LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice.

OBJECTIVE: Mutations in the cardiac sodium channel gene SCN5A cause long QT syndrome (LQTS). We previously generated an LQTS mouse model (TG-NS) that overexpresses the LQTS mutation N1325S in SCN5A. The TG-NS mice manifested the clinical features of LQTS including spontaneous VT, syncope and sudden death. However, the long-term prognosis of LQTS on the structure of the heart has not been investigated in this or any other LQTS models and human patients. METHODS AND RESULTS: Impaired systolic function and reduced left ventricular fractional shortening were detected by echocardiography, morphological and histological examination in two lines of adult mutant transgenic mice. Histological and TUNEL analyses of heart sections revealed fibrosis lesions and increased apoptosis in an age-dependent manner. Cardiomyocyte apoptosis was associated with the increased activation of caspases 3 and 9 in TG-NS hearts. Western blot analysis showed a significantly increased expression of the key Ca(2+) handling proteins L-type Ca(2+) channel, RYR2 and NCX in TG-NS hearts. Increased apoptosis and an altered expression of Ca(2+) handling proteins could be detected as early as 3months of age when echocardiography showed little or no alterations in TG-NS mice. CONCLUSIONS: Our findings revealed for the first time that the LQTS mutation N1325S in SCN5A causes cardiac fibrosis and contractile dysfunction in mice, possibly through cellular mechanisms involving aberrant cardiomyocyte apoptosis. Therefore, we provide the experimental evidence supporting the notion that some LQTS patients have an increased risk of structural and functional cardiac damage in a prolonged disease course.

Comprehensive left atrial appendage optimization of thrombus using surface echocardiography: the CLOTS multicenter pilot trial.

BACKGROUND: The aim of this study was to determine the ability to identify thrombus within the left atrial appendage (LAA) in the setting of atrial fibrillation (AF) using transthoracic echocardiography (TTE). In AF, the structure and function of the LAA has historically been evaluated using transesophageal echocardiography (TEE). The role of TTE remains undefined. METHODS: The Comprehensive Left Atrial Appendage Optimization of Thrombus (CLOTS) multicenter study enrolled 118 patients (85 men; mean age, 67 +/- 13 years) with AF of >2 days in duration undergoing clinically indicated TEE. On TEE, the LAA was evaluated for mild spontaneous echo contrast (SEC), severe SEC, sludge, or thrombus. Doppler Tissue imaging (DTI) peak S-wave and E-wave velocities of the LAA walls (anterior, posterior, and apical) were acquired on TTE. Transthoracic echocardiographic harmonic imaging (with and without intravenous contrast) was examined to determine its ability to identify LAA SEC, sludge, or thrombus. RESULTS: Among the 118 patients, TEE identified 6 (5%) with LAA sludge and 2 (2%) with LAA thrombi. Both LAA thrombi were identified on TTE using harmonic imaging with contrast. Anterior, posterior, and apical LAA wall DTI velocities on TTE varied significantly among the 3 groups examined (no SEC, mild SEC, severe SEC, sludge or thrombus). An apical E velocity < or = 9.7 cm/s on TTE best identified the group of patients with severe SEC, sludge, or thrombus. An anterior S velocity < or = 5.2 cm/s on TTE best identified the group of patients with sludge or thrombus. CONCLUSIONS: The CLOTS multicenter pilot trial determined that TTE is useful in the detection of thrombus using harmonic imaging combined with intravenous contrast (Optison; GE Healthcare, Milwaukee, WI). Additionally, LAA wall DTI velocities on TTE are useful in determining the severity of LAA SEC and detecting sludge or thrombus.

Contrast-enhanced tissue Doppler imaging of the left atrial appendage is a new quantitative measure of spontaneous echocardiographic contrast in atrial fibrillation.

AIMS: Although left atrial appendage spontaneous echo contrast (LAASEC) is a marker of increased thromboembolic risk in atrial fibrillation, it has previously only been evaluated qualitatively. We sought to determine if an intravenous contrast echocardiographic agent combined with tissue Doppler imaging (TDI) of the LAA could accurately quantify LAA-SEC in patients with atrial fibrillation. METHODS AND RESULTS: We prospectively identified 55 patients with persistent atrial arrhythmias (mean age 63+/-13 years) undergoing a transesophageal echocardiography (TEE), with LAA-SEC prior to direct current cardioversion. In addition to off-line calculation of backscatter index and shear rate, quantification of the velocity in a color TDI region of interest was performed in the LAA cavity following a 0.5-mL intravenous bolus of Optison. LAA-SEC was qualitatively graded by a blindedreader as mild (n = 29) or severe (n = 26), and was compared off-line to TEE-derived quantitative variables. Compared to patients with mild LAA-SEC, those with severe LAA-SEC had significantly decreased LAA emptying velocity, LAA TDI mean velocities and shear rate. Over the whole group, the mean maximal velocity of the LAA using TDI correlated with LAA emptying velocity (r = 0.59; P < 0.0001), shear rate (r = 0.55; P < 0.0001) and LAA area (r = 0.34; P = 0.014). Severe LAA-SEC was found with 72% sensitivity and 82% specificity if TDI mean velocity was <6.13 cm/s. On logistic regression analysis, LAA-TDI was the only predictor of qualitative LAA-SEC grade. CONCLUSION: Contrast-enhanced TDI is an original new tool that provides a quantification of the mean velocity of LAA-SEC that might improve our decision making in patients with atrial fibrillation.

Alterations of regional myocardial function in a swine model of myocardial infarction assessed by echocardiographic 2-dimensional strain imaging.

BACKGROUND: Tissue Doppler strain and strain rate imaging have been introduced for quantitative assessment of regional myocardial function. These techniques are largely limited to the evaluation of overall longitudinal myocardial function. This study attempted to apply radial strain, circumferential strain, radial displacement, and strain-based torsion analysis to differentiating the infarct, adjacent, and remote zones in a swine model of myocardial infarction. METHODS: Seven pigs, body weight 24 to 26 kg, were subjected to myocardial infarction by occlusion of the left anterior descending coronary artery (LAD) and followed up for 8 weeks. Regional radial and circumferential deformations were quantified noninvasively by ultrasonic strain rate imaging before LAD occlusion, LAD occlusion immediately, and 4, 6, and 8 weeks after LAD occlusion. Strain-based left ventricular torsion was assessed at the same time points. RESULTS: Both radial and circumferential strains, and torsion, were decreased significantly in the LAD territory areas as a result of myocardial ischemia and infarction. There were no significant changes in radial and circumferential strains, or torsion, in the areas of adjacent and remote zones over time. CONCLUSIONS: These findings demonstrate that speckle-tracking strain imaging may be suitable for noninvasive quantification of left ventricular segmental function of ischemic heart disease.

Clinical features of mixed physiology of constriction and restriction: echocardiographic characteristics and clinical outcome.

AIMS: An entity of patients with mixed physiology of constriction and restriction has been reported, however, the characteristics of these patients have not been well documented. We evaluated the clinical features and the outcome of these patients. METHODS AND RESULTS: Study subjects consisted of 38 patients (57+/-14 years, 8 females, 30 males) who were diagnosed as having mixed physiology based on transthoracic and/or transesophageal echocardiography, MRI (or CT), cardiac catheterization, endomyocardial biopsy and/or surgical findings. Prior radiation therapy was the most frequent (50%) cause of mixed physiology followed by coronary artery bypass graft without prior radiation (24%) and heart transplantation (8%). The respiratory variation of peak early diastolic transmitral flow velocity by pulsed Doppler transesophageal echocardiography was 10.7% in patients with sinus rhythm and 18.1% in patients with atrial arrhythmia. Pericardial thickening was noted adjacent to the right-sided chambers in 19 patients, left-sided chambers in 10 patients, or both in 9 patients. All-cause 5-year mortality was 40% and unrelated to age, etiology, left ventricular systolic function and therapeutic course. There was a statistically significant difference (p<0.01) between the survival rates in patients with mixed physiology and in patients with pure constriction (n=125). CONCLUSIONS: Due to the high mortality in this disease, discrimination of the entity from the patients with pure constriction is mandatory. Transthoracic and transesophageal echocardiography are helpful noninvasive techniques in the diagnosis and the understanding of the physiology of patients with mixed constriction and restriction.

Relation of brachial artery reactivity to nitroglycerin and heart rate recovery following exercise in healthy male volunteers.

The parasympathetic nervous system facilitates peripheral arterial vasodilation and is also responsible for a decrease in heart rate immediately after exercise (heart rate recovery [HRR]). The relation among parasympathetic tone measured by HRR after exercise, endothelium-mediated vasodilation, and nitroglycerin-mediated vasodilation (determined with brachial artery ultrasound) was assessed in 25 healthy young men. One-minute HRR was nonsignificantly related to endothelium-mediated vasodilation (r = -0.35, p = 0.08) but was significantly related to nitroglycerin-mediated vasodilation (r = -0.63, p = 0.0008), a finding that persisted after adjustment for heart rate at rest, insulin resistance, lipid variables, and blood pressure. This suggests that parasympathetic tone may be inversely related to the responsiveness of arterial smooth muscle to nitrates in healthy humans.

Safety of stress testing in patients with hypertrophic cardiomyopathy.

Two hundred sixty-three consecutive patients with hypertrophic cardiomyopathy underwent stress testing. Major complications occurred in 0.04% of patients and minor events occurred in 23%.

Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions.

We observed the impact of percutaneous transluminal septal myocardial ablation (PTSMA) and myectomy on the conduction system in patients with obstructive hypertrophic cardiomyopathy (HC). Septal reduction intervention is capable of eliminating the left ventricular outflow tract obstruction in patients with obstructive HC; however, conduction system abnormalities are frequent consequences of these procedures. A standard 12-lead electrocardiogram and Doppler echocardiogram were obtained in 204 patients who underwent PTSMA (n = 70) or myectomy (n = 134) before and at average of 3 months after intervention. Of 146 patients who had normal conduction systems before intervention, the duration of the QRS complex was significantly prolonged from 98 +/- 15 to 130 +/- 25 ms (p <0.0001), with right bundle branch block (RBBB) developing in 62% patients after PTSMA, and from 100 +/- 13 to 154 +/- 20 ms (p <0.0001), with left bundle branch block (LBBB) developing in 93% patients after myectomy. No significant difference in the QRS duration was found in the remaining 58 patients who had preexisting conduction abnormalities after intervention. In 174 patients without a preexisting permanent pacemaker, a pacemaker was implanted in 22% versus 13% of patients who underwent PTSMA (overall and without preexisting conduction block, respectively) and 10% versus 2% of patients with myectomy. The duration of baseline QRS was an independent predictor for the requirement of a permanent pacemaker (p <0.0001). Thus, RBBB often develops after PTSMA and LBBB is very frequently produced by myectomy. A possible requirement of a permanent pacemaker should always be considered before intervention when patients have preexisting RBBB or LBBB.

Use of strain imaging in detecting segmental dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: The distribution and magnitude of left ventricular hypertrophy are not uniform in patients with hypertrophic cardiomyopathy (HCM). Previous echocardiographic studies have focused on global left ventricular function. Recently, myocardial Doppler strain (epsilon) imaging, a newly developed technique, has allowed the quantification of regional myocardial motion. The aim of this study was to characterize regional left ventricular systolic function by myocardial Doppler epsilon imaging in patients with HCM. METHODS: Included in this study were 31 patients with asymmetric septal hypertrophy and HCM, and 41 age-matched healthy patients. Regional longitudinal axial systolic epsilon was assessed at the basal, mid, and apical segments of the septal and lateral walls and compared between both groups. RESULTS: Patients with HCM had reduced epsilon at the ventricular septum (-10.3 +/- 5.7%) compared with control patients (-19.4 +/- 3.3%, P <.001). In the HCM group, epsilon in the midseptum (-1.3 +/- 8.2%) was significantly less than at the basal (-12.2 +/- 8.7%, P <.01) and apical septum (-17.3 +/- 10.4%, P <.01), and was also less than at the midlateral wall (-9.4 +/- 5.3%, P <.05). There was a significant correlation between midseptal epsilon and intraventricular septum to posterior wall thickness ratio (r = 0.81, P <.001). CONCLUSION: Midseptal longitudinal epsilon was markedly decreased, even reversed in patients with HCM (paradoxic longitudinal systolic expansion), which was directly related to the degree of septal hypertrophy. Myocardial Doppler epsilon imaging could offer a unique approach to quantify regional systolic dysfunction in these patients.

Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction.

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO(-/-)). MPO(-/-) demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO(-/-), leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO(-/-) and accelerated rupture in the PAI-1(-/-). These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.

Contrast and harmonic imaging improves accuracy and efficiency of novice readers for dobutamine stress echocardiography.

BACKGROUND: Newer contrast agents as well as tissue harmonic imaging enhance left ventricular (LV) endocardial border delineation, and therefore, improve LV wall-motion analysis. Interpretation of dobutamine stress echocardiography is observer-dependent and requires experience. This study was performed to evaluate whether these new imaging modalities would improve endocardial visualization and enhance accuracy and efficiency of the inexperienced reader interpreting dobutamine stress echocardiography. METHODS AND RESULTS: Twenty-nine consecutive patients with known or suspected coronary artery disease underwent dobutamine stress echocardiography. Both fundamental (2.5 MHZ) and harmonic (1.7 and 3.5 MHZ) mode images were obtained in four standard views at rest and at peak stress during a standard dobutamine infusion stress protocol. Following the noncontrast images, Optison was administered intravenously in bolus (0.5-3.0 ml), and fundamental and harmonic images were obtained. The dobutamine echocardiography studies were reviewed by one experienced and one inexperienced echocardiographer. LV segments were graded for image quality and function. Time for interpretation also was recorded. Contrast with harmonic imaging improved the diagnostic concordance of the novice reader to the expert reader by 7.1%, 7.5%, and 12.6% (P < 0.001) as compared with harmonic imaging, fundamental imaging, and fundamental imaging with contrast, respectively. For the novice reader, reading time was reduced by 47%, 55%, and 58% (P < 0.005) as compared with the time needed for fundamental, fundamental contrast, and harmonic modes, respectively. With harmonic imaging, the image quality score was 4.6% higher (P < 0.001) than for fundamental imaging. Image quality scores were not significantly different for noncontrast and contrast images. CONCLUSION: Harmonic imaging with contrast significantly improves the accuracy and efficiency of the novice dobutamine stress echocardiography reader. The use of harmonic imaging reduces the frequency of nondiagnostic wall segments.

Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility.

BACKGROUND: Myocardial fiber strain is directly related to left ventricular (LV) contractility. Strain rate can be estimated as the spatial derivative of velocities (dV/ds) obtained by tissue Doppler echocardiography (TDE). The purposes of the study were (1) to determine whether TDE-derived strain rate may be used as a noninvasive, quantitative index of contractility and (2) to compare the relative accuracy of systolic strain rate against TDE velocities alone. METHODS AND RESULTS: TDE color M-mode images of the interventricular septum were recorded from the apical 4-chamber view in 7 closed-chest anesthetized mongrel dogs during 5 different inotropic stages. Simultaneous LV volume and pressure were obtained with a combined conductance-high-fidelity pressure catheter. Peak elastance (Emax) was determined as the slope of end-systolic pressure-volume relationships during caval occlusion and was used as the gold standard of LV contractility. Peak systolic TDE myocardial velocities (Sm) and peak (epsilon'(p)) and mean (epsilon'(m)) strain rates obtained at the basal septum were compared against Emax by linear regression. Emax as well as TDE systolic indices increased during inotropic stimulation with dobutamine and decreased with the infusion of esmolol. A stronger association was found between Emax and epsilon'(p) (r=0.94, P<0.01, y=0.29x+0.46) and epsilon'(m) (r=0.88, P<0.01) than for Sm (r=0.75, P<0.01). CONCLUSIONS: TDE-derived epsilon'(p) and epsilon'(m) are strong noninvasive indices of LV contractility. These indices appear to be more reliable than S(m), perhaps by eliminating translational artifact.

Impact of left ventricular outflow tract area on systolic outflow velocity in hypertrophic cardiomyopathy: a real-time three-dimensional echocardiographic study.

OBJECTIVES: The aim of this study was to use real-time three-dimensional echocardiography (3DE) to investigate the quantitative relation between minimal left ventricular (LV) outflow tract area (A(LVOT)) and maximal LV outflow tract (LVOT) velocity in patients with hypertrophic obstructive cardiomyopathy (HCM). BACKGROUND: In patients with HCM, LVOT velocity should change inversely with minimal A(LVOT) unless LVOT obstruction reduces the pumping capacity of the ventricle. METHODS: A total of 25 patients with HCM with systolic anterior motion (SAM) of the mitral valve leaflets underwent real-time 3DE. The smallest A(LVOT) during systole was measured using anatomically oriented two-dimensional "C-planes" within the pyramidal 3DE volume. Maximal velocity across LVOT was evaluated by two-dimensional Doppler echocardiography (2DE). For comparison with 3DE A(LVOT), the SAM-septal distance was determined by 2DE. RESULTS: Real-time 3DE provided unique information about the dynamic SAM-septal relation during systole, with A(LVOT) ranging from 0.6 to 5.2 cm(2) (mean: 2.2 +/- 1.4 cm(2)). Maximal velocity (v) correlated inversely with A(LVOT) (v = 496 A(LVOT)(-0.80), r = -0.95, p < 0.001), but the exponent (-0.80) was significantly different from -1.0 (95% confidence interval: -0.67 to -0.92), indicating a significant impact of small A(LVOT) on the peak LVOT flow rate. By comparison, the best correlation between velocity and 2DE SAM-septal distance was significantly (p < 0.01) poorer at -0.83, indicating the superiority of 3DE for assessing A(LVOT). CONCLUSIONS: Three-dimensional echocardiography-measured A(LVOT) provides an assessment of HCM geometry that is superior to 2DE methods. These data indicate that the peak LVOT flow rate appears to be significantly decreased by reduced A(LVOT). Real-time 3DE is a potentially valuable clinical tool for assessing patients with HCM.