No abstract

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Background-Alterations in the balance of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) are involved in left ventricular (LV) remodeling. Whether their expression is related to interstitial fibrosis or LV dysfunction in patients with chronic pressure overload-induced LV hypertrophy, however, is unknown. Methods and Results-Therefore, cardiac biopsies were taken in 36 patients with isolated aortic stenosis (AS) and in 29 control patients without LV hypertrophy. Microarray analysis revealed significantly increased mRNA expression of collagen types I, III, and IV and transcripts involved in collagen synthesis, including procollagen endopeptidase and lysine and proline hydroxylases, in AS compared with control patients. Collagen deposition was greater in AS than in control patients and was most pronounced in AS patients with severe diastolic dysfunction. Cardiac mRNA expression of TIMP-1 and TIMP-2 was significantly increased in AS compared with control patients (mRNA transcript levels normalized to GAPDH: TIMP-1, 0.67Ϯ0.1 in AS versus 0.37Ϯ0.08 in control patients; TIMP-2, 9.5Ϯ2.6 in AS versus 1.6Ϯ0.4 in control patients; PϽ0.05 for both) but did not differ significantly for MMP-1, -2, or -9. Cardiac TIMP-1 and -2 transcripts were significantly related to the degree of interstitial fibrosis and proportional to diastolic dysfunction in AS patients. Conclusions-Cardiac expression of TIMP-1 and TIMP-2 is significantly increased in chronic pressure-overloaded human hearts compared with controls and is related to the degree of interstitial fibrosis.

Adenosine (Ado) accumulates in tissues under metabolic stress. On myocardial cells, the nucleoside interacts with various receptor subtypes (A(1), A(3), and probably A(2A) and A(2B)) that are coupled, via G proteins, to multiple effectors, including enzymes, channels, transporters and cytoskeletal components. Studies using Ado receptor agonists and antagonists, as well as animals overexpressing the A(1) receptor indicate that Ado exerts anti-ischemic action. Ado released during preconditioning (PC) by short periods of ischemia followed by reperfusion induces cardioprotection to a subsequent sustained ischemia. This protective action is mediated by A(1) and A(3) receptor subtypes and involves the activation and translocation of PKC to sarcolemmal and to mitochondrial membranes. PKC activation leads to an increased opening of ATP-sensitive K(+) (K(ATP)) channels. Recent studies implicate mitochondrial rather than sarcolemmal K(ATP) channels in the protective action of PC. Other effectors possibly contributing to cardioprotection by Ado or PC, and which seem particularly involved in the delayed (second window of) protection, include MAP kinases, heat shock proteins and iNOS. Because of its anti-ischemic effects, Ado has been tested as a protective agent in clinical interventions such as PTCA, CABG and tissue preservation, and was found in most cases to enhance the post-ischemic recovery of function. The mechanisms underlying the role of Ado and of mitochondrial function in PC are not completely clear, and uncertainties remain concerning the role played by newly identified potential effectors such as free radicals, the sarcoplasmic reticulum, etc. In addition, more studies are needed to clarify the signalling mechanisms by which A(3) receptor activation or overexpression may promote apoptosis and cellular injury, as reported by a few recent studies.

Our results indicate that a sudden rise in ICP can cause irreversible myocardial damage.

This European multicentre experience, with the largest cohort of patients with sutureless valves to date, shows excellent clinical and haemodynamic results that remain stable even up to the 5-year follow-up. Even in this elderly patient cohort with 40% octogenarians, both early and late mortality rates were very low. There were no valve migrations, structural valve degeneration or valve thrombosis in the follow-up. The sutureless technique is a promising alternative to biological aortic valve replacement.

Background-Durability assessment of mitral valve repair for degenerative valve incompetence is actually limited to reoperation as the primary indicator, with valve-related risk factors for late death as a secondary indicator. We assessed serial echocardiographic follow-up of valve function as an indicator of the durability of mitral valve repair. Methods and Results-In

Background-Prosthesis-patient mismatch (P-PtM) after aortic valve replacement results in disturbed valve performance associated with increased pressure gradients. However, it is unknown whether this can be related to future structural valve deterioration (SVD) of the bioprosthesis. Methods and Results-In 564 patients (mean age, 74Ϯ5 years) receiving an aortic valve bioprosthesis, clinical follow-up (median, 6.1 years; maximum, 16.4 years) was analyzed including echocardiography. SVD was diagnosed in 40 patients (7%) as substantially increased stenosis (nϭ24) or regurgitation (nϭ16) of the operated valve over time. When patients with P-PtM (effective orifice area index Ͻ0.85 cm 2 /m 2 ; nϭ285) developed SVD, it was preferentially of the stenosis type, whereas when patients without P-PtM (nϭ279) developed SVD, the majority was of the incompetence type (PϽ0.05). Multivariable analysis including patient-and valve-related variables revealed that P-PtM and label size Յ21 were independent predictors of SVD (Pϭ0.04 and Pϭ0.02, respectively). A nonparametric Turnbull estimate analysis showed that SVD is virtually nonexistent for up to 9 years in patients without P-PtM. Thereafter, SVD starts to occur and is mainly of the incompetence-type SVD (79% of cases). In patients with P-PtM, SVD starts to occur after 2 to 3 years after implantation and is mainly of the stenosis-type SVD (81% of cases). Conclusions-These data suggest that stenosis-type SVD is an early, P-PtM-related, and thus preventable phenomenon.Incompetence-type SVD is a time-dependent, nonspecific wear damage to bioprosthetic valves, which is not related to P-PtM. (Circulation. 2010;121:2123-2129.)