Better outcome of ablation for sustained outflow-tract ventricular tachycardia when tachycardia is inducible.

AIMS In patients presenting with spontaneous sustained ventricular tachycardia (VT) from the outflow-tract region without overt structural heart disease ablation may target premature ventricular contractions (PVCs) when VT is not inducible. We aimed to determine whether inducibility of VT affects ablation outcome. METHODS AND RESULTS Data from 54 patients (31 men; age, 52 ± 13 years) without overt structural heart disease who underwent catheter ablation for symptomatic sustained VT originating from the right- or left-ventricular outflow region, including the great vessels. A single morphology of sustained VT was inducible in 18 (33%, SM group) patients, and 11 (20%) had multiple VT morphologies (MM group). VT was not inducible in 25 (46%) patients (VTni group). After ablation, VT was inducible in none of the SM group and in two (17%) patients in the MM group. In the VTni group, ablation targeted PVCs and 12 (48%) patients had some remaining PVCs after ablation. During follow-up (21 ± 19 months), VT recurred in 46% of VTni group, 40% of MM inducible group, and 6% of the SM inducible group (P = 0.004). Analysis of PVC morphology in the VTi group further supported the limitations of targeting PVCs in this population. CONCLUSION Absence of inducible VT and multiple VT morphologies are not uncommon in patients with documented sustained outflow-tract VT without overt structural heart disease. Inducible VT is associated with better outcomes, suggesting that attempts to induce VT to guide ablation are important in this population.

Long Term Outcomes Following Catheter Ablation of Ventricular Tachycardia in Patients with and without Structural Heart Disease.

BACKGROUND Long-term outcomes following ventricular tachycardia (VT) ablation are sparsely described. OBJECTIVES To describe long term prognosis following VT ablation in patients with no structural heart disease (no SHD), ischemic (ICM) and non-ischemic cardiomyopathy (NICM). METHODS Consecutive patients (n=695; no SHD 98, ICM 358, NICM 239 patients) ablated for sustained VT were followed for a median of 6 years. Acute procedural parameters (complete success [non-inducibility of any VT]) and outcomes after multiple procedures were reported. RESULTS Compared with patients with no SHD or NICM, ICM patients were the oldest, had more males, lowest left ventricular ejection fraction (LVEF), highest drug failures, VT storms and number of inducible VTs. Complete procedure success was highest in no SHD, compared ICM and NICM patients (79%, 56%, 60% respectively, P<0.001). At 6 years, ventricular arrhythmia (VA)-free survival was highest in no SHD (77%) than ICM (54%) and NICM (38%, P<0.001) and overall survival was lowest in ICM (48%), followed by NICM (74%) and no SHD patients (100%, P<0.001). Age, LVEF, presence of SHD, acute procedural success (non-inducibility of any VT), major complications, need for non-radiofrequency ablation modalities, and VA recurrence were independently associated with all cause mortality. CONCLUSIONS Long term follow up following VT ablation shows excellent prognosis in the absence of SHD, highest VA recurrence and transplantation in NICM and highest mortality in patients with ICM. The extremely low mortality for those without SHD suggests that VT in this population is very rarely an initial presentation of a myopathic process.

Cosegregation analysis of natriuretic peptide genes and blood pressure in the spontaneously hypertensive rat

1. The natriuretic peptide precursor A (Nppa) and B (Nppb) genes are candidate genes for hypertension and cardiac hypertrophy in the spontaneously hypertensive rat (SHR). The purpose of the present study was to determine the role of the Nppa and Nppb genes in the development of hypertension in the SHR. 2. A cohort (n = 162) of F2 segregating intercross animals was established between strains of hypertensive SHR and normotensive Wistar-Kyoto rats. Blood pressure and heart weight were measured in each rat at 12-16 weeks of age. Rats were genotyped using 11 informative microsatellite markers, distributed in the vicinity of the Nppa marker on rat chromosome 5 including an Nppb marker. The phenotype values were compared with genotype using the computer package MAP-MAKER 3.0 (Whitehead Institute, Boston, MA, USA) to determine whether there was a link between the genetic variants of the natriuretic peptide family and blood pressure or cardiac hypertrophy. 3. A strong correlation was observed between the Nppa marker and blood pressure. A quantitative trait locus (QTL) for blood pressure on chromosome 5 was identified between the Nppa locus and the D5Mgh15 marker, less than 2 cM from the Nppa locus. The linkage score for the blood pressure QTL on chromosome 5 was 3.8 and the QTL accounted for 43% of the total variance of systolic blood pressure, 54% of diastolic blood pressure and 59% of mean blood pressure. No association was found between the Nppb gene and blood pressure. This is the first report of linkage between the Nppa marker and blood pressure in the rat. There was no correlation between the Nppa or Nppb genes or other markers in this region and either heart weight or left ventricular weight in F2 rats. 4. These findings suggest the existence of a blood pressure-dependent Nppa marker variant or a gene close to Nppa predisposing to spontaneous hypertension in the rat. It provides a strong foundation for further detailed genetic studies in congenic strains, which may help to narrow down the location of this gene and lead to positional cloning.

Relationship between longitudinal and radial contractility in subclinical diabetic heart disease

Subclinical left ventricular (W) dysfunction may be identified by reduced longitudinal contraction. We sought to define the effects of subclinical LV dysfunction on radial contractility in 53 patients with diabetes mellitus with no LV hypertrophy, normal ejection fraction and no ischaemia as assessed by dobutamine echocardiography, in comparison with age-matched controls. Radial peak myocardial systolic velocity (S-m) and early diastolic velocity (E-m), strain and strain rate were measured in the mid-posterior and mid-anteroseptal walls in parasternal views and each variable was averaged for individual patients (radial contractility). These variables were also measured in the mid-posterior and mid-anteroseptal walls in the apical long-axis view and each variable was averaged for individual patients (longitudinal contractility). Mean radial S-m, strain and strain rate were significantly increased in diabetic patients (2.9+/-0.6 cm/s, 28+/-5% and 1.8+/-0.4 s(-1) respectively) compared with controls (2.4+/-0.7 cm/s, 23+/-4% and 1.6+/-0.3 s(-1) respectively; all P<0.001), but there was no difference in E-m (3.3&PLUSMN;1.2 compared with 3.1&PLUSMN;1.1 cm/s, P=not significant). In contrast, longitudinal S-m, E-m, strain and strain rate were significantly lower in diabetic patients (3.6&PLUSMN;1.1 cm/s, 4.3&PLUSMN;1.6 cm/s, 21&PLUSMN;4% and 1.6&PLUSMN;0.3 s(-1) respectively) than in controls (4.3&PLUSMN;1.0 cm/s, 5.7&PLUSMN;2.3 cm/s, 26&PLUSMN;4% and 1.9&PLUSMN;0.3 s(-1) respectively; all P<0.00 1). Thus radial contractility appears to compensate for reduced longitudinal contractility in subclinical LV dysfunction occurring in the absence of ischaemia or LV hypertrophy.

Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT4 receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT4 receptors in porcine and human ventricle. 5-HT4 mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT4 receptor mRNA. Ventricular 5-HT4(b) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC50=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 muM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC50=60 nM) and PKA activity by 39% of (-)-iso-proterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca2+ and 1.2 mM Mg2+ followed by a switch to 2.5 mM Ca2+ and 1 mM Mg2+, 5-HT (1-100 muM, 3-isobutyl-1-melhylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of I I patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT4 receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT4 receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Determinants of subclinical diabetic heart disease

Aims/hypothesis: Subclinical left ventricular (LV) dysfunction has been shown by tissue Doppler and strain imaging in diabetic patients in the absence of coronary disease or LV hypertrophy, but the prevalence and aetiology of this finding remain unclear. This study sought to identify the prevalence and the determinants of subclinical diabetic heart disease. Methods: A group of 219 unselected patients with type 2 diabetes without known cardiac disease underwent resting and stress echocardiography. After exclusion of coronary artery disease or LV hypertrophy, the remaining 120 patients ( age 57 +/- 10 years, 73 male) were studied with tissue Doppler imaging. Peak systolic strain of each wall and systolic (Sm) and diastolic ( Em) velocity of each basal segment were measured from the three apical views and averaged for each patient. Significant subclinical LV dysfunction was identified according to Sm and Em normal ranges adjusted by age and sex. Strain and Em were correlated with clinical, therapeutic, echocardiographic and biochemical variables, and significant independent associations were sought using a multiple linear regressionmodel. Results: Significant subclinical LV dysfunction was present in 27% diabetic patients. Myocardial systolic dysfunction by peak strain was independently associated with glycosylated haemoglobin level ( p< 0.001) and lack of angiotensin- converting enzyme inhibitor treatment ( p= 0.003). Myocardial diastolic function ( Em) was independently predicted by age ( p= 0.013), hypertension ( p= 0.001), insulin ( p= 0.008) and metformin ( p= 0.01) treatment. Conclusions/ interpretation: In patients with diabetes mellitus, subclinical LV dysfunction is common and associated with poor diabetic control, advancing age, hypertension and metformin treatment; ACE inhibitor and insulin therapies appear to be protective.

Use of real-time three-dimensional echocardiography to measure left atrial volume: Comparison with other echocardiographic techniques

Objectives: Left atrial (LA) volume (LAV) is a prognostically important biomarker for diastolic dysfunction, but its reproducibility on repeated testing is not well defined. LA assessment with 3-dimensional. (3D) echocardiography (3DE) has been validated against magnetic resonance imaging, and we sought to assess whether this was superior to existing measurements for sequential echocardiographic follow-up. Methods: Patients (n = 100; 81 men; age 56 +/- 14 years) presenting for LA evaluation were studied with M-mode (MM) echocardiography, 2-dimensional (2D) echocardiography, and 3DE. Test-retest variation was performed by a complete restudy by a separate sonographer within 1 hour without alteration of hemodynamics or therapy. In all, 20 patients were studied for interobserver and intraobserver variation. LAVs were calculated by using M-mode diameter and planimetered atrial area in the apical. 4-chamber view to calculate an assumed sphere, as were prolate ellipsoid, Simpson's biplane, and biplane area-length methods. All were compared with 3DE. Results: The average LAV was 72 +/- 27 mL by 3DE. There was significant underestimation of LAV by M-mode (35 +/- 20 mL, r = 0.66, P < .01). The 3DE and various 2D echocardiographic techniques were well correlated: LA planimetry (85 +/- 38 mL, r = 0.77, P < .01), prolate ellipsoid (73 +/- 36 mL, r = 0.73, P = .04), area-length (64 +/- 30 mL, r = 0.74, P < .01), and Simpson's biplane (69 +/- 31 mL, r = 0.78, P = .06). Test-retest variation for 3DE was most favorable (r = 0.98, P < .01), with the prolate ellipsoid method showing most variation. Interobserver agreement between measurements was best for 3DE (r = 0.99, P < .01), with M-mode the worst (r = 0.89, P < .01). Intraobserver results were similar to interobserver, the best correlation for 3DE (r = 0.99, P < .01), with LA planimetry the worst (r = 0.91, P < .01). Conclusions. The 2D measurements correlate closely with 3DE. Follow-up assessment in daily practice appears feasible and reliable with both 2D and 3D approaches.

Increased calcium influx mediates increased cardiac stiffness in hyperthyroid rats

Cardiac remodeling (hypertrophy and fibrosis) and an increased left ventricular diastolic stiffness characterize models of hypertension such as the SHR and DOCA-salt hypertensive rats. By contrast, hyperthyroidism induces hypertrophy and hypertension, yet collagen expression and deposition is unchanged or decreased, whereas diastolic stiffness is increased. We determined the possible role of increased calcium influx in the development of increased diastolic stiffness in hyperthyroidism by administering verapamil (15 mg/[kg(.)d] orally) to rats given triiodothyronine (T-3) (0.5 mg/[kg.d] subcutaneously for 14 d). Administration of T3 significantly increased body temperature (control: 36.7 +/- 0.2 degrees C; T-3: 39.6 +/- 0.2 degrees C), left ventricular wet weight (control: 2.09 +/- 0.02 mg/kg; T-3 3.07 +/- 0.07 mg/kg), systolic blood pressure (control: 128 +/- 5 mmHg; T-3: 156 +/- 4 mmHg), and left ventricular diastolic stiffness (control: 20.6 +/- 2.0; T-3: 28.8 +/- 1.4). Collagen content of the left ventricle was unchanged. Contractile response to noradrenaline in thoracic aortic rings was reduced. Relaxation in response to acetylcholine (ACh) was also reduced in T-3-treated rats, whereas sodium nitroprusside response was unchanged. Verapamil treatment of hyperthyroid rats completely prevented the increased diastolic stiffness and systolic blood pressure while attenuating the increased body temperature and left ventricular weight; collagen content remained unchanged. ACh response in thoracic aortic rings was restored by verapamil. Thus, in hyperthyroid rats, an increased calcium influx is a potential mediator of the increased diastolic stiffness independent of changes in collagen.

Analysis of cardiac ventricular wall motion based on a three-dimensional electromechanical biventricular model

This paper describes a biventricular model, which couples the electrical and mechanical properties of the heart, and computer simulations of ventricular wall motion and deformation by means of a biventricular model. In the constructed electromechanical model, the mechanical analysis was based on composite material theory and the finite-element method; the propagation of electrical excitation was simulated using an electrical heart model, and the resulting active forces were used to calculate ventricular wall motion. Regional deformation and Lagrangian strain tensors were calculated during the systole phase. Displacements, minimum principal strains and torsion angle were used to describe the motion of the two ventricles. The simulations showed that during the period of systole, (1) the right ventricular free wall moves towards the septum, and at the same time, the base and middle of the free wall move towards the apex, which reduces the volume of the right ventricle; the minimum principle strain (E3) is largest at the apex, then at the middle of the free wall and its direction is in the approximate direction of the epicardial muscle fibres; (2) the base and middle of the left ventricular free wall move towards the apex and the apex remains almost static; the torsion angle is largest at the apex; the minimum principle strain E3 is largest at the apex and its direction on the surface of the middle wall of the left ventricle is roughly in the fibre orientation. These results are in good accordance with results obtained from MR tagging images reported in the literature. This study suggests that such an electromechanical biventricular model has the potential to be used to assess the mechanical function of the two ventricles, and also could improve the accuracy ECG simulation when it is used in heart torso model-based body surface potential simulation studies.

Prevalence of heart failure and systolic ventricular dysfunction in older Australians: the Canberra Heart Study

Objective: To estimate the prevalence of heart failure (HF) and left ventricular (LV) systolic dysfunction in a population-based sample of older Australians. Design, setting and participants: A cross-sectional survey of 2000 randomly selected residents of Canberra, aged 60-86 years, conducted between February 2002 and June 2003. Participants were assessed by history, physical examination by a cardiologist, and echocardiography. Main outcome measures: Age- and sex-specific prevalence rates of clinical HF and LV systolic dysfunction (defined as LV ejection fraction

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Progression of left atrial volume index in a population at risk for heart failure:a substudy of the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) trial

AIMS: Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre-heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation.

METHODS AND RESULTS: This was a prospective substudy within the framework of the STOP-HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow-up time between assessments was 15 ± 6 months. 'Progressors' (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m(2) (and baseline LAVI between 20 and 34 mL/m(2)). This cut-off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta-blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 'Progressors' matched to 30 'Non-progressors'. For 'Progressors', relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05).

CONCLUSION: Accelerated LAVI increase was found to occur in up to 14% of all pre-HF patients undergoing serial echocardiograms over a relatively short follow-up period. In a randomly selected subcohort of 'Progressors', changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at-risk group.

Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure

BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.

METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich α2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P≤0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-α (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-βR1 (P<0.001) and α-smooth muscle actin (P=0.025) expression.

CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, β-blocker therapy, and BNP.

Avaliação dos valores séricos de troponina cardíaca I (cTnI) e capacidade antioxidante total (TAC) em felídeos com doença renal crónica e seu valor de prognóstico : estudo preliminar

Dissertação de Mestrado Integrado em Medicina Veterinária