Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome 1.

Hereditary long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on the surface ECG and a high risk for arrhythmia-related sudden death. Mutations in a cardiac voltage-gated potassium channel, KCNQ1, account for the most common form of LQTS, LQTS1. The objective of this study was the characterization of a novel KCNQ1 mutation linked to LQTS. Electrophysiological properties and clinical features were determined and compared to characteristics of a different mutation at the same position. Single-strand conformation polymorphism analysis followed by direct sequencing was performed to screen LQTS genes for mutations. A novel missense mutation in the KCNQ1 gene, KCNQ1 P320H, was identified in the index patient presenting with recurrent syncope and aborted sudden death triggered by physical stress and swimming. Electrophysiological analyses of KCNQ1 P320H and the previously reported KCNQ1 P320A mutation indicate that both channels are non-functional and suppress wild type I(Ks) in a dominant-negative fashion. Based on homology modeling of the KCNQ1 channel pore region, we speculate that the proline residue at position 320 limits flexibility of the outer pore and is required to maintain the functional architecture of the selectivity filter/pore helix arrangement. Our observations on the KCNQ1 P320H mutation are consistent with previous studies indicating that pore mutations in potassium channel alpha-subunits are associated with more severe electrophysiological and clinical phenotypes than mutations in other regions of these proteins. This study emphasizes the significance of mutation screening for diagnosis, risk-assessment, and mutation-site specific management in LQTS patients.

Identification and genotype related classification of children with long QT-syndrome using 24 h Holter recordings.

The long QT syndrome (LQTS) belongs to the family of hereditary diseases and can cause life-threatening arrhythmias and leads to sudden cardiac death. Mutations on six genes are responsible for changes in the electrophysiological properties of myocardial cells that are involved in the repolarization phase. In the surface ecg this is expressed by a prolonged QT interval and genotypespecific shapes for the T-Wave. The aim of the study was to find parameters that quantify properties of the repolarization phase which can be used in addition to the established Schwartz score in the process of diagnosing LQTS. Furthermore, ecg features were evaluated for the separation of the LQT subtypes LQT1, LQT2 and LQT3. The combination of the features PtA50 and QTc yielded with 93% sensitivity and 100% specificity the best results in the field of patient identification. Despite the small dataset consisting of 14 patients that was available for the second aim, the achieved results for the morphology indices motivate further research in this field.

Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome.

OBJECTIVE: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family. METHODS: Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique. RESULTS: A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1). CONCLUSION: This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.

Long-term results after reconstruction of the left ventricular outflow tract by aortoventriculoplasty.

BACKGROUND: Aortoventriculoplasty is an established method of reconstruction of complex left ventricular outflow tract (LVOT) obstruction by insertion of a mechanical valve prosthesis after patch enlargement of the LVOT. Little data exist with respect to long-term outcome. METHODS: Between March 1991 and June 2001, 24 patients with a median age of 10.7 (range, 2.1 to 66) years underwent aortoventriculoplasty, which was performed as a primary procedure in 4 and as a secondary intervention in 20 patients. On follow-up, all patients were restudied with an actual prospective evaluation. Data were statistically analyzed using a paired t test. RESULTS: There was one early death from low cardiac output. Four patients had to be reoperated on for bleeding. All 23 postoperative survivors were followed up for 63 (range, 12 to 123) months. Aortic anulus size of 14 (7 to 19) mm could be significantly enlarged to a size of 24 (19 to 27) mm for insertion of a mechanical valve prosthesis (p < 0.001). Blood flow velocity across the LVOT significantly decreased to 1.8 (1.3 to 2.9) m/s (preoperative, 4.1 [2.7 to 5.8] m/s) (p < 0.001). There were no late deaths. One patient underwent late repair of a paraprosthetic leak. On follow-up, there was no hemorrhage related to anticoagulation observed, but there was one minor thromboembolic complication. Relief of LVOT obstruction and good function of the valve prostheses could be demonstrated in all patients. CONCLUSIONS: Aortoventriculoplasty is an easily applicable, low-risk procedure for the effective relief of complex LVOT obstruction, and provides excellent long-term results.

Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.

AIMS: Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2). METHODS AND RESULTS: The novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes were excluded. To investigate the pathophysiological implications of the mutation, we generated transgenic mice expressing human wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut cTNT). Animals were characterized by echocardiography, histology, and gene expression analysis. Mut cTNT mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Remarkably, left ventricular non-compaction was not observed. CONCLUSION: Familial co-segregation and the cardiomyopathy phenotype of mut cTNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a non-compaction phenotype is not required for the development of cardiomyopathy in this specific TNNT2 mutation leading to LVNC.

Replacement of valved right ventricular to pulmonary artery conduits: an observational study with focus on right ventricular geometry.

OBJECTIVE: Timing of the operation for exchange of right ventricular (RV) to pulmonary artery (PA) conduits is a matter of considerable debate. We aimed to study the course of right ventricular dimension in patients undergoing conduit exchange. PATIENTS AND METHODS: We retrospectively studied all patients who underwent implantation and or replacement of RV/PA conduits during the time period between 1990 and 2005. Clinical and echocardiographic data were recorded as obtained at follow-up visits. RESULTS: A total of 229 (144 boys and 85 girls) underwent surgery for implantation and or replacement of RV/PA conduits during the study period. Patients were assigned to three age groups including 37 infants, 125 children aged 1-10 years and 67 patients more than 10 years of age. 185 pulmonary (81%) and 44 aortic homografts (19%) were implanted. Fifty-eight of these 185 patients (25%) required exchange of conduits after a median time of 6.4 (8 months-12 years) (median (range)). The follow-up was 7.55 (0.1-17) years. The survival of the patients after homograft change was 98%. Freedom from failure for aortic and pulmonary homografts at an interval of 10 years for all patients was 38.5% for aortic and 56.2% for pulmonary homografts (P = 0.018; Mann-Whitney). Age at conduit exchange (coefficient: -4.917; P < 0.001) and right ventricular end-diastolic dimension (RVDD) before conduit exchange (coefficient: 8.255; P < 0.001) were related to RVDD as measured by M-mode echocardiography at follow-up ("best subset" regression analysis; R squared = 0.746). RVDD decreased in 48/58 patients, remained unchanged in 8/58 and increased in 2/59 patients at follow-up. An increased RVDD was positively correlated to the duration of artificial ventilation after the operation for conduit exchange (R = 0.56; P < 0.001). CONCLUSIONS: Reoperation for exchange of degenerated conduits should be performed early to prevent the development of irreversible structural myocardial changes and persistence of right ventricular dilatation.

Endothelin-1 and asymmetric dimethylarginine in children with left-to-right shunt after intracardiac repair.

BACKGROUND: Endothelin-1 (ET-1) is an endogenous vasoconstrictive peptide hormone and asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase. We hypothesized that both could contribute to pulmonary hypertension in patients with left-to-right shunt after intracardiac repair. PATIENTS AND METHODS: We prospectively analyzed ET-1 and ADMA plasma levels in 31 patients (m = 16; f = 15) at an age of 0.6 [0.2-27] years (median [range]) with left-to-right shunt (ASD II: n = 12; VSD: n = 11; AVSD: n = 8) presenting with a Qp/Qs of 2.7 [1.4-6.3] and a pulmonary arterial mean pressure (PAP) of 23 [13-57] mmHg. Blood specimens were taken prior to cardiopulmonary bypass (CPB), after weaning from CPB and at 3, 6, 12 and 24 h after CPB. RESULTS: 12/31 patients were found to have pulmonary hypertension prior to intracardiac repair and 11/12 patients showed persistent pulmonary hypertension during the first 24 h after CPB. Patients with pulmonary hypertension at 12 h after CPB showed significant higher plasma ET-1 compared with patients with normal PAP (1.4 [0-7.9] versus 0.5 [0-2.5] pg/ml; P = 0.048 (Mann-Whitney)). Plasma ADMA decreased from 1.3 [0.75-2.3] micromol/l before CPB to 0.7 [0.4-2.1] micromol/l at 12 h (P < 0.05). However patients with pulmonary hypertension did not show different ADMA plasma levels. CONCLUSIONS: Increased plasma ET-1 but not inhibition of nitric oxide synthase by ADMA is associated with pulmonary hypertension after intracardiac repair.

Diastolic biventricular impairment at long-term follow-up after atrial switch operation for complete transposition of the great arteries: an exercise tissue Doppler echocardiography study.

OBJECTIVE: The aim of this study was to investigate regional myocardial function after atrial switch operation for transposition of the great arteries (TGA) using tissue Doppler echocardiography with strain rate (SR) imaging. METHODS: In all, 24 patients with TGA aged 12 to 33 years and 10 control subjects underwent tissue Doppler echocardiography/SR imaging at rest and during bicycle exercise at 1 and 2 W/kg. Longitudinal function was quantified by strain, SR, and peak velocities measured in the free wall of the systemic ventricle, in septum and in the lateral wall of the subpulmonary ventricle. RESULTS: In patients with TGA, both ventricles showed reduced peak systolic SR values at rest. The increase in peak early diastolic velocity with exercise was reduced in the systemic ventricle (-47 +/- 23 mm/s at rest to -73 +/- 35 mm/s at 2 W/kg, P < .05) and absent in the subpulmonary ventricle (-78 +/- 38 mm/s at rest to -75 +/- 19 mm/s at 2 W/kg) of patients with TGA. CONCLUSION: Exercise tissue Doppler echocardiography/SR imaging identified severely reduced relaxation reserve of both ventricles as typical feature of myocardial dysfunction after atrial repair for TGA.

An exercise tissue Doppler and strain rate imaging study of diastolic myocardial dysfunction after Kawasaki syndrome in childhood.

OBJECTIVE: Myocardial dysfunction due to coronary arterial lesions is an important complication after Kawasaki syndrome in childhood. Tissue Doppler echocardiography, and strain rate imaging, have shown their value in detecting regional myocardial dysfunction in coronary arterial disease. We aimed to examine the diagnostic value of these methods in patients with coronary arterial lesions after Kawasaki syndrome. METHODS: We assessed regional myocardial function in 17 asymptomatic patients with coronary arterial lesions. Follow-up coronary angiographies were available in all cases. Tissue Doppler echocardiography, and strain rate imaging, were performed at rest and during bicycle exercise. Examination included peak systolic and diastolic velocities, peak systolic strain and strain rate. We enrolled 17 age- and gender-matched persons to serve as a control group. RESULTS: Segmental left ventricular longitudinal function did not significantly differ between the groups with respect to peak systolic velocity, strain, and strain rate. Diastolic abnormalities were identified in segments supplied by coronary arteries with stenotic lesions. Peak diastolic velocity decreased significantly during exercise in those areas, from 77 plus or minus 34 to 59 plus or minus 56 millimetres per second, p smaller than 0.05. Under exercise, a peak diastolic velocity value under 90 millimetres per second enabled us to identify coronary arterial stenosis with a sensitivity of 75 percent and specificity of 64 percent. CONCLUSIONS: After Kawasaki syndrome, diastolic impairment develops in segments supplied by stenotic coronary arteries before systolic dysfunction is detectable. Exercise tissue Doppler echocardiography has the potential to detect these subtle abnormalities, and help monitor progression of the disease.

Exercise tissue Doppler echocardiography with strain rate imaging in healthy young individuals: feasibility, normal values and reproducibility.

PURPOSE OF THE STUDY: The study was done to determine the clinical feasibility and reproducibility of tissue Doppler echocardiography (TDE) with strain rate imaging (SRI) at rest and under physical exercise in healthy young individuals and to report normal values for parameters of regional myocardial function under exercise. METHODS: Forty-five young volunteers (age 9-29 years) underwent echocardiography with TDE/SRI at rest and during a bicycle exercise test (2 W/kg body weight). RESULTS: Velocities could be obtained in 93% of segments, whereas strain rate was measurable at least in 80% of segments. Inter- and intraobserver variability for measurement of velocities under exercise was 14% and 9%, respectively for strain rate 28% and 20%. Except for peak strain, values for all other parameters were higher during exercise with the clearest response in the left lateral and the right ventricular wall. CONCLUSIONS: (1) Tissue Doppler with strain rate imaging is a practical and robust method for assessment of regional function of both ventricles under exercise. (2) Systolic motion, local myocardial relaxation and contractility increased significantly under physical exercise. These normal values obtained from healthy young subjects can serve as a reference database for further clinical studies.

Anomalous connection of the right superior caval vein to the morphologically left atrium.

Anomalous drainage of the right superior caval vein into the morphologically left atrium as an isolated cardiac malformation is a rare anomaly. Most patients present with cyanosis. Thus far, about 20 cases have been reported in the literature. We report a case of cyanosis due to this malformation in a male neonate, which was complicated by the meconium aspiration syndrome. The malformation was diagnosed by echocardiography and cardiac catheterization. Surgery resulted in complete recovery.

Magnetic resonance blood flow measurements in the follow-up of pediatric patients with aortic coarctation - a re-evaluation.

BACKGROUND: Previous studies have suggested the feasibility of a non-invasive quantification of vascular trans-stenotic pressure gradients (DeltaP) by phase-contrast MR imaging (PC-MRI). Our purpose was to assess the value of MRI estimated pressure gradients as a screening tool for assessing hemodynamically significant (re-)coarctation of the aorta (CoA) in pediatric patients. METHODS: Forty-three patients (median age (range), 16 (5-25) years) with CoA (38 postoperative and 5 native) and clinically suspected hemodynamically significant stenosis underwent quantitative and semi-quantitative PC-MRI blood flow measurements and 3D MR-angiography, Doppler ultrasound (US) and conventional catheter angiography (CCA, n=20). Estimated DeltaP for each modality was correlated with percent stenosis. RESULTS: The percent stenosis correlated only moderately with DeltaP(MRI) (r=0.55, p<0.001) and DeltaP(CCA) (r=0.48, p<0.001). Only moderate correlations were observed between DeltaP(MRI) vs. DeltaP(CCA) (r=0.54, p=0.02) and vs. DeltaP(US) (r=0.40, p=0.01). In contrast, semi-quantitative analysis of PC-MRI flow profiles predicted with good sensitivity (88%) and specificity (88%) who would be operated on. Thirteen patients met hemodynamic and percent stenosis criteria by CCA for surgical intervention. CONCLUSION: Measured pressure gradients using PC-MRI should be used cautiously when assessing patients for recoarctation of the aorta. The analysis of blood flow profiles by PC-MRI might be a promising alternative in assessing the hemodynamic significance of CoA.

Late results after extended pulmonary artery reconstruction in the arterial switch operation.

BACKGROUND: Pulmonary artery stenosis remains the most frequent late complication and cause of reintervention after the arterial switch operation for transposition of the great arteries. We investigated the influence of an extended pericardial patch augmentation of the neopulmonary root and pulmonary artery on late pulmonary artery stenosis development. METHODS: Augmentation of the neopulmonary root and pulmonary artery was achieved by reconstructing the posterior wall using a large glutaraldehyde-treated autologous pericardial patch. Reviewed were regular follow-up echocardiograms from 58 out of 87 patients undergoing the arterial switch operation who presented a follow-up period of at least 5 years. An actual follow-up echocardiographic evaluation focusing on the maximal instantaneous transpulmonary continuous-wave (cw)-Doppler gradient was performed, followed by cardiac catheterization when indicated (peak cw-Doppler gradient > 40 mm Hg). RESULTS: Follow-up was 8.9 [5 to 15] years. There was no reintervention due to residual pulmonary artery stenosis. Actual Doppler examination revealed a transpulmonary peak gradient of 19.5 [0 to 56] mm Hg, compared with 20 [0 to 60] mm Hg at discharge. Forty-three patients (74.1%) had no or only trivial pulmonary artery stenosis (pressure gradient < 25 mm Hg), 14 patients (24.2%) had mild stenosis (25 to 49 mm Hg), and 1 patient (1.7%) had moderate stenosis (50 to 79 mm Hg). CONCLUSIONS: Compared with the majority of literature data, we could demonstrate a low incidence of late pulmonary artery stenosis after the arterial switch operation by employing an extended pericardial patch reconstruction technique with augmentation of the neopulmonary root and pulmonary artery.

Skipping of Exon 1 in the KCNQ1 gene causes Jervell and Lange-Nielsen syndrome.

The Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive form of the long QT syndrome linked with a profound hearing loss caused by mutations affecting both alleles of either the KCNQ1 or the KCNE1 gene. We carried out a mutant screening of the KCNQ1 and KCNE1 genes in a clinical diagnosed German family with JLNS. Family members were examined by single strand conformation polymorphism analysis and PCR and amplified products were characterized by DNA sequence analysis. We identified a splice donor mutation of exon 1 in the KCNQ1 gene (G477+1A). Analysis of lymphocyte RNA by RT-PCR revealed that two symptomatic patients, homozygous for the mutant allele, exclusively produce KCNQ1 transcripts lacking exon 1 leading to a frameshift that introduced a premature termination codon at exon 4. Mutant subunits, functionally characterized in Xenpous oocytes, were unable to form homomeric channels but strongly reduced IKs (slowly activating delayed rectifier potassium current) in vitro (mutant isoforms 1 and 2 by 62 and 86%, respectively), a fact supposed to lead to severely affected heterozygous individuals. However, individuals heterozygous for the mutant allele exhibit an asymptomatic cardiac phenotype. Thus, the observed dominant-negative effect of mutant subunits in vitro is absent in vivo leaving heterozygous individuals unaffected. These data suggest mechanisms that prevent production of truncated KCNQ1 channel subunits in cardiomyocytes of individuals heterozygous for the mutant allele.

Transesophageal electrocardiography and atrial pacing in children.

The technique and spectrum of clinical application of transesophageal electrocardiography and atrial pacing in children is demonstrated in this article. Special emphasis is laid on the usefulness of the method in newborns and infants for the management of supraventricular tachycardia.

Termination of atrial reentrant tachycardias by using transesophageal atrial pacing.

Atrial reentrant tachycardia (ART) is not an uncommon complication in patients after surgery for congenital heart defects, particularly after extensive atrial procedures with sutures lines or baffeling maneuvers. Primary atrial flutter is a rare dysrhythmia in newborns. Two issues of ART or atrial flutter can be addressed by the esophageal approach: First, ART (often with 2:1 A-V conduction) may be difficult to detect on the surface ECG as the P waves usually do not show the typical flutter morphology or are hidden in the T wave. Recordings over the esophageal lead clearly determine the underlying rhythm. Second, termination of ART by pacing the atria can easily be performed by using an esophageal electrode. We performed 62 conversions of ART in 39 pts. (median age 12.5 years), among them 7 newborns with typical atrial flutter. The pacing algorithm started with 4 extrastimuli and pacing intervals 20 msec shorter than the atrial cycle length of tachycardia. Conversion was achieved in 50/62 (81%) cases; in 12 of 62 (19%) cases conversion was performed externally as the transesophageal approach was insufficient to restore sinus rhythm. Intravenous infusion of amiodarone prior to atrial pacing seems to be helpful in some patients for termination of ART. We recommend transesophageal atrial pacing as a first step of acute management of atrial flutter and other forms of ART in neonates, infants, and children because it is a minimal invasive procedure with high success rates.

Successful closure of the arterial duct in the setting of rubella syndrome.

A 9-year-old boy, with significant left-to-right shunting across a large duct in the context of rubella syndrome, was tested during catheterization to establish the feasability of occluding the duct with a device. The testing, including temporary closure of the duct and monitoring of pulmonary vascular reactivity to vasodilative substances, lead to the decision to implant an Amplatzer occluder. Sixteen months later, there was no residual shunting across the duct, and pulmonary arterial pressures had normalised. It remains unclear why the patient had not developed irreversible pulmonary vascular disease.

Repolarization analysis in children with the long QT syndrome.

QT duration changes were analysed in 26 children with long QT syndrome (median age 9 years). With 12-lead Holter recordings, we found that macroscopically QT adaptation to heart rate changes was slow and only 3 of 26 patients showed abrupt changes in QT interval duration. These changes in the time domain were always accompanied by changes of STT morphology in the 3 of 26 patients. Application of Bazett's heart rate correction algorithm was inappropriate to show true QT changes in this young patient group due to temporary typical large cycle length variations, where moreover an overcorrection of the heart rate impact resulted in reflection of RR interval changes rather than true QT duration changes.

Sympathovagal imbalance in pediatric patients with neurocardiogenic syncope during asymptomatic time periods.

UNLABELLED: The pathophysiology of neurocardiogenic syncope (NCS) is only poorly understood. Several studies indicate that NCS is associated with an imbalance of the autonomic nervous system (ANS). We hypothesized that pediatric patients with NCS exhibit alterations of the neurovegetative status also during asymptomatic time periods. To test this hypothesis the non-invasive method of Heart Rate Variability (HRV)-Analysis was used. METHOD: Holter records (12 channel, 180 Hz; obtained during an asymptomatic 24-hour period) of 32 patients (18 male, 14 female, mean age 14.6 yrs) with a history of syncope and a positive Head-Up tilt (HUT) were compared to the recordings of 33 healthy control subjects (19 male, 14 female, mean age 13.5 yrs) with negative history of syncope and HUT. Time domain and frequency domain features were calculated. Analysis segments were divided in different signal duration groups (1, 3, 6, 24 hours). RESULTS: For all time scales the standard deviation of wavelet coefficients yields the best discrimination properties. Analysis of the total time duration (24h) shows only moderate discrimination (sensitivity 84%, specificity 45%) between patient and controls. However, analysis of 3 and 6 hour segments (starting and 6 a.m.) showed significant discrimination: sigma wave scale 13 (6-9 a.m.) sensitivity 78%, specificity 71%., sigma wave scale 11 (6-12 a.m.) sensitivity 84%, specificity 61%. The best combination of two parameters is denoted by SDNN and sigma wave scale 11 (6-12 a.m.) with sensitivity 70%, specificity 75%. CONCLUSION: The results indicate that during an asymptomatic 24-hour-period patients with NCS exhibit an imbalance of the ANS especially in the morning (6-12 a.m.). The findings suggest a time-dependent increased sympathetic or reduced vagal activity in pediatric patients with NCS. Patients could benefit from a time-adjusted medical therapy with beta-blocking agents.