Blockade of CaMKII depresses conduction preferentially in the right ventricular outflow tract and promotes ischemic ventricular fibrillation in the rabbit heart.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates the principle ion channels mediating cardiac excitability and conduction, but how this regulation translates to the normal and ischemic heart remains unknown. Diverging results on CaMKII regulation of Na+ channels further prevent predicting how CaMKII activity regulates excitability and conduction in the intact heart. To address this deficiency, we tested the effects of the CaMKII blocker KN93 (1 and 2.75 µM) and its inactive analog KN92 (2.75 µM) on conduction and excitability in the left (LV) and right (RV) ventricles of rabbit hearts during normal perfusion and global ischemia. We used optical mapping to determine local conduction delays and the optical action potential (OAP) upstroke velocity (dV/dtmax). At baseline, local conduction delays were similar between RV and LV, whereas the OAP dV/dtmax was lower in RV than in LV. At 2.75 µM, KN93 heterogeneously slowed conduction and reduced dV/dtmax, with the largest effect in the RV outflow tract (RVOT). This effect was further exacerbated by ischemia, leading to recurrent conduction block in the RVOT and early ventricular fibrillation (at 6.7 ± 0.9 vs. 18.2 ± 0.8 min of ischemia in control, P < 0.0001). Neither KN92 nor 1 µM KN93 depressed OAP dV/dtmax or conduction. Rabbit cardiomyocytes isolated from RVOT exhibited a significantly lower dV/dtmax than those isolated from the LV. KN93 (2.75 µM) significantly reduced dV/dtmax in cells from both locations. This led to frequency-dependent intermittent activation failure occurring predominantly in RVOT cells. Thus CaMKII blockade exacerbates intrinsically lower excitability in the RVOT, which is proarrhythmic during ischemia.NEW & NOTEWORTHY We show that calcium/calmodulin-dependent protein kinase II (CaMKII) blockade exacerbates intrinsically lower excitability in the right ventricular outflow tract, which causes highly nonuniform chamber-specific slowing of conduction and facilitates ventricular fibrillation during ischemia. Constitutive CaMKII activity is necessary for uniform and safe ventricular conduction, and CaMKII block is potentially proarrhythmic.

Individual-based versus aggregate meta-analysis in multi-database studies of pregnancy outcomes: the Nordic example of selective serotonin reuptake inhibitors and venlafaxine in pregnancy.

PURPOSE: Compare analyses of a pooled data set on the individual level with aggregate meta-analysis in a multi-database study. METHODS: We reanalysed data on 2.3 million births in a Nordic register based cohort study. We compared estimated odds ratios (OR) for the effect of selective serotonin reuptake inhibitors (SSRI) and venlafaxine use in pregnancy on any cardiovascular birth defect and the rare outcome right ventricular outflow tract obstructions (RVOTO). Common covariates included maternal age, calendar year, birth order, maternal diabetes, and co-medication. Additional covariates were added in analyses with country-optimized adjustment. RESULTS: Country adjusted OR (95%CI) for any cardiovascular birth defect in the individual-based pooled analysis was 1.27 (1.17-1.39), 1.17 (1.07-1.27) adjusted for common covariates and 1.15 (1.05-1.26) adjusted for all covariates. In fixed effects meta-analyses pooled OR was 1.29 (1.19-1.41) based on crude country specific ORs, 1.19 (1.09-1.29) adjusted for common covariates, and 1.16 (1.06-1.27) for country-optimized adjustment. In a random effects model the adjusted OR was 1.07 (0.87-1.32). For RVOTO, OR was 1.48 (1.15-1.89) adjusted for all covariates in the pooled data set, and 1.53 (1.19-1.96) after country-optimized adjustment. Country-specific adjusted analyses at the substance level were not possible for RVOTO. CONCLUSION: Results of fixed effects meta-analysis and individual-based analyses of a pooled dataset were similar in this study on the association of SSRI/venlafaxine and cardiovascular birth defects. Country-optimized adjustment attenuated the estimates more than adjustment for common covariates only. When data are sparse pooled data on the individual level are needed for adjusted analyses. Copyright © 2016 John Wiley & Sons, Ltd.

Norepinephrine-associated left ventricular outflow tract obstruction and systolic anterior movement.

In the perioperative setting, norepinephrine is used to increase blood pressure, an effect mediated mostly via arterial and venous vasoconstriction. Thus, norepinephrine is, allegedly, less likely to cause or worsen left ventricular outflow tract obstruction (LVOTO) than other inotropes. We report a case of norepinephrine-associated dynamic LVOTO and systolic anterior movement in a predisposed patient. This report highlights that unrecognised dynamic LVOTO may worsen shock parameters in patients treated with norepinephrine who have underlying myocardial hypertrophy.

Cardiac chamber hypertrophy following hematopoietic stem cell transplantation for primary immunodeficiency.

Children with primary immune deficiency (PID) who receive hematopoietic stem cell transplantation (HSCT) often suffer from graft-versus-host disease (GVHD), which is commonly treated with corticosteroids (CS). CS may cause hypertension, development of cardiac chamber hypertrophy (CCH), and left ventricular outflow tract obstruction (LVOTO). We followed the development of CCH and LVOTO by serial echocardiograms in 10 children with PID before and 6 to 12 weeks after HSCT, and correlated their development with age of transplant, GVHD, use of CS and hypertension. CCH developed in all 4 children transplanted before 1 year of age who received high dose CS treatment for grade III or IV acute GVHD (aGVHD), but not in the 6 children who were transplanted at later ages or who had not received high-dose CS (P = .07). Significant correlation (P < .002) was found between CCH and blood pressure measurements that deviated above the 99th percentile. One child also suffered from severe LVOTO. CCH and LVOTO improved when CS treatment was discontinued and blood pressure normalized. We conclude that following HSCT, young children who suffer from aGVHD, treated with high CS doses, and have excessive hypertension are at risk of developing CCH.

[Myocardial bridging of the left anterior descending coronary artery and dobutamine-induced left ventricular outflow tract gradient -- a case report]. / Mostek miesniowy w obrebie galezi przedniej zstepujacej lewej tetnicy wiencowej oraz podwyzszony w czasie dobutaminowej próby obciazeniowej gradient podzastawkowy w drodze odplywu z lewej komory serca -- opis przypadku.

We present a case of a 47-year-old patient with arterial hypertension and progressive ST segment changes with a T wave inversion during 2 years of observation. Coronary angiography showed myocardial bridging of LAD and no significant coronary artery stenosis. During subsequent two last years the patient was repeatedly hospitalised due to chest pain. During the last hospitalisation a dobutamine stress testing was performed which provoked an increased left ventricular outflow tract gradient. This finding may be attributed to an early phase of hypertrophic cardiomyopathy, or dobutamine specific phenomenon.

Myocardial infarction induced by oral terazosin in a patient with predisposing structural cardiomyopathy: case report. / Infarto agudo de miocardio asociado al uso de terazosina oral en presencia de cardiopatía estructural predisponente: reporte de caso.

We describe a 71-year-old male patient who developed acute myocardial infarction (AMI) due to a dynamic left ventricular outflow tract obstruction induced by terazosin. After receiving terazosin, the patient had a syncope followed by angina. The electrocardiogram showed Q waves and ST segment elevation in the precordial and inferior leads. Coronary angiography evidenced a chronically occluded left anterior descending artery. Doppler-echocardiography revealed apical akinesia, hyperdynamic basal segments, systolic anterior motion of the mitral valve (SAM) and dynamic left ventricular outflow tract obstruction. Therapy with intravenous fluids and atenolol resulted in marked clinical improvement. Acute myocardial infarction resulted from low coronary perfusion pressure in a patient with a chronically diminished coronary reserve.

Describimos el caso de un hombre de 71 años de edad, que presentó un infarto agudo de miocardio debido a la obstrucción dinámica del tracto de salida del ventrículo izquierdo inducida por la terazosina. Luego de recibir dicha medicación el paciente presentó un síncope y posteriormente angina de pecho. El electrocardiograma evidenció ondas Q y sobreelevación del segmento ST en las derivaciones precordiales e inferiores. La angiografía coronaria evidenció una oclusión crónica de la arteria descendente anterior y el ecocardiograma Doppler reveló aquinesia apical, segmentos basales hiperdinámicos, movimiento anterior sistólico de la válvula mitraI y obstrucción dinámica del tracto de salida del ventrículo izquierdo. La administración intravenosa de suero fisiológico y atenolol determinó una clara mejoría clínica. Un infarto agudo de miocardio hemodinámico fue el resultado de la caída de la presión de perfusión coronaria en un paciente con disminución crónica de la reserva coronaria.

Catecholamine therapy inducing dynamic left ventricular outflow tract obstruction.

Hypertrophic obstructive cardiomyopathy with significant hypertrophy of the basal septum is the most frequently reported cause of left ventricular outflow tract (LVOT) obstruction. Additionally, other conditions such as dehydration, sepsis, vasodilatation, or mitral valve repair have been associated with LVOT obstruction. In this report, we present a case of a patient without hypertrophy who developed severe dynamic left ventricular outflow tract obstruction during catecholamine stimulation for shock that complicated severe pancreatitis. The present case serves as a reminder that hypovolemia together with a hyperdynamic state resulting from catecholamine administration may result in the development of dynamic LVOT obstruction even if baseline cardiac evaluation is unremarkable. Early detection and intensive efforts to reverse the underlying conditions, including cessation of catecholamine therapy and correction of hypovolemia are essential.

Relation between dynamic midventricular obstruction and unexplained chest pain in patients with normal echocardiograms at rest.

The relation between dynamic mid-ventricular obstruction provoked by dobutamine infusion and chest pain was investigated in 16 patients with normal echocardiograms at rest who had histories of unexplained chest pain. Chest pain was induced in 63% of dynamic mid-ventricular obstruction and beta blockers suppressed either dynamic mid-ventricular obstruction or Chest pain.

Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy.

Amyl nitrite may be used to provoke latent gradients in patients with hypertrophic cardiomyopathy (HC) without significant resting outflow tract gradients, but afterload reduction may not be comparable to a more physiologic stressor such as symptom-limited exercise testing. This study compared the ability of amyl nitrite and exercise testing to provoke outflow tract gradients in 57 patients (40 men and 17 women, mean age +/- SD 49 +/- 16 years) with HC (septal thickness 19 +/- 5 mm, average resting gradient 13 +/- 10 mm Hg) who underwent echocardiography at rest, after amyl nitrite inhalation, and after maximal exercise. No significant gradient (< 50 mm Hg) was induced after either provocation in 26 patients (46%); in 15 patients (26%), inducibility was achieved after both stressors, in 6 (11%) after exercise only, and in 10 (18%) after amyl only. Patients with amyl-induced gradients differed from those in whom gradients were noninducible on the basis of smaller outflow tract dimensions (p < 0.001), larger resting gradients (p < 0.001), and a greater prevalence of "septal bulge" morphology (p = 0.02). Those with exercise-induced gradients were able to attain a greater workload (p = 0.07), have larger resting gradients (p = 0.02), and also tended to have a septal bulge morphology (p < or = 0.01). Although outflow tract obstruction increased to similar levels after amyl nitrite (49 +/- 39 mm Hg) and symptom-limited exercise (47 +/- 39 mm Hg), gradients induced by exercise and amyl correlated poorly (r = 0.54).(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic predictors of an adverse response to a nifedipine trial in primary pulmonary hypertension: diminished left ventricular size and leftward ventricular septal bowing.

BACKGROUND: The clinical course in primary pulmonary hypertension (PPH) is improved by calcium channel blocker therapy in those with a favorable hemodynamic response during a trial of high-dose oral nifedipine. Although trials of nifedipine are performed only in patients who demonstrate pulmonary vasodilator reserve to short-acting agents, this response does not predict the safety of nifedipine treatment, which can result in severe first-dose hypotension and death. STUDY OBJECTIVES: To identify echocardiographic parameters that predict first-dose nifedipine-induced hypotension in patients with PPH. METHODS: The pretrial echocardiograms of 23 consecutive PPH patients (mean age, 42.3 +/- 13 years; 77% female) undergoing evaluation of pulmonary vasodilator reserve with nifedipine were analyzed. Patients were classified as those who suffered first-dose nifedipine hypotension (group 1) and those who did not (group 2). Echocardiographic measures of chamber size and septal geometry in the two groups were compared. RESULTS: Five measures reflecting diminished left ventricular (LV) size and leftward ventricular septal bowing were found to be associated with nifedipine hypotension: LV transverse diameter in systole (LVDs; p = 0.007), LV transverse diameter in diastole (LVDd; p = 0.05), LV area in systole (LVAs; p = 0.009), LV area in diastole (LVAd; p = 0.03), the ratio of RV to LVAs (p = 0. 02), and leftward ventricular septal bowing (p = 0.01). The LV dimensions found to best predict nifedipine-induced hypotension were LVDs < 2.7 cm, LVDd < 4.0 cm, LVAs < 15.5 cm(2), and LVAd < 20.0 cm(2). CONCLUSIONS: Readily available echocardiographic parameters in patients with PPH are predictive of nifedipine-induced hypotension, and can be used to select patients in whom a trial of nifedipine should be avoided.

The clinical impact of dynamic intraventricular obstruction during dobutamine stress echocardiography.

We selected 73 consecutive patients without myocardial-infarction, hypertrophic cardiomyopathy or hypertension complaining of effort chest discomfort/dyspnoea, and/or reporting exercise ischaemic ECG changes, and submitted them to simultaneous dobutamine stress echocardiography (DSE) and 99mTc tetrofosmin SPECT (T SPECT) and to coronary angiography to evaluate the clinical impact of intraventricular obstruction (IVO) during dobutamine infusion. Sixteen patients (22%, 7 males, mean age+/-SD 63+/-8 years, group 1) developed IVO (mean CW Doppler velocity+/-SD: 3.8+/-1.0 m/s) and 57 (41 males, mean age+/-SD 63+/-10 years, group 2) did not. The two groups had similar incidence of angina and ischaemic ECG changes at exercise tolerance test. DSE did not demonstrate wall motion abnormalities in any group 1 patient while T SPECT showed a perfusion defect in the only one with coronary artery disease (CAD). DSE reproduced symptoms in a higher percentage of patients with than without IVO, while there was no statistical difference in the reproduction of ischaemic ECG changes, despite CAD prevalence was much lower in group 1. Group 1 patients remained asymptomatic on beta-blockers at 12-month follow-up. Dobutamine-induced IVO, by reproducing symptoms, suggests that IVO plays a role in the clinical setting in patients without CAD complaining of unexplained reduced effort tolerance who should undergo DSE.

[Intraventricular transient obstruction related to bronchodilator treatment]. / Obstrucción intraventricular transitoria en relación con tratamiento broncodilatador.

A 66-year-old woman with a previous history of chronic lung disease, without evidence of heart disease and without signs of left ventricular hypertrophy developed a dynamic intraventricular obstruction documented by a Doppler-derived gradient of 25 mmHg and by physical signs consisting of a brisk carotid pulse and a harsh systolic murmur while she was on treatment with theophylline and hexoprenaline. Both physical signs and Doppler-derived gradient disappeared after withdrawal of bronchodilator drugs.

Hypertrophic intraventricular flow obstruction after very-low-dose dexamethasone (Minidex) in preterm infants: case presentation and review of the literature.

The use of dexamethasone in preterm infants developing bronchopulmonary dysplasia has been proven to be effective. Hypertrophic cardiomyopathy is a frequently reported, although transient, side effect of high-dose dexamethasone administration. The recent introduction of very low dexamethasone dose, called 'Minidex', promised equal effectiveness compared to high-dose dexamethasone without relevant side effects. Our study presents two patients developing hypertrophic cardiomyopathy with intraventricular cardiac obstruction after administration of 'Minidex'. Marked cardiac side effects may occur even during very-low-dose dexamethasone treatment in preterm neonates. Betablocker and discontinuation of dexamethasone seem to allow spontaneous reversal of myocardial hypertrophy and obstruction. After all, systematic surveys of the incidence of cardiac complications in a larger population of preterm infants treated with very low doses of dexamethasone are needed.

Prednisone induced two-way myocardial development in a patient with systemic lupus erythematosus.

We present a series of echocardiography images to demonstrate the myocardial response to a high dose of prednisone. A young woman with systemic lupus erythematosus (SLE) associated with interventricular septal hypertrophy exhibited a high pressure gradient between the ascending aorta and left ventricular outflow tract as well as significant systolic anterior motion (SAM) and mitral regurgitation (MR) during high-dose prednisone treatment. However, the pressure gradient decreased dramatically and the MR disappeared rapidly when the dose of prednisone was reduced. To the best of our knowledge, this is the only adult case of myocardial hypertrophy that is assumed to be related to prednisone use.

Lamotrigine-trigged obstructive hypertrophic cardiomyopathy, epilepsy and metabolic myopathy.

Lamotrigine has the advantage to have an antidepressive effect and to be well tolerated in the majority of the cases. Lamotrigine, however, may exert cardiac side effects in patients with hypertrophic cardiomyopathy and latent obstruction of the left ventricular outflow tract, as illustrated by the following case report. In a 67 year-old male with epilepsy, metabolic myopathy and malignant hyperthermia hypertrophic cardiomyopathy was diagnosed by echocardiography. By Doppler-echocardiography the maximal gradient in the left ventricular outflow tract was 57 mm Hg. Because or recurrent seizures, the lamotrigine dosage was increased from 100 mg/d to 200 mg and then to 300 mg/d. After the first intake of 300 mg lamotrigine, the patient felt weak, dizzy and complained about exertional dyspnoea and chest pain. Doppler-echocardiography showed now a maximal gradient of 106 mm Hg in the left ventricular outflow tract. After reducing the lamotrigine dosage to 100 mg/d and adding levetirazetam (1000 mg/d), the patient's condition improved immediately and the outflow-tract-gradient regressed to 12 mm Hg. Cardiac catheterization showed an outflow-tract-gradient of 25-36 mm Hg and normal coronary arteries. From this observation we conclude that care should be taken when prescribing lamotrigine to patients with obstructive hypertrophic cardiomyopathy.