His-Purkinje system re-entry in patients with clustering ventricular tachycardia episodes

AIMS: Multiple arrhythmia re-inductions were recently shown in His-Purkinje system (HPS) ventricular tachycardia (VT). We hypothesized that HPS VT was a frequent mechanism of repetitive or incessant VT and assessed diagnostic criteria to select patients likely to have HPS VT. METHODS AND RESULTS: Consecutive patients with clustering VT episodes (>3 sustained monomorphic VT within 2 weeks) were included in the analysis. HPS VT was considered plausible in patients with (i) impaired left ventricular function associated with dilated cardiomyopathy or valvular heart disease; or (ii) ECG during VT similar to sinus rhythm QRS or to bundle-branch block QRS. HPS VT was plausible in 12 of 48 patients and HPS VT was demonstrated in 6 of 12 patients (50%, or 13% of the whole study group). Median VT cycle length was 318 ms (250-550). Catheter ablation was successful in all six patients. CONCLUSION: His-Purkinje system VT is found in a significant number of patients with repetitive or incessant VT episodes, and in a large proportion of patients with predefined clinical or electrocardiographic characteristics. Since it is easily amenable to catheter ablation, our data support the screening of all patients with repetitive VT in this regard and an invasive approach in a selected group of patients.

Ventricular tachycardia arising from the aortomitral continuity in structural heart disease: characteristics and therapeutic considerations for an anatomically challenging area of origin

BACKGROUND: The aortomitral continuity (AMC) has been described as a site of origin for ventricular tachycardias (VT) in structurally normal hearts. There is a paucity of data on the contribution of this region to VTs in patients with structural heart disease. METHODS AND RESULTS: Data from 550 consecutive patients undergoing catheter ablation for VT associated with structural heart disease were reviewed. Twenty-one (3.8%) had a VT involving the peri-AMC region (age, 62.7+/-11 years; median left ventricular ejection fraction, 43.6+/-17%). Structural heart disease was ischemic in 7 (33%), dilated cardiomyopathy in 10 (47.6%), and valvular cardiomyopathy in 4 (19%) patients, respectively. After 1.9+/-0.8 catheter ablation procedures (including 3 transcoronary ethanol ablations) the peri-AMC VT was not inducible in 19 patients. The remaining 2 patients underwent cryosurgical ablation. Our first catheter ablation procedure was less often successful (66.7%) for peri-AMC VTs compared with that for 246 VTs originating from the LV free wall (81.4%, P=0.03). During a mean follow-up of 1.9+/-2.1 years, 12 (57.1%) patients remained free of VT, peri-AMC VT recurred in 7 patients, and 1 patient had recurrent VT from a remote location. Three patients died. Analysis of 50 normal coronary angiograms demonstrated an early septal branch supplying the peri-AMC area in 58% of cases that is a potential target for ethanol ablation. CONCLUSIONS: VTs involving the peri-AMC region occur in patients with structural heart disease and appear to be more difficult to ablate compared with VTs originating from the free LV wall. This region provides unique challenges for radiofrequency ablation, but cryosurgery and transcoronary alcohol ablation appear feasible in some cases.

Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model

AIM As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure. METHODS Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed. RESULTS FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20 ± 3.90% in NLC to 26.83 ± 4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3. CONCLUSION Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.

Reversal of myocyte hypertrophy by ventricular unloading: cardiac improvement without adrenergic receptor up-regulation and relocalization.

In previous studies, we found that the improved contractile ability of cardiac myocytes from patients who have had left ventricular assist device (LVAD) support was due to a number of beneficial changes, most notably in calcium handling (increased sarcoplasmic reticulum calcium binding and uptake), improved integrity of cell membranes due to phospholipid reconstruction (reduced lysophospholipid content), and an upregulation of adrenoreceptors (increased adrenoreceptor numbers). However, in the case presented here, there was no increase in adrenoreceptor number, which is something that we usually find in core tissue at the time of LVAD removal or organ transplantation; also, there was no homogeneous postassist device receptor distribution. However, the patient was well maintained for 10 months following LVAD implantation, until a donor organ was available, regardless of the lack of adrenoreceptor improvement. We conclude from these studies that cardiac recovery is the result of the initiation of multiple repair mechanisms, and that the lack of expected changes, in this case increased adrenoreceptors, is not always an accurate indicator of anticipated outcome. We suggest that interventions and strategies have to consider multiple, beneficial changes due to unloading and target a number of biochemical and structural areas to produce improvement, even if not all of these improvements occur.

Age-related normal structural and functional ventricular values in cardiac function assessed by magnetic resonance

BACKGROUND The heart is subject to structural and functional changes with advancing age. However, the magnitude of cardiac age-dependent transformation has not been conclusively elucidated. METHODS This retrospective cardiac magnetic resonance (CMR) study included 183 subjects with normal structural and functional ventricular values. End systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) were obtained from the left and the right ventricle in breath-hold cine CMR. Patients were classified into four age groups (20-29, 30-49, 50-69, and ≥70 years) and cardiac measurements were compared using Pearson's rank correlation over the four different groups. RESULTS With advanced age a slight but significant decrease in ESV (r=-0.41 for both ventricles, P<0.001) and EDV (r=-0.39 for left ventricle, r=-0.35 for right ventricle, P<0.001) were observed associated with a significant increase in left (r=0.28, P<0.001) and right (r=0.27, P<0.01) ventricular EF reaching a maximal increase in EF of +8.4% (P<0.001) for the left and +6.1% (P<0.01) for the right ventricle in the oldest compared to the youngest patient group. Left ventricular myocardial mass significantly decreased over the four different age groups (P<0.05). CONCLUSIONS The aging process is associated with significant changes in left and right ventricular EF, ESV and EDV in subjects with no cardiac functional and structural abnormalities. These findings underline the importance of using age adapted values as standard of reference when evaluating CMR studies.

Prognostic significance of multidetector CT in normotensive patients with pulmonary embolism: results of the protect study.

BACKGROUND In patients with acute pulmonary embolism (PE), rapid and accurate risk assessment is paramount in selecting the appropriate treatment strategy. The prognostic value of right ventricular dysfunction (RVD) assessed by multidetector CT (MDCT) in normotensive patients with PE has lacked adequate validation. METHODS The study defined MDCT-assessed RVD as a ratio of the RV to the left ventricle short axis diameter greater than 0.9. Outcomes assessed through 30 days after the diagnosis of PE included all-cause mortality and 'complicated course', which consisted of death from any cause, haemodynamic collapse or recurrent PE. RESULTS MDCT detected RVD in 533 (63%) of the 848 enrolled patients. Those with RVD on MDCT more frequently had echocardiographic RVD (31%) than those without RVD on MDCT (9.2%) (p<0.001). Patients with RVD on MDCT had significantly higher brain natriuretic peptide (269±447 vs 180±457 pg/ml, p<0.001) and troponin (0.10±0.43 vs 0.03±0.24 ng/ml, p=0.001) levels in comparison with those without RVD on MDCT. During follow-up, death occurred in 25 patients with and in 13 patients without RVD on MDCT (4.7% vs 4.3%; p=0.93). Those with and those without RVD on MDCT had a similar frequency of complicated course (3.9% vs 2.3%; p=0.30). CONCLUSIONS The PROgnosTic valuE of CT study showed a relationship between RVD assessed by MDCT and other markers of cardiac dysfunction around the time of PE diagnosis, but did not demonstrate an association between MDCT-RVD and prognosis.

[Ventricular assist device – Possibilities of long-term mechanical circulatory support]

In Switzerland 200’000 people suffer from congestive heart failure. Approximately 10’000 patients find themselves in an advanced state of the disease. When conservative treatment options are no longer available heart transplantation is the therapy of choice. Should this not be an option due to long waiting lists or medical issues assist device therapy becomes an option. Assist device therapy is separated in short-term and long-term support. Long-term support is nowadays performed with ventricular assist devices (VADs). The native heart is still in place and supported in parallel to the remaining function of the heart. The majority of patients are treated with a left ventricular assist device (LVAD). The right ventrical alone (RVAD) as well as bi-ventricular support (BiVAD) is rarely needed. The modern VADs are implantable and create a non-pulsative bloodflow. A percutaneous driveline enables energy supply and pump-control. Indication strategies for VAD implantations include bridge to transplant (short term support), bridge to candidacy and bridge to transplant. VADs become more and more a definite therapeutic option (destination therapy). VAD therapy might be a realistic alternative to organ transplantation in the near future.

Thrombus formation in the left ventricle after large myocardial infarction – assessment with cardiac magnetic resonance imaging

INTRODUCTION Left ventricular thrombus (LVT) formation may worsen the post-infarct outcome as a result of thromboembolic events. It also complicates the use of modern antiplatelet regimens, which are not compatible with long-term oral anticoagulation. The knowledge of the incidence of LVT may therefore be of importance to guide antiplatelet and antithrombotic therapy after acute myocardial infarction (AMI). METHODS In 177 patients with large, mainly anterior AMI, standard cardiac magnetic resonance imaging (CMR) including cine and late gadolinium enhancement (LGE) imaging was performed shortly after AMI as per protocol. CMR images were analysed at an independent core laboratory blinded to the clinical data. Transthoracic echocardiography (TTE) was not mandatory for the trial, but was performed in 64% of the cases following standard of care. In a logistic model, 3 out of 61 parameters were used in a multivariable model to predict LVT. RESULTS LVT was detected by use of CMR in 6.2% (95% confidence interval [CI] 3.1%-10.8%). LGE sequences were best to detect LVT, which may be missed in cine sequences. We identified body mass index (odds ratio 1.18; p = 0.01), baseline platelet count (odds ratio 1.01, p = 0.01) and infarct size as assessed by use of CMR (odds ratio 1.03, p = 0.02) as best predictors for LVT. The agreement between TTE and CMR for the detection of LVT is substantial (kappa = 0.70). DISCUSSION In the current analysis, the incidence of LVT shortly after AMI is relatively low, even in a patient population at high risk. An optimal modality for LVT detection is LGE-CMR but TTE has an acceptable accuracy when LGE-CMR is not available.

Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart

The role and even the existence of myocyte proliferation in the adult heart remain controversial. Documentation of cell cycle regulators, DNA synthesis, and mitotic images has not modified the view that myocardial growth can only occur from hypertrophy of an irreplaceable population of differentiated myocytes. To improve understanding the biology of the heart and obtain supportive evidence of myocyte replication, three indices of cell proliferation were analyzed in dogs affected by a progressive deterioration of cardiac performance and dilated cardiomyopathy. The magnitude of cycling myocytes was evaluated by the expression of Ki67 in nuclei. Ki67 labeling of left ventricular myocytes increased 5-fold, 12-fold, and 17-fold with the onset of moderate and severe ventricular dysfunction and overt failure, respectively. Telomerase activity in vivo is present only in multiplying cells; this enzyme increased 2.4-fold and 3.1-fold in the decompensated heart, preserving telomeric length in myocytes. The contribution of cycling myocytes to telomerase activity was determined by the colocalization of Ki67 and telomerase in myocyte nuclei. More than 50% of Ki67-positive cells expressed telomerase in the overloaded myocardium, suggesting that these myocytes were the morphological counterpart of the biochemical assay of enzyme activity. Moreover, we report that 20–30% of canine myocytes were telomerase competent, and this value was not changed by cardiac failure. In conclusion, the enhanced expression of Ki67 and telomerase activity, in combination with Ki67-telomerase labeling of myocyte nuclei, support the notion that myocyte proliferation contributes to cardiac hypertrophy of the diseased heart.

Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice.

We have recently characterized a cardiac model of ventricular chamber defects in retinoid X receptor alpha (RXR alpha) homozygous mutant (-/-) gene-targeted mice. These mice display generalized edema, ventricular chamber hypoplasia, and muscular septal defects, and they die at embryonic day 15. To substantiate our hypothesis that the embryos are dying of cardiac pump failure, we have used digital bright-field and fluorescent video microscopy and in vivo microinjection of fluorescein-labeled albumin to analyze cardiac function. The affected embryos showed depressed ventricular function (average left ventricular area ejection fraction, 14%), ventricular septal defects, and various degrees of atrioventricular block not seen in the RXR alpha wild-type (+/+) and heterozygous (+/-) littermates (average left ventricular area ejection fraction, 50%). The molecular mechanisms involved in these ventricular defects were studied by evaluating expression of cardiac-specific genes known to be developmentally regulated. By in situ hybridization, aberrant, persistent expression of the atrial isoform of myosin light chain 2 was identified in the ventricles. We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle. The conduction system disturbances found in the RXR alpha -/- embryos may reflect a requirement of the developing conduction system for the RXR alpha signaling pathway, or it may be secondary to the failure of septal development.

Epicardial Radiofrequency Ablation Failure During Ablation Procedures for Ventricular Arrhythmias: Reasons and Implications for Outcomes.

BACKGROUND Radiofrequency ablation (RFA) from the epicardial space for ventricular arrhythmias is limited or impossible in some cases. Reasons for epicardial ablation failure and the effect on outcome have not been systematically analyzed. METHODS AND RESULTS We assessed reasons for epicardial RFA failure relative to the anatomic target area and the type of heart disease and assessed the effect of failed epicardial RFA on outcome after ablation procedures for ventricular arrhythmias in a large single-center cohort. Epicardial access was attempted during 309 ablation procedures in 277 patients and was achieved in 291 procedures (94%). Unlimited ablation in an identified target region could be performed in 181 cases (59%), limited ablation was possible in 22 cases (7%), and epicardial ablation was deemed not feasible in 88 cases (28%). Reasons for failed or limited ablation were unsuccessful epicardial access (6%), failure to identify an epicardial target (15%), proximity to a coronary artery (13%), proximity to the phrenic nerve (6%), and complications (<1%). Epicardial RFA was impeded in the majority of cases targeting the left ventricular summit region. Acute complications occurred in 9%. The risk for acute ablation failure was 8.3× higher (4.5-15.0; P<0.001) after no or limited epicardial RFA compared with unlimited RFA, and patients with unlimited epicardial RFA had better recurrence-free survival rates (P<0.001). CONCLUSIONS Epicardial RFA for ventricular arrhythmias is often limited even when pericardial access is successful. Variability of success is dependent on the target area, and the presence of factors limiting ablation is associated with worse outcomes.

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.

Cardiac function in fetuses of poorly-controlled pre-gestational diabetic pregnancies - a pilot study

Objective: Cardiac impairment is frequently found in babies of diabetic mothers. It is still controversial whether this is due to poor glucose control. The aim of this study is to compare the cardiac function in fetuses of well- and poorly-controlled pre-gestational diabetic pregnancy in third trimester. Methods:Women with type 1 pre-gestational diabetes were enrolled at 30-32 weeks. Cardiac size and interventricular septal wall thickness were measured by M-mode at end-diastolic phase. The right and left ventricular ejection fractions were calculated. At the mitral and tricuspid valves inflow, the ratio between early ventricular filling and active atrial filling (E/A) at both atrioventricular valves were measured by Doppler echocardiography. Peak velocities of ascending aorta and pulmonary artery were assessed. The angle of isonation was kept at 6.5%) were compared with those with satisfactorily controlled diabetes (HbA1c less than or equal to 6.5%). Results: A total of 21 women with pre-gestational diabetes were recruited for this study. Eight women with well-controlled diabetes were compared with 9 women who had poorly-controlled diabetes. HbA1c in the poorly-controlled group was 7.3% and in the well-controlled group it was 5.4% (p < 0.001). There was no difference between the two groups in cardiac size, interventricular septal wall thickness, ejection fraction, aorta and pulmonary artery peak flow velocities. The right atrioventricular E/A ratio was significantly lower among the poorly-controlled diabetic pregnancies (0.71 vs. 0.54; p < 0.05). Conclusion: Fetuses of poorly-controlled diabetic mothers had a lower right atrioventricular E/A ratio. This may be due to metabolic acidosis, non-hypertrophic cardiac dysfunction or fetal polycythemia. Copyright (C) 2003 S. Karger AG, Basel.

Echocardiographic detection of early diabetic myocardial disease

OBJECTIVES We sought to determine whether disturbances of myocardial contractility and reflectivity could be detected in diabetic patients without overt heart disease and whether these changes were independent and incremental to left ventricular hypertrophy (LVH). BACKGROUND Left ventricular (LV) dysfunction is associated with diabetes mellitus, but LVH is common in this population and the relationship between diabetic LV dysfunction and LVH is unclear. METHODS We studied 186 patients with normal ejection fraction and no evidence of CAD: 48 with diabetes mellitus only (DM group), 45 with LVH only (LVH group), 45 with both diabetes and LVH (DH group), and 48 normal controls. Peak strain and strain rate of six walls in apical four-chamber, long-axis, and two-chamber views were evaluated and averaged for each patient. Calibrated integrated backscatter (113) was assessed by comparison of the septal or posterior wall with pericardial IB intensity. RESULTS All patient groups (DM, DH, LVH) showed reduced systolic function compared with controls, evidenced by lower peak strain (p < 0.001) and strain rate (p = 0.005). Calibrated 113, signifying myocardial reflectivity, was greater in each patient group than in controls (p < 0.05). Peak strain and strain rate were significantly lower in the DH group than in those in the DM alone (p < 0.03) or LVH alone (p = 0.01) groups. CONCLUSIONS Diabetic patients without overt heart disease demonstrate evidence of systolic dysfunction and increased myocardial reflectivity. Although these changes are similar to those caused by LVH, they are independent and incremental to the effects of LVH. (C) 2003 by the American College of Cardiology Foundation.