Sildenafil for Pulmonary Hypertension in the Early Postoperative Period After Mitral Valve Surgery.

OBJECTIVES: The phosphodiesterase-5 inhibitor sildenafil was developed for the treatment of pulmonary hypertension. The authors investigated the efficacy and safety of sildenafil in the early postoperative period after mitral valve surgery in patients with pulmonary hypertension. DESIGN: A double-blind, placebo-controlled randomized trial was performed. SETTING: The trial was performed in a single tertiary referral center. PARTICIPANTS: Fifty consecutive patients who experienced pulmonary hypertension and underwent mitral valve surgery. INTERVENTIONS: Patients were randomly assigned to the following 2 groups: 25 patients received 20 mg sildenafil every 8 hours, and the remaining 25 patients received placebo during the same period. Hemodynamic parameters were studied by using a pulmonary artery catheter at baseline and every 6 hours up to 36 hours. RESULTS: Patients who received sildenafil showed a decrease in mean pulmonary pressure, from 32 ± 7 mmHg at baseline to 26 ± 3 mmHg after 36 hours, whereas no change was seen in patients who received placebo (mean pulmonary pressure 34 ± 6 mmHg at baseline and 35 ± 5 mmHg after 36 h) (p < 0.001). No significant changes in systemic hemodynamic and oxygenation were observed. Patients who received sildenafil compared with those who received placebo had a median mechanical lung ventilation time of 16 (10-31) hours versus 19 (13-41) hours (p = 0.431), intensive care unit stay of 74 (44-106) hours versus 91 (66-141) hours (p = 0.410), and a total hospitalization stay of 7 (5-10) days versus 11 (7-15) days (p = 0.009). CONCLUSIONS: The immediate postoperative administration of sildenafil after mitral valve surgery is safe. Sildenafil demonstrates a favorable decreasing effect on pulmonary vascular pressure without systemic hypotension and ventilation-perfusion mismatch.

Effect of supplemented intake of omega-3 fatty acids on arrhythmias in patients with ICD: fish oil therapy may reduce ventricular arrhythmia.

PURPOSE: The aim of this study was to evaluate the effects of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on ventricular tachyarrhythmic episodes (VTEs) in implantable cardioverter defibrillator (ICD) recipients with ischemic cardiomyopathy. METHODS: One hundred five ICD recipients with ischemic cardiomyopathy received 3.6 g of EPA and DHA and placebo for 6 months, each at a random order, with a 4-month washout period between treatments. Eighty-seven patients completed the 16-month study protocol. The primary end point was any VTE (including sustained and non-sustained ventricular tachycardias at a rate of >150 bpm) as recorded by the ICDs. Secondary end points included device therapy (anti-tachycardia pacing (ATP) or shocks). RESULTS: During treatment with fish oils, there was a significant increase in EPA and DHA concentrations in red blood cells (RBCs) and subcutaneous fat tissue. Among 87 patients who completed the study protocol, the mean number of VTEs was significantly lower during treatment with fish oil (1.7) vs. placebo (5.6; p = 0.035). Appropriate device therapy for VTE occurred in 18 (21%) patients. Fish oil therapy was associated with a trend toward fewer VTEs terminated with ATP (2.8 ± 13.7 vs. 0.5 ± 2.1, respectively; p = 0.077). VTE terminated by ICD shocks, however, was rare, and rates were similar between both groups (0.11 ± 0.6 vs. 0.10 ± 0.4, p = not significant, respectively). CONCLUSIONS: Our data suggest that fish oil therapy may be associated with a reduction in the frequency of VTE in ICD recipients with ischemic cardiomyopathy.

Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models.

BACKGROUND: The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency. OBJECTIVES: The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model. METHODS: We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2D307H) or CASQ2 knockout (CASQ2Δ/Δ). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAVCASQ2) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7-8 weeks after gene therapy. RESULTS: CASQ2Δ/Δ mice injected intracardiacally with AAVCASQ2 expressed 40% ± 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2Δ/Δ mice (n = 10; P < .05). Intraperitoneal therapy led to a significantly elevated expression of the CASQ2 protein, which was comparable in CASQ2D307H (n = 12) and CASQ2Δ/Δ (n = 4) mice. All control mice with CPVT2 had nonsustained ventricular tachycardia (VT) and 8 of 13 had sustained VT on provocation. Expressing ≥33% of the normal CASQ2 level was needed to protect from nonsustained VT as well as stress-induced premature ventricular contractions. Lower levels of expression prevented sustained VT in AAVCASQ2-treated mice (0 of 26; P < .001 vs controls). CONCLUSION: AAVCASQ2 displays a long-lasting capacity to attenuate and potentially cure CPVT2. Systemic delivery is feasible and convenient, reproducibly providing adequate levels of transgene expression. Antiarrhythmic efficacy depends on the CASQ2 level: ≥33% of the normal CASQ2 level is needed to prevent arrhythmia. However, even lower levels of protein protect from sustained VT, thereby potentially reducing the risk of sudden death.

Tricuspid Regurgitation following Lead Extraction: Risk Factors and Clinical Course.

BACKGROUND: Transvenous lead extraction can lead to tricuspid valve damage. OBJECTIVES: To assess the incidence, risk factors and clinical outcome of tricuspid regurgitation (TR) following lead extraction. METHODS: We prospectively collected data on patients who underwent lead extraction at the Sheba Medical Center prior to laser use (i.e., before 2012). Echocardiography results before and following the procedure were used to confirm TR worsening, defined as an echocardiographic increase of at least one TR grade. Various clinical and echocardiographic parameters were analyzed as risk factors for TR. Clinical and echocardiographic follow-up was conducted to assess the clinical significance outcome of extraction-induced TR. RESULTS: Of 152 patients who underwent lead extraction without laser before 2012, 86 (56%) (192 electrodes) had echocardiography results before and within one week following the procedure. New or worsening TR was discovered in 13 patients (15%). Use of mechanical tools and younger age at extraction were found on multivariate analysis to be factors for TR development (P = 0.04 and P = 0.03 respectively). Average follow-up was 22.25 ± 21.34 months (range 8-93). There were no significant differences in the incidence of right-sided heart failure (50% vs. 23%, P = 0.192) or hospitalizations due to heart failure exacerbations (37.5% vs. 11%, P = 0.110). No patient required tricuspid valve repair or replacement. Death rates were similar in the TR and non-TR groups (20% vs. 33%). CONCLUSIONS: TR following lead extraction is not uncommon but does not seem to affect survival or outcomes such as need for valve surgery. Its long-term effects remain to be determined.

Morphological features of the P-waves at surface electrocardiogram as surrogate to mechanical function of the left atrium following a successful modified maze procedure.

AIMS: Absent left atrium (LA) mechanical contraction may occur following the modified Cox-maze operation, and was found to impose a potential risk for the occurrence of thrombo-embolic stroke. It is unknown whether certain morphological P-wave characteristics can surrogate absent LA mechanical activity. The aim of this study was to evaluate the morphological features of the P-waves on the surface electrocardiogram (ECG) of patients who underwent the maze operation and to relate them to the contractile profile of the LA. METHODS AND RESULTS: Electrocardiogram tracings of 150 consecutive patients that were in sustained sinus rhythm following the maze operation were evaluated. P-waves were scrutinized for morphology, duration, axis, and amplitude. Clinical, surgery-related, and echocardiographic data were collected and analysed. Forty-seven patients (31%) had no evidence of LA contraction at 3 months after surgery (baseline assessment) and on follow-up echocardiography. Multivariate analysis showed that a positive-only P-wave deflection at lead V1 (P = 0.03), a negative-only deflection at aVL, and a P-wave amplitude of ≤ 0.05 mV at the septal-anterior leads (P < 0.001 for both) were associated with absent LA mechanical contraction. In a secondary analysis, a risk score involving the above three parameters was developed for the prediction of stroke occurrence. Patients at the high-risk score group had a 30% survival freedom of stroke compared with 70% for patients at intermediate risk (P < 0.001). CONCLUSION: Absent LA mechanical contraction following the modified maze operation may be accompanied by a distinguished pattern of the P-waves on the surface ECG.

Left atrial contractile function following a successful modified Maze procedure at surgery and the risk for subsequent thromboembolic stroke.

OBJECTIVES: The aim of this study was to evaluate whether certain post-Maze left atrial (LA) contractile profiles may pose a risk for ischemic stroke. BACKGROUND: The mechanical contraction of the left atrium may be modified after the Maze procedure. Whether this imposes a risk for stroke, even in the presence of sinus rhythm and after removal of the LA appendage, is not known. METHODS: Clinical, surgery-related, and echocardiographic data from 150 patients who underwent radiofrequency and cryoablation Maze procedures without the use of atrial incisions between 2004 and 2009 and were in sustained sinus rhythm were collected and analyzed. The occurrence of stroke was evaluated by reviewing clinical records. All stroke events were adjudicated by a neurologist. RESULTS: At a mean follow-up time of 24.5 months, 15 patients (10%) had experienced ischemic strokes. Forty-seven patients (31%) had no evidence of LA mechanical contraction at 3 months after surgery (baseline assessment) and on follow-up echocardiography. Multivariate analysis showed that a lack of LA mechanical contraction at baseline was associated with a 5-fold increase in the risk for stroke (p = 0.02) during follow-up. Larger atria imposed a significant risk as well; LA volume index ≥33 ml/m(2) was associated with a 3-fold risk increase (p = 0.03). These effects were maintained regardless of the lack of mechanical valve implantation and anticoagulation treatment. CONCLUSIONS: Absence of LA contraction and LA volume index ≥33 ml/m(2) result in a significant increase in the risk for thromboembolic stroke after the Maze procedure for patients in sinus rhythm.

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value. OBJECTIVE: This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers. METHODS: The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2. RESULTS: Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes. CONCLUSION: M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2.

BACKGROUND: Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population. METHODS AND RESULTS: We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38; P=0.005) and the postmenopausal period (hazard ratio, 8.10; P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19; P=0.05; P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause. CONCLUSIONS: The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.

LQT5 masquerading as LQT2: a dominant negative effect of KCNE1-D85N rare polymorphism on KCNH2 current.

AIMS: KCNE1 encodes an auxiliary subunit of cardiac potassium channels. Loss-of-function variations in this gene have been associated with the LQT5 form of the long QT syndrome (LQTS), secondary to reduction of I(Ks) current. We present a case in which a D85N rare polymorphism in KCNE1 is associated with an LQT2 phenotype. METHODS AND RESULTS: An 11-year old competitive athlete presented with mild bradycardia and a QTc interval of 470 ms. An LQT2 phenotype, consisting of low-voltage bifid T waves, was evident in the right precordial electrocardiogram leads. During the tachycardia phase following adenosine, QTc increased to 620 ms. Genetic analysis revealed a rare heterozygous polymorphism in KCNE1 predicting the substitution of asparagine for aspartic acid at position 85 of minK (D85N). Patch clamp experiments showed that KCNE1-D85N, when co-expressed with KCNH2 in TSA201 cells, significantly reduced I(Kr). Homozygous co-expression of the mutant with KCNH2 reduced I(Kr) tail current by 85%, whereas heterozygous co-expression reduced the current by 52%, demonstrating for the first time a dominant-negative effect of D85N to reduce I(Kr). Co-expression of the mutant with KCNQ1, either homozygously or heterozygously, produced no change in I(Ks). CONCLUSIONS: Our results suggest that a rare polymorphism KCNE1-D85N underlies the development of an LQT2 phenotype in this young athlete by interacting with KCNH2 to cause a dominant-negative effect to reduce I(Kr). Our data provide further evidence in support of the promiscuity of potassium channel ß subunits in modulating the function of multiple potassium channels leading to a diversity of clinical phenotypes.

Time dependence of life-threatening ventricular tachyarrhythmias after coronary revascularization in MADIT-CRT.

BACKGROUND: Coronary revascularization (CR) may confer electrical stability in patients with ischemic cardiomyopathy. However, data regarding the effect of CR on the development of ventricular tachyarrhythmias in this population are limited. OBJECTIVE: The purpose of this study was to evaluate the association between CR and arrhythmic risk in postmyocardial infarction (post-MI) patients with left ventricular dysfunction. METHODS: The risk for life-threatening ventricular tachyarrhythmias (defined as a first appropriate defibrillator therapy for ventricular tachycardia [VT]/ventricular fibrillation [VF] or death) was compared between post-MI patients with and those without prior CR (n = 612 and 147, respectively) enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). RESULTS: The 3-year cumulative rate of VT/VF or death was significantly higher among patients without prior CR (42%) than in patients who underwent prior CR (32%, P = .02). Multivariate analysis demonstrated that patients without prior CR had 48% increased risk (P = .01) for VT/VF or death. Risk reduction associated with CR was related to elapsed time from CR, assessed both as a categorical variable (tertiles for time from CR: ≥7 years, hazard ratio [HR] = 1.93, P = .001; 1.5-7 years, HR = 1.70, P = .01 vs <1.5 years) and as a continuous measure (4%, P = .002, increased risk for VT/VF or death per 1-year increment of elapsed time from CR). The effect of CR on arrhythmic risk was similar in patients treated with a defibrillator alone or when combined with cardiac resynchronization therapy. CONCLUSION: Post-MI patients with left ventricular dysfunction who undergo CR experience a time-dependent reduction in the risk for subsequent life-threatening ventricular tachyarrhythmias.

Exercise training alters the molecular response to myocardial infarction.

PURPOSE: We and others have shown that swimming exercise training performed before irreversible coronary occlusion improves the outcome of the heart injury and alters gene expression at the remodeling phase. The purpose of the current study was to identify temporal changes in the molecular response to myocardial infraction of prior exercise trained rats during the acute, the subacute, and the chronic phases postinfarction. METHODS: Rats underwent a 7-wk swimming or sedentary protocol and were subjected to surgical induction of acute myocardial infarction (MI). Hearts were removed before and at 4 h, 2 d, and 4 wk after surgery. RNA extracted from the surviving myocardium of the MI hearts or from corresponding tissues in the non-MI hearts was subjected to multitranscript profiling. Results for representative transcripts were validated by reverse transcription and quantitative polymerase chain reaction amplification. RESULTS: Global analysis of the 3686 detected transcripts generated a two-branch dendrogram that distinguished the pre-MI and the 4-h groups from the 2-d and the 4-wk groups and indicated that early after MI, the impact of infarction on the genes expressed overrides the training effect, whereas at 4 wk, the exercised hearts differ markedly from the nonexercised. Clustering the 1500 genes that showed the highest variance over time indicated differential expression of transcription regulators and proapoptotic genes 4 h and 2 d after MI and of stress-related and profibrotic genes 4 wk later in the exercised compared with sedentary hearts. CONCLUSION: Swimming exercise training conducted before acute MI reprograms the surviving myocardium for altered molecular response to MI that explains, in part, the protected cardiac phenotype of the exercised animals.

Qual a contribuição do tilt training (treinamento postural) na prevenção da síncope vasovagal ? / Tilt training: does it have a role in preventing vasovagal syncope? / ¿Cuál es el aporte del tilt training (entrenamiento postural) a la prevención del síncope vasovagal?

Histórico: A síncope vasovagal é um dos quadros clínicos mais comuns em adultos jovens. Estudos anteriores demonstram a eficácia do tilt training (treinamento postural) no tratamento desse transtorno clínico. Realizou-se um estudo prospectivo e randomizado com o objetivo de avaliar a contribuição do tilt training no tratamento de adultos jovens acometidos pela síncope vasovagal. Métodos: Quarenta e seis soldados , 25 dos quais do sexo masculino, média de idade de 19,4 mais ou menos 0,8 anos e diagnóstico clínico de síncope vasovagal pelo tilt teste, foram divididos aleatoriamente em dois grupos: um grupo controle e outro acometido de tilt training diariamente, por três meses. Nos dois grupos, os participantes foram instruídos a aumentar a ingestão de líquidos e sal e evitar situações indutoras de síncope, tais como permanecer em pé por períodos longos. Resultados: A adesão ao programa de treinamento, caracterizada pela realização de 50 por cento ou mais das sessões diárias de tilt training, foi de 91 por cento durante o primeiro mês, caindo para 58 por cento nos três meses. Os que realizaram o treinamento apresentaram uma média (distância interquartilica) e 5,0 episódios de síncope (0,5 a 16,0) durante um ano de acompanhamento, enquanto o grupo controle apresentou média de 2,0 episódios (0 a 6,0, P igual 0,737). Após a randomização não houve diferença significativa no tempo de ocorrência do primeiro episódio entre os dois grupos: média de 1,0 por mês (0,5 a 2,0) no grupo em tratamento...

Background: Vasovagal syncope is one of the most common medical conditions in young adults. Previous trials have shown effectiveness of tilt training in treating this condition. We conducted a prospective, randomized study in order to evaluate the role of tilt-training in young adults with vasovagal syncope. Methods: Forty-six soldiers (mean age 19.4 ± 0.8 years, 25 males), with a clinical diagnosis of vasovagal syncope supported by positive tilt test, were randomized to either three months of daily tilt training (treatment group), or no training (control group). Patients in both groups were instructed to increase fluid and salt intake, and to refrain from syncope-inducing situations, such as prolonged standing. Results: Compliance, defined as performing 50% or more of the tilt training daily sessions, was 91% during the first month, and declined to 58% during three months. Treatment group patients had a median (interquartile range) of 5.0 (0.5–16.0) syncope episodes during one-year follow up, compared to a median of 2.0 (0–6.0) episodes in the control group (P = 0.737). Also, there was no difference in time to first syncope after randomization between groups: a median of 1.0 (0.5–2.0) month in the treatment group, compared to 0.8 (0.5–2.0) month in the control group (P = 0.336). Conclusions: Adding daily three-month tilt training to modifications in lifestyle does not improve treatment results in youngadults with vasovagal syncope. Good compliance is difficult to achieve in a tilt training program.

Historial: El síncope vasovagal es uno de los cuadros clínicos más comunes en adultos jóvenes. Estudios anteriores han demostrado la eficiencia del tilt training (entrenamiento postural) en el tratamiento de ese trastorno clínico. Se llevó a cabo un estudio prospectivo y randomizado con el objetivo de evaluar el aporte del tilt training al tratamiento de adultos jóvenes acometidos por el síncope vasovagal. Métodos: Cuarenta y seis soldados, 25 de ellos del sexo masculino, promedio de edad de 19,4 ± 0,8 años y diagnóstico clínico de síncope vasovagal por el tilt test, fueron divididos aleatoriamente en dos grupos: un grupo control y otro sometido a tilt training diariamente, por tres meses. En ambos grupos, los participantes fueron instruidos a aumentar la ingesta de líquidos y sal y evitar situaciones inductoras del síncope, tales como permanecer en pie por largos períodos. Resultados: La adhesión al programa de entrenamiento, caracterizada por la realización del 50% o más de las sesiones diarias de tilt training, fue del 91% durante el primer mes, bajando al 58% a los tres meses. Quienes llevaron a cabo el entrenamiento presentaron un promedio (distancia intercuartílica) de 5,0 episodios de síncope (0,5 a 16,0) durante un año de acompañamiento, mientras el grupo control presentó un promedio de 2,0 episodios (0 a 6,0; P = 0,737). Tras la randomización, no hubo diferencia significativa en el tiempo de ocurrencia del primer episodio de síncope entre ambos grupos: promedio de 1,0 por mes (0,5 a 2,0) en el grupo en tratamiento y 0,8 (0,5 a 2,0) en el grupo control (P = 0,336). Conclusiones: La realización diaria del tilt training, aliada a los cambios de estilo de vida, no produjo mejora en el resultado del tratamiento de adultos jóvenes con síncope vasovagal. Se verificó asimismo la dificultad de obtener buena adhesión al programa de entrenamiento postural.

Tilt training: does it have a role in preventing vasovagal syncope?

BACKGROUND: Vasovagal syncope is one of the most common medical conditions in young adults. Previous trials have shown effectiveness of tilt training in treating this condition. We conducted a prospective, randomized study in order to evaluate the role of tilt-training in young adults with vasovagal syncope. METHODS: Forty-six soldiers (mean age 19.4 +/- 0.8 years, 25 males), with a clinical diagnosis of vasovagal syncope supported by positive tilt test, were randomized to either three months of daily tilt training (treatment group), or no training (control group). Patients in both groups were instructed to increase fluid and salt intake, and to refrain from syncope-inducing situations, such as prolonged standing. RESULTS: Compliance, defined as performing 50% or more of the tilt training daily sessions, was 91% during the first month, and declined to 58% during three months. Treatment group patients had a median (interquartile range) of 5.0 (0.5-16.0) syncope episodes during one-year follow up, compared to a median of 2.0 (0-6.0) episodes in the control group (P = 0.737). Also, there was no difference in time to first syncope after randomization between groups: a median of 1.0 (0.5-2.0) month in the treatment group, compared to 0.8 (0.5-2.0) month in the control group (P = 0.336). CONCLUSIONS: Adding daily three-month tilt training to modifications in lifestyle does not improve treatment results in young adults with vasovagal syncope. Good compliance is difficult to achieve in a tilt training program.

Prior exercise training improves the outcome of acute myocardial infarction in the rat. Heart structure, function, and gene expression.

OBJECTIVES: The aim of this research was to investigate the structural, functional, and molecular features of the remodeling heart in prior swim-trained infarcted rats. BACKGROUND: Physical exercise training is a known protective factor against cardiovascular morbidity and mortality. The structural and molecular aspects underlying this protection in the remodeling heart have not been investigated. METHODS: After seven weeks of swimming exercise training, rats underwent surgical ligation of the left coronary artery followed by a four-week sedentary period. Untrained control rats underwent the same surgical protocol. Left ventricular function was assessed by echocardiography four weeks after infarction, and hearts were sampled for histological and molecular analysis. Ribonucleic acid from the surviving left ventricle was analyzed by complementary deoxyribonucleic acid arrays followed by Northern blotting or quantitative reverse transcription polymerase chain reaction of selected messenger ribonucleic acids (mRNAs). RESULTS: Scar area was 1.6-fold smaller (p = 0.0002), arteriolar density was 1.7-fold higher (p = 0.0002), and left ventricular shortening fraction was 1.9-fold higher (p = 0.003) in the exercise-trained compared with sedentary hearts. Eleven genes whose expression level varied by at least +/-1.5-fold distinguished the prior exercised rats from their sedentary counterparts. Compared with sedentary, the exercised hearts displayed 9- and 2.4-times lower levels of atrial natriuretic peptide and aldolase mRNA (p = 0.03 and 0.04, respectively), and a 2.7- and 1.9-fold higher abundance of cytochrome c-oxidase and fatty acid binding protein, respectively (p < 0.03, each). CONCLUSIONS: Swimming exercise training before acute myocardial infarction reduces scar size, increases arteriole density, and manifests adaptation of stress- and energy-metabolism-related genes that may contribute to the improved heart function observed during remodeling.

Association of intentional changes in body weight with coronary heart disease event rates in overweight subjects who have an additional coronary risk factor.

Despite evidence that weight loss improves the severity of coronary heart disease (CHD) risk factors, a direct association between weight loss and CHD incidence has not been demonstrated. In 1994-2001, the authors conducted an observational study of intentional weight loss as related to CHD incidence among patients recruited from a network of clinics in Israel who received nutritional counseling from a dietitian to support the medical recommendation to lose weight. Subjects were outpatients aged 50-75 years with a body mass index of > or =27 kg/m(2), without CHD or cancer but with at least one risk factor for CHD in addition to overweight. Outcomes were documented over 4 years by repeated weight measurements and by medical record verification. Among 1,669 patients, 224 (13.4%) incidents of CHD were recorded. For subjects who underwent at least 6 months of dietetic counseling, the risk-factor-adjusted odds ratio for CHD incidence associated with a weight loss of 4.5 kg (the median level of weight loss) was 0.57 (95% confidence interval: 0.39, 0.84). In this, the largest known study of its type reported to date, intentional weight loss from a 6-month diet predicted lower incidence of CHD over 4 years.

Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.

INTRODUCTION: Evidence is inconclusive concerning the role of implantable cardioverter defibrillators (ICDs) to treat patients with hemodynamically stable ventricular tachycardia (VT). The goal of this study was to estimate future risk of unstable ventricular arrhythmias in patients who received ICDs for stable VT. METHODS AND RESULTS: We reviewed complete ICD follow-up data from 82 patients (age 66.1 +/- 11.3 years; left ventricular ejection fraction 32.3%+/- 11.2%; mean +/- SD) who received ICDs for stable VT. During the follow-up period of 23.6 +/- 21.5 months (mean +/- SD), 15 patients (18%) died, and 10 (12%) developed unstable ventricular arrhythmia, 8 of whom had the unstable arrhythmia as the first arrhythmia after ICD placement. Estimated 2- and 4-year survival in the whole group was 80% and 74%, respectively. Estimated 2- and 4-year probability of any VT and unstable VT was 67% and 77% and 11% and 25%, respectively. There were no differences in age, ejection fraction, sex, underlying heart disease, cycle length, symptoms, baseline electrophysiologic study results, or QRS characteristics of qualifying VT between patients who developed unstable ventricular arrhythmia and patients who did not. Twenty-nine patients (35%) had at least one inappropriate shock, and 11 (13%) underwent further surgery for ICD-related complications. CONCLUSION: Patients who present with hemodynamically stable VT are at risk for subsequent unstable VT. ICD treatment offers potential salvage of patients with stable VT who subsequently develop unstable VT/ventricular fibrillation, although complications and inappropriate shocks are considerable. No predictors could be found for high and low risk for unstable arrhythmias. These findings support ICD treatment for stable VT survivors.

Modulation of ventricular fibrillation in isolated perfused heart by dofetilide.

The authors studied the involvement of IKr potassium current in ventricular fibrillation during perfusion. Electrophysiologic parameters were measured before and after dofetilide administration (2.5, 7.5, and 12.5 x 10-7 M, n = 8) in isolated perfused feline hearts. During pacing, these parameters included epicardial conduction time, refractoriness, and the fastest rate for 1:1 pacing/response capture. During 8 minutes of electrically induced tachyarrhythmias, they included heart rate and normalized entropy reflecting the degree of organization. In all groups, arrhythmia rate was slower in the right ventricle than in the left ventricle. Dofetilide decreased the arrhythmia rate more than it increased organization, reduced its maintenance, or increased difficulty in initiation. Refractoriness was prolonged in a reverse use-dependent way which was less than 1:1 pacing/response capture. Unexpectedly, a moderate prolongation of conduction time was observed. Inverse correlation was found between the arrhythmia rate and changes in refractoriness and conduction time and between the degree of organization and refractoriness (both ventricles) and conduction time (right ventricle). Dofetilide, which intensively blocks IKr current and unexpectedly suppressed conduction, has different quantitative effects on fibrillation features. These changes in fibrillation suggest that these effects are mainly associated with refractoriness prolongation and do not seem to be attenuated by conduction suppression.

Incidence of dual AV node physiology following termination of AV nodal reentrant tachycardia by adenosine-5'-triphosphate: a comparison with drug administration in sinus rhythm.

Administration of adenosine triphosphate (ATP) in sinus rhythm identifies dual atrioventricular node physiology (DAVNP) in 75% of patients with inducible slow/fast AV nodal reentrant tachycardia (AVNRT). The incidence of DAVNP following termination of AVNRT with ATP is unknown. Incremental doses of ATP (10-60 mg) were administered, first in sinus rhythm and then during tachycardia induced at electrophysiologic study, to 84 patients with inducible AVNRT and to 18 control patients with inducible AV reentrant tachycardia (AVRT) and no electrophysiologic evidence of DAVNP. Study end-points were the occurrence of DAVNP or > or = 2nd degree AV block following administration of ATP in sinus rhythm and tachycardia termination following administration of ATP during tachycardia. Of the 82 patients with AVNRT who completed the study, 62 (75.6%) exhibited DAVNP following administration of 17.1 +/- 9.4 mg ATP in sinus rhythm, while 30 (36.5%) exhibited DAVNP at the termination of AVNRT following administration of 10.6 +/- 2.4 mg ATP. The occurrence of DAVNP following the administration of 10 mg ATP in sinus rhythm.was a good predictor (62%) of its occurrence after termination of AVNRT with ATP. The dose of ATP had a strong correlation between the presence of DAVNP following AVNRT termination and the ATP doses needed for tachycardia termination. Of the 18 control patients, none had DAVNP at ATP test during sinus rhythm but 1 (5.5%) showed slight (60 msec) PR jump after termination of AVRT with ATP. In conclusion, DAVNP is present in a relatively high proportion (36.5%) of patients following termination of AVNRT with ATP but is much less frequent (5.5%) in control patients. Thus, findings at termination of tachycardia by ATP may be useful in the noninvasive diagnosis of the mechanism of a paroxysmal supraventricular tachycardia.

Effect of basic fibroblast growth factor on left ventricular geometry in rats subjected to coronary occlusion and reperfusion.

BACKGROUND: Previous studies have demonstrated myocardial salvage by basic fibroblast growth factor administration following chronic myocardial ischemia or acute myocardial infarction. OBJECTIVES: To study the effect of bFGF on left ventricular morphometry following coronary occlusion and reperfusion episode in rats. METHODS: bFGF (0.5 mg) or placebo was continuously administered for a period of one week using an implanted osmotic pump. Animals were sacrificed 6 weeks after surgery and myocardial cross-sections were stained with Massontrichrome and with anti-proliferating cell nuclear antigen antibody. RESULTS: LV area, LV cavity diameter, LV cavity/wall thickness ratio, and injury size were unchanged compared with control animals. Proliferating endothelial cells were significantly more abundant in injured compared with normal myocardium, but with no differences between animals treated or not treated with bFGF. CONCLUSIONS: One week of systemic bFGF administration following coronary occlusion and reperfusion had no additional effect on LV geometry or cellular proliferation in rats.

Transcutaneous detection of aortic arch atheromas by suprasternal harmonic imaging.

OBJECTIVES: The goal of the present study was to examine whether suprasternal harmonic imaging (SHI) (i.e., harmonic imaging from the suprasternal windows) can visualize protruding arch atheromas (PAAs) and reliably predict the presence or absence of significant lesions. BACKGROUND: Protruding arch atheromas are a major source of cerebral and peripheral embolism and probably the most frequent cause of stroke during cardiac catheterization and open-heart surgery. Preprocedural screening by transesophageal echocardiography (TEE) would be desirable but is limited by the nature of the examination. METHODS: Of 354 patients who underwent a TEE study in our laboratory during the study period, 106 were referred for detection of a source of embolism. Findings were classified based on the French Aortic Plaque study criteria as: 1) no or minimal atherosclerotic changes; 2) PAAs < 4 mm; 3) PAAs > or =4 mm or presence of a mobile component. RESULTS: Adequate transcutaneous image quality could be achieved in 89 patients (84%). Protruding arch atheromas were present in 42 patients (47%) and absent in 47 (53%). Positive and negative predictive values for large PAAs on TEE were 91% and 98%, respectively. In one case, SHI detected a complex PAA inaccessible for TEE due to interposition of the left bronchus as demonstrated by dual helical computed tomography. Inter-observer agreement for SHI was 91%. CONCLUSIONS: Suprasternal harmonic imaging reliably predicted or excluded the presence of PAAs in a sizable, consecutive group of patients referred to TEE for detection of a source of embolism. It represents an excellent screening test and provides complimentary views of regions, which may be blind spots for TEE.