The «Amish¼ NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation.

MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM_000256.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated.

Post-Coital Acute Rupture of a Fenestrated Aortic Valve.

Fenestrated aortic valve is a frequent condition which is, for most of the time, asymptomatic and generally has no influence on aortic valve competence. However, aortic valve regurgitation could occur, especially in the case of fibrous strand rupture. In this situation, acute aortic regurgitation is poorly tolerated and requires urgent surgical correction. Herein is presented the case of a 70-year-old patient who was admitted as an emergency for acute heart failure after coital exertion. Echocardiography revealed severe acute aortic regurgitation due to leaflet prolapse. Intraoperative inspection of the valve showed a strand rupture of the isolated fenestration.

Impact of bileaflet mitral valve prolapse on quantification of mitral regurgitation with cardiac magnetic resonance: a single-center study.

BACKGROUND: To quantify mitral regurgitation (MR) with CMR, the regurgitant volume can be calculated as the difference between the left ventricular (LV) stroke volume (SV) measured with the Simpson's method and the reference SV, i.e. the right ventricular SV (RVSV) in patients without tricuspid regurgitation. However, for patients with prominent mitral valve prolapse (MVP), the Simpson's method may underestimate the LV end-systolic volume (LVESV) as it only considers the volume located between the apex and the mitral annulus, and neglects the ventricular volume that is displaced into the left atrium but contained within the prolapsed mitral leaflets at end systole. This may lead to an underestimation of LVESV, and resulting an over-estimation of LVSV, and an over-estimation of mitral regurgitation. The aim of the present study was to assess the impact of prominent MVP on MR quantification by CMR. METHODS: In patients with MVP (and no more than trace tricuspid regurgitation) MR was quantified by calculating the regurgitant volume as the difference between LVSV and RVSV. LVSVuncorr was calculated conventionally as LV end-diastolic (LVEDV) minus LVESV. A corrected LVESVcorr was calculated as the LVESV plus the prolapsed volume, i.e. the volume between the mitral annulus and the prolapsing mitral leaflets. The 2 methods were compared with respect to the MR grading. MR grades were defined as absent or trace, mild (5-29% regurgitant fraction (RF)), moderate (30-49% RF), or severe (≥50% RF). RESULTS: In 35 patients (44.0 ± 23.0y, 14 males, 20 patients with MR) the prolapsed volume was 16.5 ± 8.7 ml. The 2 methods were concordant in only 12 (34%) patients, as the uncorrected method indicated a 1-grade higher MR severity in 23 (66%) patients. For the uncorrected/corrected method, the distribution of the MR grades as absent-trace (0 vs 11, respectively), mild (20 vs 18, respectively), moderate (11 vs 5, respectively), and severe (4 vs 1, respectively) was significantly different (p < 0.001). In the subgroup without MR, LVSVcorr was not significantly different from RVSV (difference: 2.5 ± 4.7 ml, p = 0.11 vs 0) while a systematic overestimation was observed with LVSVuncorr (difference: 16.9 ± 9.1 ml, p = 0.0007 vs 0). Also, RVSV was highly correlated with aortic forward flow (n = 24, R 2 = 0.97, p < 0.001). CONCLUSION: For patients with severe bileaflet prolapse, the correction of the LVSV for the prolapse volume is suggested as it modified the assessment of MR severity by one grade in a large portion of patients.

[Multidisciplinary cardiogenetic counselling]. / Consultation multidisciplinaire de cardiogénétique.

Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working together to bring probands and their families useful and necessary informations to help them understanding causes, consequences and support of their disease. This approach is developped in close collaboration with the treating physician.

La consultation multidisciplinaire de cardiogénétique offre une approche globale spécialisée aux patients souffrant de canalopathies ou de cardiomyopathies héréditaires. Une mutation génétique est identifiée dans près de 50 % des cas. Les différents experts engagés travaillent conjointement pour apporter aux patients et à leurs familles les renseignements utiles et nécessaires pour comprendre les causes, les conséquences et la prise en charge de la maladie concernée. La consultation se fait en étroite collaboration avec les médecins traitants.

[Approach to chronic mitral regurgitation in 2016]. / L' insuffisance mitrale: mise au point en 2016.

Mitral regurgitation (MR) is the most frequent valvular disease in industrialised countries. MR is classified as primary (mostly degenerative with valve prolapse) or secondary (mainly due to underlying ischemic heart disease resulting in deformation of the valve structure). Surgical repair represents the optimal treatment for severe primary MR, whereas the benefits of surgical correction of secondary MR are controversial. Over the past few years, transcatheter techniques have been developed to treat MR, such as the percutaneous edge-to-edge procedure (MitraClip). These approaches represent a novel therapeutic choice for patients judged inoperable by the "heart team". This review article aims to summarize the principles of MR assessment and discuss current therapeutic options for severe MR, taking into account the latest advances in the field.

Urgent reoperative transapical valve-in-valve shortly after a transapical aortic valve implantation.

Urgent reoperative transapical aortic valve-in-valve has never been proposed as a treatment option in case of a failed transcatheter aortic valve implantation (TAVI) or in case of worsening of an existing paravalvular leak, if this complication occurs right after, or a few days after, the primary transapical aortic valve implantation. Experienced surgeons should argue that after a transapical TAVI, the apex is damaged and fragile, with a high risk of irreparable ventricular tears and life-threatening bleeding if a second transapical procedure is scheduled during the acute phase. Nevertheless, if the patient is inoperable and the vascular status, including the ascending aorta, limits alternative accesses, the urgent reoperative transapical valve-in-valve becomes an alternative. We illustrate, for the first time ever, our experience with an 81-year old female patient who underwent a transapical (TA) TAVI with a Sapien XT 23 mm. The day after the procedure, the patient haemodynamically worsened in combination with a worsening of a known (grade 1-2) paravalvular leak. Thus, on postoperative day two, an urgent transapical valve-in-valve was performed, and a second Sapien XT 23 mm was placed, with an excellent haemodynamic result and absence of leak. The redo apical access did not appear very complicated and the postoperative recovery was uneventful.

[Cardiac magnetic resonance in acute myocarditis: a new non-invasive diagnostic gold standard?]. / IRM cardiaque: imagerie de référence dans le diagnostic de la myocardite aiguë?

Acute myocarditis was until recently one of the most difficult diagnoses in cardiology. The spectrum of signs and symptoms is very wide, the usual non-invasive tests lack specificity and the myocardial biopsy is only performed in a minority of cases to confirm the diagnosis. Due to its unique ability to directly image myocardial necrosis, fibrosis and oedema, cardiac magnetic resonance (CMR) is now considered the primary tool for noninvasive assessment of patients with suspected myocarditis. CMR is also useful for monitoring disease activity under treatment. Myocarditis has been associated with the development of dilated cardiomyopathy; CMR could play a role in the follow-up of such cases to detect the progression toward a dilatative phenotype. Precise mapping of myocardial lesions with cardiac MRI is invaluable to guide myocardial biopsy and increase its diagnostic yield by improving sensitivity.

Reduced atrial emptying after orthotopic heart transplantation masquerading as restrictive transmitral Doppler flow pattern?*.

BACKGROUND: An elevated early (E) to late (A) diastolic filling velocities ratio, typically seen in advanced diastolic dysfunction, has also been observed after cardioversion of atrial fibrillation as a consequence of the depressed left atrial (LA) contractility. We hypothesized that the impaired LA contractile function demonstrated after orthotopic cardiac transplantation (OCT) could also lead to this "pseudorestrictive" pattern. METHOD: E/A ratio related to the tissue Doppler early mitral annular velocity (Ea) as preload-independent index of LV relaxation was evaluated in all consecutive OCT patients between 2005 and 2007. RESULTS: The study population comprised 48 patients 97 ± 77 months after OCT. Thirty-two patients (67%) had an E/A ratio > 2. LV systolic function and myocardial relaxation assessed by the Ea velocity were similar compared to patients with normal ratio (61 ± 6% vs. 60 ± 12%, P = 0.854 and 15 ± 4 cm/s vs. 14 ± 3 cm/s, r = 0.15, P = 0.323, respectively). On the other hand, the proportion of the recipient and donor LA cuffs as estimated by the recipient/global LA area ratio and the LA emptying fraction significantly correlated with the E/A ratio (r = 0.40, P = 0.005 and r =-0.33, P = 0.022, respectively). CONCLUSION: Our study shows that there is a high prevalence of elevated E/A ratio after standard OCT which seems mainly related to reduced LA contractility. Recognition of this "pseudorestrictive" pattern may avoid misdiagnosis of diastolic dysfunction.

Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. METHOD AND RESULTS: The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5'-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. CONCLUSIONS: Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.

Aortic remodelling in Fabry disease.

AIMS: To evaluate thoracic aortic dilation in patients with Fabry disease (FD). METHODS AND RESULTS: A cohort of 106 patients with FD (52 males; 54 females) from three European centres were studied. The diameter of the thoracic aorta was assessed at three levels (sinus of Valsalva, ascending aorta, and descending aorta) using echocardiograms and cardiovascular magnetic resonance imaging. Aortic dilation at the sinus of Valsalva was found in 32.7% of males and 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. No aortic dilation was observed in the descending aorta. There was no correlation between aortic diameter at the sinus of Valsalva and cardiovascular risk factors. CONCLUSION: Fabry disease should be considered as a cardiovascular disease that affects the heart and arterial vasculature, including the thoracic aorta. Thus, patients with FD should be closely monitored for the presence, and possible progression and complications of aortic dilation. CLINICAL TRIAL REGISTRATION: Protocol 101/01. Ethics committee, Faculty of Medicine, Lausanne.

[Cardiomyopathy and cardiac magnetic resonance]. / Rôle de l'IRM cardiaque dans le dépistage des cardiomyopathies de l'adulte.

Cardiovascular magnetic resonance (CMR) is a rapidly emerging non-invasive imaging technique free of X-Ray and offers higher spatial resolution than alternative forms of cardiac imaging for the assessment of left ventricular (LV) anatomy, function, and viability due to the unique capability of myocardial tissue characterization after gadolinium-chelates contrast administration. This imaging technique has clinical utility over a broad spectrum of heart diseases: ranging from ischaemic to non ischaemic aetiologies. Cardiomyopathies (CMP) are a heterogeneous group of diseases of the myocardium associated with architectural abnormalities and mechanical dysfunction. CMR can help excluding coronary artery disease and can provide positive diagnostic features for several CMP resulted in better diagnosis and management, Leading to improvements in mortality.

Effects of an aging vascular model on healthy and diseased hearts.

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

The effect of a myocardial infarction on the normalized time-varying elastance curve.

It has been suggested that the shape of the normalized time-varying elastance curve [E(n)(t(n))] is conserved in different cardiac pathologies. We hypothesize, however, that the E(n)(t(n)) differs quantitatively after myocardial infarction (MI). Sprague-Dawley rats (n = 9) were anesthetized, and the left anterior descending coronary artery was ligated to provoke the MI. A sham-operated control group (CTRL) (n = 10) was treated without the MI. Two months later, a conductance catheter was inserted into the left ventricle (LV). The LV pressure and volume were measured and the E(n)(t(n)) derived. Slopes of E(n)(t(n)) during the preejection period (alpha(PEP)), ejection period (alpha(EP)), and their ratio (beta = alpha(EP)/alpha(PEP)) were calculated, together with the characteristic decay time during isovolumic relaxation (tau) and the normalized elastance at end diastole (E(min)(n)). MI provoked significant LV chamber dilatation, thus a loss in cardiac output (-33%), ejection fraction (-40%), and stroke volume (-30%) (P < 0.05). Also, it caused significant calcium increase (17-fold), fibrosis (2-fold), and LV hypertrophy. End-systolic elastance dropped from 0.66 +/- 0.31 mmHg/microl (CTRL) to 0.34 +/- 0.11 mmHg/microl (MI) (P < 0.05). Normalized elastance was significantly reduced in the MI group during the preejection, ejection, and diastolic periods (P < 0.05). The slope of E(n)(t(n)) during the alpha(PEP) and beta were significantly altered after MI (P < 0.05). Furthermore, tau and end-diastolic E(min)(n) were both significantly augmented in the MI group. We conclude that the E(n)(t(n)) differs quantitatively in all phases of the heart cycle, between normal and hearts post-MI. This should be considered when utilizing the single-beat concept.

Ventricular-arterial coupling in a rat model of reduced arterial compliance provoked by hypervitaminosis D and nicotine.

The vitamin D(3) and nicotine (VDN) model is one of isolated systolic hypertension (ISH) in which arterial calcification raises arterial stiffness and vascular impedance. The effects of VDN treatment on arterial and cardiac hemodynamics have been investigated; however, a complete analysis of ventricular-arterial interaction is lacking. Wistar rats were treated with VDN (VDN group, n = 9), and a control group (n = 10) was included without the VDN. At week 8, invasive indexes of cardiac function were obtained using a conductance catheter. Simultaneously, aortic pressure and flow were measured to derive vascular impedance and characterize ventricular-vascular interaction. VDN caused significant increases in systolic (138 +/- 6 vs. 116 +/- 13 mmHg, P < 0.01) and pulse (42 +/- 10 vs. 26 +/- 4 mmHg, P < 0.01) pressures with respect to control. Total arterial compliance decreased (0.12 +/- 0.08 vs. 0.21 +/- 0.04 ml/mmHg in control, P < 0.05), and pulse wave velocity increased significantly (8.8 +/- 2.5 vs. 5.1 +/- 2.0 m/s in control, P < 0.05). The arterial elastance and end-systolic elastance rose significantly in the VDN group (P < 0.05). Wave reflection was augmented in the VDN group, as reflected by the increase in the wave reflection coefficient (0.63 +/- 0.06 vs. 0.52 +/- 0.05 in control, P < 0.05) and the amplitude of the reflected pressure wave (13.3 +/- 3.1 vs. 8.4 +/- 1.0 mmHg in control, P < 0.05). We studied ventricular-arterial coupling in a VDN-induced rat model of reduced arterial compliance. The VDN treatment led to development of ISH and provoked alterations in cardiac function, arterial impedance, arterial function, and ventricular-arterial interaction, which in many aspects are similar to effects of an aged and stiffened arterial tree.

Increased carotid intima-media thickness in the absence of atherosclerotic plaques in an adult population with Fabry disease.

AIM: Fabry disease is considered primarily as a progressive small vessel disease, with ischaemic degenerative lesions involving the kidneys, brain and heart. Macrovascular involvement in male patients includes an accelerated wall hypertrophy of the radial artery and a thickening of the intima-media of the common carotid artery. The aim of this study is to evaluate the prevalence and severity of carotid artery atherosclerosis in hemizygous and heterozygous patients with Fabry disease, compared with a matched control population. METHODS: The common carotid artery intima-media thickness (IMT) of 53 patients with Fabry disease (24 men, 29 women) was measured by high-definition ultrasonography, and the presence or absence of atherosclerotic plaques reported. Results were compared with those of 120 age-matched healthy individuals (83 men, 37 women). RESULTS: The common carotid artery IMT was increased to the same extent in male and female patients with Fabry disease (706+/-211 microm and 749+/-395 microm, respectively) compared with that of the control population (614+/-113 microm). In the Fabry population, IMT did not correlate with either systolic blood pressure or with renal function (plasma creatinine). In the control population, only systolic blood pressure was positively and significantly correlated with IMT. Atherosclerotic plaques in the common carotid artery were not observed in any patient with Fabry disease, whereas 34% of the control population had carotid artery plaques, as evidenced by focal non-homogeneous intima-media thickening greater than 1.2 mm. CONCLUSION: This study presents evidence of a major increase in common carotid artery IMT, both in hemizygous and heterozygous patients with Fabry disease, in the absence of focal atherosclerotic plaques. These results suggest that the conduit arteries may be protected from atherosclerosis in Fabry disease.

Cardiac and vascular hypertrophy in Fabry disease: evidence for a new mechanism independent of blood pressure and glycosphingolipid deposition.

OBJECTIVE: Fabry disease is an X-linked disorder resulting from alpha-galactosidase A deficiency. The cardiovascular findings include left ventricular hypertrophy (LVH) and increased intima-media thickness of the common carotid artery (CCA IMT). The current study examined the possible correlation between these parameters. To corroborate these clinical findings in vitro, plasma from Fabry patients was tested for possible proliferative effect on rat vascular smooth muscle cells (vascular smooth muscle cell [VSMC]) and mouse neonatal cardiomyocytes. METHODS AND RESULTS: Thirty male and 38 female patients were enrolled. LVH was found in 60% of men and 39% of women. Increased CCA IMT was equally present in males and females. There was a strong positive correlation between LV mass and CCA IMT (r2=0.27; P<0.0001). VSMC and neonatal cardiomyocyte proliferative response in vitro correlated with CCA IMT (r2=0.39; P<0.0004) and LV mass index (r2=0.19; P=0.028), respectively. CONCLUSIONS: LVH and CCA IMT occur concomitantly in Fabry suggesting common pathogenesis. The underlying cause may be a circulating growth-promoting factor whose presence has been confirmed in vitro.

Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: validation and correlation by conductance catheter.

The rodent model of myocardial infarction (MI) is extensively used in heart failure studies. However, long-term follow-up of echocardiographic left ventricular (LV) function parameters such as the myocardial performance index (MPI) and its ratio with the fractional shortening (LVFS/MPI) has not been validated in conjunction with invasive indexes, such as those derived from the conductance catheter (CC). Sprague-Dawley rats with left anterior descending coronary artery ligation (MI group, n = 9) were compared with a sham-operated control group (n = 10) without MI. Transthoracic echocardiography (TTE) was performed every 2 wk over an 8-wk period, after which classic TTE parameters, especially MPI and LVFS/MPI, were compared with invasive indexes obtained by using a CC. Serial TTE data showed significant alterations in the majority of the noninvasive functional and structural parameters (classic and novel) studied in the presence of MI. Both MPI and LVFS/MPI significantly (P < 0.05 for all reported values) correlated with body weight (r = -0.58 and 0.76 for MPI and LVFS/MPI, respectively), preload recruitable stroke work (r = -0.61 and 0.63), LV end-diastolic pressure (LVEDP) (r = 0.82 and -0.80), end-diastolic volume (r = 0.61 and -0.58), and end-systolic volume (r = 0.46 and -0.48). Forward stepwise linear regression analysis revealed that, of all variables tested, LVEDP was the only independent determinant of MPI (r = 0.84) and LVFS/MPI (r = 0.83). We conclude that MPI and LVFS/MPI correlate strongly and better than the classic noninvasive TTE parameters with established, invasively assessed indexes of contractility, preload, and volumetry. These findings support the use of these two new noninvasive indexes for long-term analysis of the post-MI LV remodeling.

Interobserver and intraobserver variability in detection of patent foramen ovale and atrial septal aneurysm with transesophageal echocardiography.

BACKGROUND: An accurate diagnosis of patent foramen ovale (PFO) and atrial septal aneurysm (ASA) may be of decisional importance in the management of patients with ischemic stroke. Very few studies have been devoted to observer agreement in the diagnosis of these atrial septum abnormalities using contrast transesophageal echocardiography, which is considered as the method of choice for the diagnosis. The aim of this study was to assess interobserver and intraobserver variability in the diagnosis of PFO and ASA with contrast echocardiography. METHODS: Three sonographers independently reviewed 100 contrast studies stored on videotape on 2 occasions each. The interobserver and intraobserver variability was assessed by calculating kappa statistics. RESULTS: The overall interobserver and intraobserver kappa values for the assessment of degree of shunting through a PFO were 0.77 (first and second reading) and 0.82, respectively. The best kappa statistics were obtained when no and small shunts (less than 10 microbubbles) were pooled and compared with larger shunts. For the diagnosis of ASA, the overall interobserver kappa value was 0.45 for the first reading and 0.71 for the second reading, whereas the overall intraobserver kappa value was 0.74. CONCLUSION: Interobserver and intraobserver agreements for the diagnosis of PFO and ASA by transesophageal echocardiography are not perfect and need to be improved, particularly for ASA. This variability has to be taken into account when deciding on a potential risky treatment to prevent recurrent strokes.