Aurelio Pinheiro

Diastolic Dysfunction in Familial Hypertrophic Cardiomyopathy Transgenic Model Mice

AIMS Several mutations in the ventricular myosin regulatory light chain (RLC) were identified to cause familial hypertrophic cardiomyopathy (FHC). Based on our previous cellular findings showing delayed calcium transients in electrically stimulated intact papillary muscle fibres from transgenic Tg-R58Q and Tg-N47K mice and, in addition, prolonged force transients in Tg-R58Q fibres, we hypothesized that the malignant FHC phenotype associated with the R58Q mutation is most likely related to diastolic dysfunction. METHODS AND RESULTS Cardiac morphology and in vivo haemodynamics by echocardiography as well as cardiac function in isolated perfused working hearts were assessed in transgenic (Tg) mutant mice. The ATPase-pCa relationship was determined in myofibrils isolated from Tg mouse hearts. In addition, the effect of both mutations on RLC phosphorylation was examined in rapidly frozen ventricular samples from Tg mice. Significantly, decreased cardiac function was observed in isolated perfused working hearts from both Tg-R58Q and Tg-N47K mice. However, echocardiographic examination showed significant alterations in diastolic transmitral velocities and deceleration time only in Tg-R58Q myocardium. Likewise, changes in Ca(2+) sensitivity, cooperativity, and an elevated level of ATPase activity at low [Ca(2+)] were only observed in myofibrils from Tg-R58Q mice. In addition, the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles. CONCLUSION Our results suggest that the N47K and R58Q mutations may act through similar mechanisms, leading to compensatory hypertrophy of the functionally compromised myocardium, but the malignant R58Q phenotype is most likely associated with more severe alterations in cardiac performance manifested as impaired relaxation and global diastolic dysfunction. At the molecular level, we suggest that by reducing the phosphorylation of RLC, the R58Q mutation decreases the kinetics of myosin cross-bridges, leading to an increased myofilament calcium sensitivity and to overall changes in intracellular Ca(2+) homeostasis.

Two-dimensional strain profiles in patients with physiological and pathological hypertrophy and preserved left ventricular systolic function: a comparative analyses.

Objective This study was designed to examine the utility of two-dimensional strain (2DS) or speckle tracking imaging to typify functional adaptations of the left ventricle in variant forms of left ventricular hypertrophy (LVH). Design Cross-sectional study. Setting Urban tertiary care academic medical centres. Participants A total of 129 subjects, 56 with hypertrophic cardiomyopathy (HCM), 34 with hypertensive left ventricular hypertrophy (H-LVH), 27 professional athletes with LVH (AT-LVH) and 12 healthy controls in sinus rhythm with preserved left ventricular systolic function. Methods Conventional echocardiographic and tissue Doppler examinations were performed in all study subjects. Bi-dimensional acquisitions were analysed to map longitudinal systolic strain (automated function imaging, AFI, GE Healthcare, Waukesha, Wisconsin, USA) from apical views. Results Subjects with HCM had significantly lower regional and average global peak longitudinal systolic strain (GLS-avg) compared with controls and other forms of LVH. Strain dispersion index, a measure of regional contractile heterogeneity, was higher in HCM compared with the rest of the groups. On receiver operator characteristics analysis, GLS-avg had excellent discriminatory ability to distinguish HCM from H-LVH area under curve (AUC) (0.893, p<0.001) or AT-LVH AUC (0.920, p<0.001). Tissue Doppler and LV morphological parameters were better suited to differentiate the athlete heart from HCM. Conclusions 2DS (AFI) allows rapid characterisation of regional and global systolic function and may have the potential to differentiate HCM from variant forms of LVH.

Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy

Background— Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy. Methods and Results— Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09±0.44 versus 1.78±0.34 cm; P=0.03). Stress myocardial blood flow (2.25±0.46 versus 1.78±0.43 mL/min per gram; P=0.01) and coronary flow reserve (2.78±0.32 versus 2.01±0.52; P<0.001) were significantly lower in DE-positive patients. Summed difference score (median, 5 versus 0; P<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (P<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities. Conclusions— We found a close relationship between DE by CMR and microvascular function in most of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in hypertrophic cardiomyopathy patients.

PET/CT Assessment of Symptomatic Individuals with Obstructive and Nonobstructive Hypertrophic Cardiomyopathy

Patients with obstructive hypertrophic cardiomyopathy (HCM) exhibit elevated left ventricular outflow tract gradients (LVOTGs) and appear to have a worse prognosis than those with nonobstructive HCM. The aim of this study was to evaluate whether patients with obstruction, compared with nonobstructive HCM, demonstrate significant differences in PET parameters of microvascular function. Methods: PET was performed in 33 symptomatic HCM patients at rest and during dipyridamole stress (peak) for the assessment of regional myocardial perfusion (rMP), left ventricular ejection fraction (LVEF), myocardial blood flow (MBF), and myocardial flow reserve (MFR). Myocardial wall thickness and LVOTG were measured with an echocardiogram. Patients were divided into the following 3 groups: nonobstructive (LVOTG < 30 mm Hg at rest and after provocation test with amyl nitrite), obstructive (LVOTG ≥ 30 mm Hg at rest and with provocation), and latent HCM (LVOTG < 30 at rest but ≥ 30 mm Hg with provocation). Results: Eleven patients were classified as nonobstructive (group 1), 12 as obstructive (group 2), and 10 as latent HCM (group 3). Except for age (42 ± 18 y for group 1, 58 ± 7 y for group 2, and 58 ± 12 y for group 3; P = 0.01), all 3 groups had similar baseline characteristics, including maximal wall thickness (2.3 ± 0.5 cm for group 1, 2.2 ± 0.4 cm for group 2, and 2.1 ± 0.7 cm for group 3; P = 0.7). During peak flow, most patients in groups 1 and 2, but fewer in group 3, exhibited rMP defects (73% for group 1, 100% for group 2, and 40% for group 3; P = 0.007) and a drop in LVEF (73% for group 1, 92% for group 2, and 50% for group 3; P = 0.09). Peak MBF (1.58 ± 0.49 mL/min/g for group 1, 1.72 ± 0.46 mL/min/g for group 2, and 1.97 ± 0.32 mL/min/g for group 3; P = 0.14) and MFR (1.62 ± 0.57 for group 1, 1.90 ± 0.31 for group 2, and 2.27 ± 0.51 for group 3; P = 0.01) were lower in the nonobstructive and higher in the latent HCM group. LVOTGs demonstrated no significant correlation with any flow dynamics. In a multivariate regression analysis, maximal wall thickness was the only significant predictor for reduced peak MBF (β = −0.45, P = 0.003) and MFR (β = −0.63, P = 0.0001). Conclusion: Maximal wall thickness was identified as the strongest predictor of impaired dipyridamole-induced hyperemia and flow reserve in our study, whereas outflow tract obstruction was not an independent determinant.

Comparison of Outcomes in Patients With Nonobstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy

Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.

Comparison and effectiveness of regadenoson versus dipyridamole on stress electrocardiographic changes during positron emission tomography evaluation of patients with hypertrophic cardiomyopathy

Dipyridamole is the most common vasodilator used with positron emission tomography for the evaluation of patients with hypertrophic cardiomyopathy (HC). The aim of this study was to evaluate whether positron emission tomographic quantification of regional myocardial perfusion (rMP), myocardial blood flow (MBF), and coronary flow reserve are comparable between dipyridamole and the newer vasodilator regadenoson in HC. An additional aim was to evaluate the association between vasodilator-induced ST-segment depression on electrocardiography and myocardial flow in HC. Nitrogen-13 ammonia positron emission tomography was performed in 57 patients with symptomatic HC at rest and during vasodilator stress (peak) with either dipyridamole (0.56 mg/kg during 4-minute infusion) or regadenoson (0.4 mg fixed bolus dose) for assessment of electrocardiographic findings, rMP (17-segment American Heart Association summed difference score), MBF, and coronary flow reserve. The dipyridamole and regadenoson groups consisted of 28 and 29 patients respectively. Baseline characteristics, including rest MBF (0.92 ± 0.22 vs 0.89 ± 0.23 ml/min/g, p = 0.60), were similar between the 2 groups. During stress, the presence and severity of abnormal rMP (summed difference score 5.5 ± 5.5 vs 5.8 ± 6.7, p = 0.80), peak MBF (1.81 ± 0.44 vs 1.82 ± 0.50 ml/min/g, p = 0.90), and coronary flow reserve (2.02 ± 0.53 vs 2.12 ± 0.12, p = 0.50) were comparable between the dipyridamole and regadenoson groups. Fewer patients exhibited side effects with regadenoson (2 vs 7, p = 0.06). Vasodilator-induced ST-segment depression showed high specificity (about 92%) but low sensitivity (about 34%) to predict abnormal rMP (summed difference score ≥2). In conclusion, measurement of rMP and quantitative flow with positron emission tomography is similar between regadenoson and dipyridamole in patients with symptomatic HC. Regadenoson is tolerated better than dipyridamole and is easier to administer. Vasodilator-induced ST-segment depression is a specific but nonsensitive marker for the prediction of abnormal rMP in patients with HC.

Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy.

A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the hearts primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 μmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s⁻¹, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 μmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.

Speckle-derived strain a better tool for quantification of stress echocardiography?

Detection of chronic coronary artery disease (CAD) via visual assessment of wall motion abnormality is subjective and variable ([1][1]). Tissue Doppler echocardiography (TDE) and tissue Doppler-based strain echocardiography (TDSE) allow quantification of regional myocardial mechanics ([2,3][2]). The

In hypertrophic cardiomyopathy reduction of relative resting myocardial blood flow is related to late enhancement, T2-signal and LV wall thickness

Objectives To quantify resting myocardial blood flow (MBF) in the left ventricular (LV) wall of HCM patients and to determine the relationship to important parameters of disease: LV wall thickness, late gadolinium enhancement (LGE), T2-signal abnormalities (dark and bright signal), LV outflow tract obstruction and age. Materials and Methods Seventy patients with proven HCM underwent cardiac MRI. Absolute and relative resting MBF were calculated from cardiac perfusion MRI by using the Fermi function model. The relationship between relative MBF and LV wall thickness, T2-signal abnormalities (T2 dark and T2 bright signal), LGE, age and LV outflow gradient as determined by echocardiography was determined using simple and multiple linear regression analysis. Categories of reduced and elevated perfusion in relation to non- or mildly affected reference segments were defined, and T2-signal characteristics and extent as well as pattern of LGE were examined. Statistical testing included linear and logistic regression analysis, unpaired t-test, odds ratios, and Fisher’s exact test. Results 804 segments in 70 patients were included in the analysis. In a simple linear regression model LV wall thickness (p<0.001), extent of LGE (p<0.001), presence of edema, defined as focal T2 bright signal (p<0.001), T2 dark signal (p<0.001) and age (p = 0.032) correlated inversely with relative resting MBF. The LV outflow gradient did not show any effect on resting perfusion (p = 0.901). Multiple linear regression analysis revealed that LGE (p<0.001), edema (p = 0.026) and T2 dark signal (p = 0.019) were independent predictors of relative resting MBF. Segments with reduced resting perfusion demonstrated different LGE patterns compared to segments with elevated resting perfusion. Conclusion In HCM resting MBF is significantly reduced depending on LV wall thickness, extent of LGE, focal T2 signal abnormalities and age. Furthermore, different patterns of perfusion in HCM patients have been defined, which may represent different stages of disease.

Computing Myocardial Motion in 4-Dimensional Echocardiography

We describe a novel method for computing dense 3D myocardial motion with high accuracy in four-dimensional (4D) echocardiography (3 dimensions spatial plus time). The method is based on a classic variational optical flow technique but exploits modern developments in optical flow research to utilize the full capabilities of 4D echocardiography. Using a variety of metrics, we present an in-depth performance evaluation of the method on synthetic, phantom, and intraoperative 4D transesophageal echocardiographic data. When compared with state-of-the-art optical flow and speckle tracking techniques currently found in 4D echocardiography, the method we present shows notable improvements in error rates. We believe the performance improvements shown can have a positive impact when the method is used as input for various applications, such as strain computation, biomechanical modeling, and automated diagnostics.