Cardiomyopathies are classified according to distinct morphological characteristics. They occur relatively frequent and are an important cause of mortality and morbidity. Isolated ventricular ...non-compaction or non-compaction cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial layer with deep intertrabecular recesses, reminiscent of the myocardium during early embryogenesis. Aims Autosomal-dominant as well as X-linked inheritance for NCCM has been described and several loci have been associated with the disease. Nevertheless, a major genetic cause for familial NCCM remains to be identified. Methods and Results We describe, in two separate autosomal-dominant NCCM families, the identification of mutations in the sarcomeric cardiac β-myosin heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). Conclusion These results confirm the genetic heterogeneity of NCCM and suggest that the molecular classification of cardiomyopathies includes an MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.
For ultrasound contrast agents (UCA), nonlinear imaging now has become fundamental. All of the current contrast-imaging methods are dominantly based on the nonlinear response of UCA bubbles. The ...discrimination between the perfused tissue and the UCA is the challenge in the field of UCA-imaging. This differentiation is usually associated or expressed by the ratio of the scattered power from the contrast agent to the scattered power from the tissue and is termed “contrast-to-tissue ratio” (CTR). Second harmonic imaging showed a better discrimination between tissue and UCA than fundamental imaging because of a higher CTR. We demonstrate, in this study, that the CTR increases as a function of the order of the harmonic frequency. Currently, due to the limited bandwidth of the transducers, only the second harmonic is selectively imaged, resulting in images with a superior quality to fundamental images, but still degraded and not optimal because of the harmonic generation in the underlying tissue (due to nonlinear propagation) and hence giving a limited CTR. To increase the CTR and to take advantage of the higher harmonics (third, fourth, fifth and the ultraharmonics and termed here super harmonics), we have developed a new phased array transducer. The array transducer contains two different types of elements arranged in an interleaved pattern (odd and even elements). The total number of elements is 96. The elements can operate separately and at a distinct frequency, enabling separate transmission and reception modes. The odd elements (48) operate at typically 2.8 MHz center frequency and 80% bandwidth. The even elements (48) have a center frequency of 900 kHz with a bandwidth of 50%.
In vitro measurements using the dual frequency probe show an increase of 40 dB in the CTR for super harmonic components over the conventional second harmonic system. The increase in CTR is in agreement with the calculations using existing models for the response of encapsulated bubbles and known theory of nonlinear propagation. Animal experiments have demonstrated the feasibility of this approach using commercially available UCA and showed a similar increase of the CTR (E-mail: bouakaz@tch.fgg.eur.nl).
Abstract Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in genes encoding sarcomeric proteins. One of the most frequent affected genes is MYBPC3 , which encodes the thick ...filament protein cardiac myosin binding protein C. Despite the prevalence of HCM, disease pathology and clinical outcome of sarcomeric mutations are largely unknown. We hypothesized that microRNAs (miRNAs) could play a role in the disease process. To determine which miRNAs were changed in expression, miRNA arrays were performed on heart tissue from HCM patients with a MYBPC3 mutation (n = 6) and compared with hearts of non-failing donors (n = 6). 532 out of 664 analyzed miRNAs were expressed in at least one heart sample. 13 miRNAs were differentially expressed in HCM compared with donors (at p < 0.01, fold change ≥ 2). The genomic context of these differentially expressed miRNAs revealed that miR-204 (fold change 2.4 in HCM vs. donor) was located in an intron of the TRPM3 gene, encoding an aspecific cation channel involved in calcium entry. RT-PCR analysis revealed a trend towards TRPM3 upregulation in HCM compared with donor myocardium (fold change 2.3, p = 0.078). In silico identification of mRNA targets of differentially expressed miRNAs showed a large proportion of genes involved in cardiac hypertrophy and cardiac beta-adrenergic receptor signaling and we showed reduced phosphorylation of cardiac troponin I in the HCM myocardium when compared with donor. HCM patients with MYBPC3 mutations have a specific miRNA expression profile. Downstream mRNA targets reveal possible involvement in cardiac signaling pathways.
Aims
The aim of this study was to determine the relationship between improved ejection fraction (EF) and occurrence of arrhythmias in patients with cardiac resynchronization therapy devices with ...defibrillator function (CRT‐D). The hypothesis was that patients who experienced a marked improvement in EF also had fewer appropriate defibrillator interventions.
Methods and results
We analysed data of 270 patients from2 prospective registries with follow‐up of ≥12 months and echocardiography performed ≥8 months after CRT‐D implantation. The discriminator was whether left ventricular ejection fraction (LVEF) improved to >35% cut‐off for primary prevention implantable cardioverter‐defibrillator (ICD) implantation. Mean age was 61 ± 11 years, LVEF 22 ± 5%, and follow‐up 40 ± 22 months. Ischaemic cardiomyopathy was present in 48%, and secondary prevention indication was present in 25%. Implantable cardioverter‐defibrillator interventions were delivered to 35% of patients. Echocardiography (20 ± 15 months after implantation) showed an improvement in LVEF from 22% (SD 5.4%) to 30% (SD 9.8%). Improvement to >35% was seen in 21% of patients. Those who improved to >35% had fewer ICD interventions than those who did not (23 vs.38%; P‐value 0.03). Analysing only patients with a primary prevention indication and stratifying again in patients with and without improvement of LVEF to >35%, the latter had highly significant more ICD‐therapies (6 vs. 31%; P‐value 0.0008).
Conclusion
Patients with CRT‐D for primary prevention, whose LVEF improved to >35% during mid‐term follow‐up, are at low risk of first ICD therapies beyond year 1. If similar findings are reported in other patient cohorts, this might impact on decision‐making at the time of battery depletion.
Mutations in the
MYBPC3
gene, encoding cardiac myosin binding protein C (cMyBP-C) are frequent causes of hypertrophic cardiomyopathy (HCM). Previously, we have presented evidence for reduced cMyBP-C ...expression (haploinsufficiency), in patients with a truncation mutation in
MYBPC3
. In mice, lacking cMyBP-C cross-bridge kinetics was accelerated. In this study, we investigated whether cross-bridge kinetics was altered in myectomy samples from HCM patients harboring heterozygous
MYBPC3
mutations (MYBPC3
mut
). Isometric force and the rate of force redevelopment (
k
tr
) at different activating Ca
2+
concentrations were measured in mechanically isolated Triton-permeabilized cardiomyocytes from MYBPC3
mut
(
n
= 18) and donor (
n
= 7) tissue. Furthermore, the stretch activation response of cardiomyocytes was measured in tissue from eight MYBPC3
mut
patients and five donors to assess the rate of initial force relaxation (
k
1
) and the rate and magnitude of the transient increase in force (
k
2
and
P
3
, respectively) after a rapid stretch. Maximal force development of the cardiomyocytes was reduced in MYBPC3
mut
(24.5 ± 2.3 kN/m
2
) compared to donor (34.9 ± 1.6 kN/m
2
). The rates of force redevelopment in MYBPC3
mut
and donor over a range of Ca
2+
concentrations were similar (
k
tr
at maximal activation: 0.63 ± 0.03 and 0.75 ± 0.09 s
−1
, respectively). Moreover, the stretch activation parameters did not differ significantly between MYBPC3
mut
and donor (
k
1
: 8.5±0.5 and 8.8 ± 0.4 s
−1
;
k
2
: 0.77 ± 0.06 and 0.74 ± 0.09 s
−1
;
P
3
: 0.08 ± 0.01 and 0.09 ± 0.01, respectively). Incubation with protein kinase A accelerated
k
1
in MYBPC3
mut
and donor to a similar extent. Our experiments indicate that, at the cMyBP-C expression levels in this patient group (63 ± 6 % relative to donors), cross-bridge kinetics are preserved and that the depressed maximal force development is not explained by perturbation of cross-bridge kinetics.
We studied the spatial relations among hyperemic myocardial blood flow (hMBF), contractile function, and morphologic tissue alterations in 19 patients with hypertrophic cardiomyopathy (HC). All ...patients were studied with oxygen-15 water positron emission tomography during rest and adenosine administration to assess myocardial perfusion. Cardiovascular magnetic resonance was performed to derive delayed contrast-enhanced images and to calculate contractile function (Ecc ) with tissue tagging. Eleven healthy subjects underwent similar positron emission tomographic and cardiovascular magnetic resonance scanning protocols and served as a control group. In the HC group, hMBF averaged 2.46 ± 0.91 ml/min/g and mean Ecc was −14.7 ± 3.4%, which were decreased compared to the control group (3.97 ± 1.48 ml/min/g and −17.7 ± 3.2%, respectively, p <0.001 for the 2 comparisons). Delayed contrast enhancement (DCE) was present only in patients with HC, averaging 6.2 ± 10.3% of left ventricular mass. In the HC group, Ecc and DCE in the septum (−13.7 ± 3.6% and 10.2 ± 13.6%) significantly differed from the lateral wall (−16.0 ± 2.8% and 2.4 ± 5.9%, p <0.001 for the 2 comparisons). In general, hMBF and Ecc were decreased in segments displaying DCE compared to nonenhanced segments (p <0.001 for the comparisons). In the HC group, univariate analysis revealed relations of hMBF to Ecc (r = −0.45, p <0.001) and DCE (r = −0.31, p <0.001). Multivariate analysis revealed that Ecc was independently related to hMBF (beta −0.37, p <0.001) and DCE (beta 0.28, p <0.001). In conclusion, in HC hMBF is impaired and related to contractile function independent from presence of DCE. When present, DCE reflected a progressed disease state as characterized by an increased perfusion deficit and contractile dysfunction.
Abstract Atherosclerosis is an inflammatory disease, complicated by progressively increasing atherosclerotic plaques that eventually may rupture. Plaque rupture is a major cause of cardiovascular ...events, such as unstable angina, myocardial infarction, and stroke. A number of noninvasive imaging techniques have been developed to evaluate the vascular wall in an attempt to identify so-called vulnerable atherosclerotic plaques that are prone to rupture. The purpose of the present review is to systematically investigate the accuracy of noninvasive imaging techniques in the identification of plaque components and morphologic characteristics associated with plaque vulnerability, assessing their clinical and diagnostic value.
We hypothesized that relief of obstruction in patients with hypertrophic cardiomyopathy (HC) by percutaneous transluminal septal myocardial ablation (PTSMA) improves microvascular dysfunction by ...relief of extravascular compression. Microvascular dysfunction in obstructive HC is related to extravascular compression by increased left ventricular (LV) mass and LV end-diastolic pressure. The study included 14 patients with obstructive HC (mean age 55 ± 12 years, 11 men) who underwent successful PTSMA and 14 healthy volunteers (mean age 31 ± 4 years, 11 men). LV hemodynamics (by Doppler echocardiography) and intramyocardial flow dynamics (by adenosine myocardial contrast echocardiography) were evaluated in healthy volunteers and before and 6 months after PTSMA in patients with HC. LV end-diastolic pressure was estimated from the ratio of transmitral early LV filling velocity to early diastolic mitral annular velocity. PTSMA reduced the invasively measured LV outflow tract gradient (119 ± 35 vs 17 ± 16 mm Hg, p <0.0001) and LV end-diastolic pressure (23 ± 3 vs 16 ± 2 mm Hg, p <0.001). Six months after PTSMA, myocardial flow reserve improved (2.73 ± 0.56 vs 3.21 ± 0.49, p <0.001), but did not normalize compared with healthy controls (vs 3.95 ± 0.77, p <0.001). Also, septal hyperemic endo-to-epi myocardial blood flow ratio improved (0.70 ± 0.11 vs 0.92 ± 0.07, p <0.001). Changes in LV end-diastolic pressure, LV mass index, and LV outflow tract peak systolic gradient correlated well with changes in hyperemic perfusion (all p <0.05). In conclusion, microvascular dysfunction improves after PTSMA due to relief of extravascular compression forces.
The aim of this study was to evaluate myocardial infarction induced by percutaneous transluminal septal myocardial ablation (PTSMA) in symptomatic patients with hypertrophic obstructive ...cardiomyopathy using contrast-enhanced (CE) magnetic resonance imaging (MRI).
Contrast-enhanced MRI delineates the extent of myocardial infarction in coronary artery disease, but its role in ethanol-induced infarction has not been established.
Cine and CE MRI were performed before and one month after PTSMA in 24 patients. Size and location of the induced infarction were related to left ventricular (LV) mass reduction, enzyme release, volume of ethanol administered, LV outflow tract gradient reduction, and coronary ablation site.
One month after PTSMA, regional hyperenhancement was visualized in the basal interventricular septum in all patients. Mean infarction size was 20 ± 9 g, corresponding to 10 ± 5% and 31 ± 16% of total LV and septal mass, respectively. Total LV mass decreased from 219 ± 64 to 205 ± 64 g (p < 0.01), and septal mass from 76 ± 25 to 68 ± 22 g (p < 0.01). Total LV mass reduction exceeded septal mass reduction (p < 0.01). Infarction size correlated with peak creatine phosphokinase-MB (β = 0.67, p < 0.01), volume of ethanol administered (β = 0.47, p = 0.02), total LV and septal mass reduction (β = 0.50, p = 0.02; β = 0.73, p < 0.01), and gradient reduction (β = 0.63, p < 0.01). Seven patients with exclusively right-sided septal infarction had smaller infarction size and less gradient reduction than remaining patients with left-sided or transmural infarction (p < 0.01). In five of these, PTSMA was performed distal in the target artery.
Contrast-enhanced MRI allowed detailed evaluation of size and location of septal myocardial infarction induced by PTSMA. Infarction size correlated well with clinical indexes of infarct size.
PDF
