LV Systolic Deformation in Hypertensive Patients
The study patients were identified through the cardiac care outpatient clinic of Chang Gung Memorial Hospital, Keeling, a tertiary referral hospital. We retrospectively studied the clinical outcomes of consecutive patients with a new diagnosis of hypertension and ApHCM between August 2011 and September 2012. Data were abstracted on demographic characteristics, coronary risk factors, symptoms, and findings on physical examination at the time of presentation, and diagnosis of ApHCM, as well as the most recent follow-up visit. The control group consisted of age-matched asymptomatic patients who had hypertension, but no ApHCM. The study was approved by the Research Ethics Review Board of Chang Gung Memorial Hospital (101–2038B).
The echocardiographic inclusion criteria for ApHCM were the following: 1) asymmetric left ventricular hypertrophy confined primarily to the left ventricular apex below the papillary muscle level; 2) apical wall thickness ≥ 15 mm; 3) a ratio of maximal apical to posterior wall thickness ≥ 1.5. Patients were excluded if they had one of following: 1) a severe valvular lesion; 2) sustained atrial or ventricular arrhythmias; 3) prior percutaneous intervention; 4) prior cardiac surgery; 5) prior myocardial infarction; 6) pericardial disease; 7) immunological disease; 8) active infection; 9) moderate to severe anemia or 10) hyper- or hypothyroidism.
Current smoking status was defined as having smoked at least half of a pack of cigarettes per year and having smoked at least one cigarette within 3 weeks before enrollment. Diabetes mellitus was defined as a fasting glucose level ≥ 126 mg/dL or use of hypoglycemic medication. Hypercholesterolemia was defined as a low-density lipoprotein level ≥ 130 mg/dL in a fasting blood sample or use of a statin medication. Hypertension was defined as use of antihypertensive medications or a blood pressure > 140/90 mmHg. Ischemic heart disease was confirmed by 1) coronary angiography, with ≥ 50% diameter stenosis in one or more coronary vessels after administration of intracoronary nitroglycerin or 2) a thallium myocardial perfusion scan showing reversible/irreversible perfusion defects. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study 4-variable equation.
Electrocardiograms were analyzed for the presence of left ventricular hypertrophy according to the Sokolow-Lyon criteria. The corrected QT interval was measured in lead V2. 'Giant' T wave negativity was defined as a negative T wave voltage ≥ 1 mV (≥ 10 mm) in any of the leads.
All echocardiograms were performed by two experienced physicians (M-J and N-I) who used a commercially available system (Vivid E9, General Electric-Vingmed, Milwaukee, Wisconsin). Images were obtained with patients in the left lateral decubitus position at end-expiration. All standard measurements were obtained in the parasternal long- and short-axis views; apical 4-chamber, 2-chamber, and long-axis views. Two-dimensional and color Doppler imaging were performed to screen for wall motion abnormalities, mitral annulus calcification, and valvular stenosis or regurgitation. For pulsed-tissue Doppler studies, a 2-mm sampling volume was used from the apical 4-chamber view in the septal mitral annulus. The maximal apical wall thickness was obtained as the average of the measurements in the apical 4-chamber and 2-chamber views at end-diastole. Left ventricular ejection fraction and stroke volume were obtained by quantitative 2-dimensional ultrasonography as previously described. Transmitral pulsed-wave Doppler and tissue Doppler were recorded in the apical 4-chamber view. Pulsed-wave Doppler velocities of the pulmonary venous flow were obtained in the right upper pulmonary vein. Tissue Doppler imaging of the septal mitral annulus was used to measure mitral annular velocities in peak systole (Sm) and in early (Em) and late diastole (Am). Diastolic function was categorized as: normal, impaired relaxation, pseudonormalized filling, and restrictive filling. The time interval from the end to the onset of the mitral annular velocity pattern during diastole (am) and the duration of the S-wave (bm) were measured and used to calculate the myocardial performance index as (am-bm)/bm. The isovolumic relaxation time (IVRT) was calculated as the time interval between Sm and Em, and the isovolumic contraction time was calculated as the time interval between Am and Sm.
Two-dimensional strain analysis was performed offline using Echopac software, version 110.1.2 (General Electric-Vingmed) by two independent observers who were unaware of the patients' conditions. All strain images were obtained at a frame rate of 60–90 frames/s. For each of the three short-axis views, the sampling points were placed manually along the endocardium at the left ventricular base, middle, and apex during end-systole. For each of the 2-, 3- and 4-chamber views, three sampling points were placed manually at the septal mitral annulus, lateral corner, and apical endocardium. A region of interest was then generated by the software covering the myocardial thickness along the entire left ventricular wall. The region of interest was adjusted manually to ensure that the inner margin conformed to the entire left ventricular endocardial border and that it included the entire thickness of the left ventricular myocardium. The software subsequently identified the tissue speckles and tracked their movement frame-by-frame throughout the cardiac cycle.
The left ventricular wall was divided into six segments arranged circumferentially at the basal, middle, and apical levels. The software algorithm then calculated longitudinal, circumferential, and radial strains for each segment in graphical form, with automated measurements recorded in tabular form. Peak systolic longitudinal, circumferential, and radial strains for each segment were recorded: the values for all the myocardial segments for each patient were averaged to obtain the global values. End-systole was defined by the time of aortic valve closure and end-diastole was defined by the time of mitral valve closure by Doppler ultrasonography from the apical 4-chamber view.
Inter- and intra-observer variability were assessed by two experienced physicians evaluating the raw data of five patients with hypertension and five patients with hypertension and ApHCM in a blinded manner at baseline and at 1 week later. They were instructed to measure strain parameters independently from each other.
The sample size calculation was based on the differences in the mean between the two groups with equal sample size, pre-specified 5% type I error, and 90% power (Z1-β = 1.00). We performed a sample size calculation using Power Analysis Statistical Software (PASS 6.0, license 13451701; NCSS Inc., Kaysville, Utah). A sample size of 12 subjects in the control and ApHCM groups would achieve 90% power to detect a difference of 20% strain between the null hypothesis that both group differences in the means are 0.00 and the alternative hypothesis that the differences in means between the two groups is 20% strain, with a 2-sided test and a significance level of 0.05.
Continuous variables with skewed distributions and p values of < 0.05 by Kolmogorov-Smirnov testing were presented as medians (25th, 75th percentiles), and those not skewed were expressed as means ± standard deviations. For normally distributed continuous variables, a two-sample unpaired t-test was performed. For variables with skewed distributions, the Wilcoxon rank sum test and Fisher's exact test were used. Receiver-operating characteristic curves were constructed, and areas under curve were calculated. Sensitivities and specificities were determined for the ability to identify ApHCM. Reproducibilities (both interobserver and intra-observer variability) of speckle-tracked echocardiographic parameters were tested using the Bland-Altman statistic. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software version 15.0 for Windows (Chicago, Illinois).
Methods
Study Population
The study patients were identified through the cardiac care outpatient clinic of Chang Gung Memorial Hospital, Keeling, a tertiary referral hospital. We retrospectively studied the clinical outcomes of consecutive patients with a new diagnosis of hypertension and ApHCM between August 2011 and September 2012. Data were abstracted on demographic characteristics, coronary risk factors, symptoms, and findings on physical examination at the time of presentation, and diagnosis of ApHCM, as well as the most recent follow-up visit. The control group consisted of age-matched asymptomatic patients who had hypertension, but no ApHCM. The study was approved by the Research Ethics Review Board of Chang Gung Memorial Hospital (101–2038B).
Diagnostic Criteria
The echocardiographic inclusion criteria for ApHCM were the following: 1) asymmetric left ventricular hypertrophy confined primarily to the left ventricular apex below the papillary muscle level; 2) apical wall thickness ≥ 15 mm; 3) a ratio of maximal apical to posterior wall thickness ≥ 1.5. Patients were excluded if they had one of following: 1) a severe valvular lesion; 2) sustained atrial or ventricular arrhythmias; 3) prior percutaneous intervention; 4) prior cardiac surgery; 5) prior myocardial infarction; 6) pericardial disease; 7) immunological disease; 8) active infection; 9) moderate to severe anemia or 10) hyper- or hypothyroidism.
Clinical Data
Current smoking status was defined as having smoked at least half of a pack of cigarettes per year and having smoked at least one cigarette within 3 weeks before enrollment. Diabetes mellitus was defined as a fasting glucose level ≥ 126 mg/dL or use of hypoglycemic medication. Hypercholesterolemia was defined as a low-density lipoprotein level ≥ 130 mg/dL in a fasting blood sample or use of a statin medication. Hypertension was defined as use of antihypertensive medications or a blood pressure > 140/90 mmHg. Ischemic heart disease was confirmed by 1) coronary angiography, with ≥ 50% diameter stenosis in one or more coronary vessels after administration of intracoronary nitroglycerin or 2) a thallium myocardial perfusion scan showing reversible/irreversible perfusion defects. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study 4-variable equation.
Electrocardiography
Electrocardiograms were analyzed for the presence of left ventricular hypertrophy according to the Sokolow-Lyon criteria. The corrected QT interval was measured in lead V2. 'Giant' T wave negativity was defined as a negative T wave voltage ≥ 1 mV (≥ 10 mm) in any of the leads.
Standard Echocardiography
All echocardiograms were performed by two experienced physicians (M-J and N-I) who used a commercially available system (Vivid E9, General Electric-Vingmed, Milwaukee, Wisconsin). Images were obtained with patients in the left lateral decubitus position at end-expiration. All standard measurements were obtained in the parasternal long- and short-axis views; apical 4-chamber, 2-chamber, and long-axis views. Two-dimensional and color Doppler imaging were performed to screen for wall motion abnormalities, mitral annulus calcification, and valvular stenosis or regurgitation. For pulsed-tissue Doppler studies, a 2-mm sampling volume was used from the apical 4-chamber view in the septal mitral annulus. The maximal apical wall thickness was obtained as the average of the measurements in the apical 4-chamber and 2-chamber views at end-diastole. Left ventricular ejection fraction and stroke volume were obtained by quantitative 2-dimensional ultrasonography as previously described. Transmitral pulsed-wave Doppler and tissue Doppler were recorded in the apical 4-chamber view. Pulsed-wave Doppler velocities of the pulmonary venous flow were obtained in the right upper pulmonary vein. Tissue Doppler imaging of the septal mitral annulus was used to measure mitral annular velocities in peak systole (Sm) and in early (Em) and late diastole (Am). Diastolic function was categorized as: normal, impaired relaxation, pseudonormalized filling, and restrictive filling. The time interval from the end to the onset of the mitral annular velocity pattern during diastole (am) and the duration of the S-wave (bm) were measured and used to calculate the myocardial performance index as (am-bm)/bm. The isovolumic relaxation time (IVRT) was calculated as the time interval between Sm and Em, and the isovolumic contraction time was calculated as the time interval between Am and Sm.
Two-dimensional Speckle-tracking Echocardiography
Two-dimensional strain analysis was performed offline using Echopac software, version 110.1.2 (General Electric-Vingmed) by two independent observers who were unaware of the patients' conditions. All strain images were obtained at a frame rate of 60–90 frames/s. For each of the three short-axis views, the sampling points were placed manually along the endocardium at the left ventricular base, middle, and apex during end-systole. For each of the 2-, 3- and 4-chamber views, three sampling points were placed manually at the septal mitral annulus, lateral corner, and apical endocardium. A region of interest was then generated by the software covering the myocardial thickness along the entire left ventricular wall. The region of interest was adjusted manually to ensure that the inner margin conformed to the entire left ventricular endocardial border and that it included the entire thickness of the left ventricular myocardium. The software subsequently identified the tissue speckles and tracked their movement frame-by-frame throughout the cardiac cycle.
The left ventricular wall was divided into six segments arranged circumferentially at the basal, middle, and apical levels. The software algorithm then calculated longitudinal, circumferential, and radial strains for each segment in graphical form, with automated measurements recorded in tabular form. Peak systolic longitudinal, circumferential, and radial strains for each segment were recorded: the values for all the myocardial segments for each patient were averaged to obtain the global values. End-systole was defined by the time of aortic valve closure and end-diastole was defined by the time of mitral valve closure by Doppler ultrasonography from the apical 4-chamber view.
Reproducibility
Inter- and intra-observer variability were assessed by two experienced physicians evaluating the raw data of five patients with hypertension and five patients with hypertension and ApHCM in a blinded manner at baseline and at 1 week later. They were instructed to measure strain parameters independently from each other.
Statistical Analyses
The sample size calculation was based on the differences in the mean between the two groups with equal sample size, pre-specified 5% type I error, and 90% power (Z1-β = 1.00). We performed a sample size calculation using Power Analysis Statistical Software (PASS 6.0, license 13451701; NCSS Inc., Kaysville, Utah). A sample size of 12 subjects in the control and ApHCM groups would achieve 90% power to detect a difference of 20% strain between the null hypothesis that both group differences in the means are 0.00 and the alternative hypothesis that the differences in means between the two groups is 20% strain, with a 2-sided test and a significance level of 0.05.
Continuous variables with skewed distributions and p values of < 0.05 by Kolmogorov-Smirnov testing were presented as medians (25th, 75th percentiles), and those not skewed were expressed as means ± standard deviations. For normally distributed continuous variables, a two-sample unpaired t-test was performed. For variables with skewed distributions, the Wilcoxon rank sum test and Fisher's exact test were used. Receiver-operating characteristic curves were constructed, and areas under curve were calculated. Sensitivities and specificities were determined for the ability to identify ApHCM. Reproducibilities (both interobserver and intra-observer variability) of speckle-tracked echocardiographic parameters were tested using the Bland-Altman statistic. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software version 15.0 for Windows (Chicago, Illinois).
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