leads (n = 15) was documented. Device interrogation data were used for electrical analysis. RESULTS: The mean time from implant was 5.9 ± 3.45 years. Structural lead failure with externalized cables was seen in 33.3% (29 of 87) of the patients. Thirty-one percent (9 of 29) of the leads with exposed cables showed electrical failure, and 29.7% (19 of 64) of the leads with normal electrical data contained externalized cables. Time from implant ≥5 years predicted structural lead failure (P < 0.05). X-ray grade compared with extracted leads demonstrated a sensitivity and specificity of 86% and 100%, respectively. CONCLUSIONS: Cine-fluoroscopy using a simple scale correlated with the structural integrity of extracted Riata leads. A high percentage of leads with extrusion showed electrical failure. Leads ≥5 years from implant showed a high rate of externalized cables. A large independent multicenter study to determine the prevalence and clinical sequelae of Riata lead failures is warranted.

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy.

CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs.