A proliferative burst during preadolescence establishes the final cardiomyocyte number.

It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ~40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.

Pulse Generator Exchange Does Not Accelerate the Rate of Electrical Failure in a Recalled Small Caliber ICD Lead.

BACKGROUND: St. Jude Riata/Riata ST defibrillator leads (St. Jude Medical, Sylmar, CA, USA) were recalled by the Food and Drug Administration in 2011 for an increased rate of failure. More than 227,000 leads were implanted and at least 79,000 patients still have active Riata leads. Studies have examined clinical predictors of lead failure in Riata leads, but none have addressed the effect of implantable cardioverter defibrillator (ICD) generator exchange on lead failure. The purpose of this study is to assess the effect of ICD generator exchange on the rate of electrical failure in the Riata lead at 1 year. METHODS: A retrospective chart review was conducted in patients who underwent implantation of a Riata/Riata ST lead at one center. Patients with a functioning Riata lead (with/without externalized conductor) at the time of ICD exchange were compared to controls with Riata leads implanted for a comparable amount of time who did not undergo generator replacement. RESULTS: Riata leads were implanted in 1,042 patients prior to the recall and 153 of these patients underwent generator exchange without lead replacement. Conductor externalization was noted in 21.5% of Riata leads in the ICD exchange cohort, which was not different from the control group (19.2%; P = 0.32). Two leads failed in the first year after generator replacement (1.5%) which did not significantly differ from the control group (2.0%; P = 0.57). At change-out, 54% received a commanded shock (18.6 ± 0.9 J) that did not result in any change in the high-voltage lead impedance (46.1 ± 1.1 ohms). CONCLUSIONS: Conductor externalization was seen frequently in our cohort of patients. ICD generator exchange did not accelerate the rate of Riata lead failure at 1 year. Although both the control and the change-out cohorts failed at a rate much greater than nonrecalled leads, generator exchange did not appear to add to the problem.

Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.

RATIONALE: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux. OBJECTIVE: Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine. METHODS AND RESULTS: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics. CONCLUSIONS: Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.

Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.

BACKGROUND: Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction. METHODS AND RESULTS: In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension. CONCLUSIONS: Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.

Generator replacement is associated with an increased rate of ICD lead alerts.

BACKGROUND: Lead malfunction is an important cause of morbidity and mortality in patients with an implantable cardioverter-defibrillator (ICD). We have shown that the failure of recalled high-voltage leads significantly increases after ICD generator replacement. However, generator replacement has not been recognized as a predictor of lead failure in general. OBJECTIVE: The purpose of this study is to assess the effect of ICD generator exchange on the rate of ICD lead alerts. METHODS: A time-dependent Cox proportional hazards model was used to analyze a database of remotely monitored ICDs. The model assessed the impact of generator exchange on the rate of lead alerts after ICD generator replacement. RESULTS: The analysis included 60,219 patients followed for 37 ± 19 months. The 5-year lead survival was 99.3% (95% confidence interval 99.2%-99.4%). Of 60,219 patients, 7458 patients (12.9%) underwent ICD generator exchange without lead replacement. After generator replacement, the rate of lead alerts was more than 5-fold higher than in controls with leads of the same age without generator replacement (hazard ratio 5.19; 95% confidence interval 3.45-7.84). A large number of lead alerted within 3 months of generator replacement. Lead alerts were more common in patients with single- vs dual-chamber ICDs and in younger patients. Sex was not associated with lead alerts. CONCLUSION: Routine generator replacement is associated with a 5-fold higher risk of lead alert compared to age-matched leads without generator replacement. This suggests the need for intense surveillance after generator replacement and the development of techniques to minimize the risk of lead damage during generator replacement.

Generator exchange is associated with an increased rate of Sprint Fidelis lead failure.

BACKGROUND: The Medtronic Sprint Fidelis defibrillator lead is at an increased risk for failure and was recalled in October 2007. Approximately 268,000 leads were implanted, and more than 100,000 patients still have active Fidelis leads. A number of studies have examined the rate and clinical predictors of lead failure, but none has addressed the effect of an implantable cardioverter-defibrillator generator exchange on subsequent lead failure. Although the manufacturer asserts that "Sprint Fidelis performance after device change-out is similar to lead performance without device change-out," published data are lacking. OBJECTIVE: To assess the effect of implantable cardioverter-defibrillator generator exchange on the rate of Fidelis lead failure. METHODS: A chart review was conducted in patients who underwent implantation of a Fidelis lead. Patients with a functioning Fidelis lead at generator exchange were compared with controls with leads implanted for a comparable amount of time not undergoing ICD replacement. RESULTS: A total of 1366 patients received a Fidelis lead prior to the recall, of which 479 were still actively followed. Seventy-two patients with a functioning lead underwent generator exchange without lead replacement. Following generator replacement, 15 leads failed. Sixty percent of the Fidelis leads failed within 3 months. Generator exchange increased the rate of lead failure compared with matched controls (20.8% vs 2.54%; P < .001). CONCLUSIONS: Generator exchange is associated with a higher than expected rate of Fidelis lead failure, often within 3 months. The risk-benefit ratio of Fidelis lead replacement at the time of generator exchange may be greater than appreciated.

Relative adrenal insufficiency in severe congestive heart failure with preserved systolic function: a case report.

Relative adrenal insufficiency in critically ill patients is an important syndrome in septic shock. The insufficient stress response of the hypothalamic-pituitary-adrenal axis in acute illness contributes to hemodynamic instability. Treatment of this state in septic shock improves patient outcomes. In this report, we describe the case of a patient with severe diastolic dysfunction who presented in cardiogenic shock associated with relative adrenal insufficiency and had a complete recovery with corticosteroid replacement. Alteration of the hypothalamic-pituitary-adrenal axis may be more prevalent than suspected in end-stage heart failure, and the diagnosis and treatment of this syndrome may ultimately improve outcomes in a subgroup of heart failure patients.

Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts.

The balance between matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, -2, -3, and -4) provoked a significant (P < 0.0001) 1.3-fold in increase in bromodeoxyuridine (BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, -2-, -3-, and -4-conditioned medium led to a 1.2-fold increase in BrdU incorporation (P < 0.0001) that was abolished by pretreatment with anti-TIMP-1, -2, -3, and -4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP-1, -2, -3, and -4 led to a significant increase in alpha-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP-2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP-3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors.