Ernesto Salcedo

Performance of 3-Dimensional Echocardiography in Measuring Left Ventricular Volumes and Ejection Fraction : A Systematic Review and Meta-Analysis

OBJECTIVES The primary aim of this systematic review is to objectively evaluate the test performance characteristics of three-dimensional echocardiography (3DE) in measuring left ventricular (LV) volumes and ejection fraction (EF). BACKGROUND Despite its growing use in clinical laboratories, the accuracy of 3DE has not been studied on a large scale. It is unclear if this technology offers an advantage over traditional two-dimensional (2D) methods. METHODS We searched for studies that compared LV volumes and EF measured by 3DE and cardiac magnetic resonance (CMR) imaging. A subset of those also compared standard 2D methods with CMR. We used meta-analyses to determine the overall bias and limits of agreement of LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF measured by 3DE and 2D echocardiography (2DE). RESULTS Twenty-three studies (1,638 echocardiograms) were included. The pooled biases ± 2 SDs for 3DE were -19.1 ± 34.2 ml, -10.1 ± 29.7 ml, and - 0.6 ± 11.8% for EDV, ESV, and EF, respectively. Nine studies also included data from 2DE, where the pooled biases were -48.2 ± 55.9 ml, -27.7 ± 45.7 ml, and 0.1 ± 13.9% for EDV, ESV, and EF, respectively. In this subset, the difference in bias between 3DE and 2D volumes was statistically significant (p = 0.01 for both EDV and ESV). The difference in variance was statistically significant (p < 0.001) for all 3 measurements. CONCLUSIONS Three-dimensional echocardiography underestimates volumes and has wide limits of agreement, but compared with traditional 2D methods in these carefully performed studies, 3DE is more accurate for volumes and more precise in all 3 measurements.

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks.

SCN5A Mutations Associate With Arrhythmic Dilated Cardiomyopathy and Commonly Localize to the Voltage-Sensing Mechanism.

OBJECTIVES The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM). BACKGROUND Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation. METHODS Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis. RESULTS We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15). CONCLUSIONS Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications.

Percutaneous Transcatheter Closure of Prosthetic Mitral Paravalvular Leaks : Are We There Yet?

A potential complication of mitral valve replacement surgery is the development of a paravalvular leak (PVL). Percutaneous transcatheter closures of PVLs using a wide array of devices have been reported in the literature, although the procedural success rate of this approach remains variable. One major challenge of transcatheter mitral PVL closure lies in the ability to adequately visualize the area of interest to facilitate defect crossing and equipment selection. Furthermore, the current spectrum of devices available for off-label use in the closure of these unique defects remains limited. This review examines the current state of transcatheter prosthetic mitral PVL closure, describes our institutions experience using advanced imaging modalities for procedural guidance, and illustrates some of the limitations associated with using existing devices in transcatheter PVL closure.

Honeybee Blue- and Ultraviolet-Sensitive Opsins: Cloning, Heterologous Expression in Drosophila, and Physiological Characterization

The honeybee (Apis mellifera) visual system contains three classes of retinal photoreceptor cells that are maximally sensitive to light at 440 nm (blue), 350 nm (ultraviolet), and 540 nm (green). We performed a PCR-based screen to identify the genes encoding the Apis blue- and ultraviolet (UV)-sensitive opsins. We obtained cDNAs that encode proteins having a high degree of sequence and structural similarity to other invertebrate and vertebrate visual pigments. The Apis blue opsin cDNA encodes a protein of 377 amino acids that is most closely related to other invertebrate visual pigments that are thought to be blue-sensitive. The UV opsin cDNA encodes a protein of 371 amino acids that is most closely related to the UV-sensitive Drosophila Rh3 and Rh4 opsins. To test whether these novel Apis opsin genes encode functional visual pigments and to determine their spectral properties, we expressed them in the R1–6 photoreceptor cells of blindninaE mutant Drosophila, which lack the major opsin of the fly compound eye. We found that the expression of either the Apis blue- or UV-sensitive opsin in transgenic flies rescued the visual defect of ninaEmutants, indicating that both genes encode functional visual pigments. Spectral sensitivity measurements of these flies demonstrated that the blue and UV visual pigments are maximally sensitive to light at 439 and 353 nm, respectively. These maxima are in excellent agreement with those determined previously by single-cell recordings fromApis photoreceptor cells and provide definitive evidence that the genes described here encode visual pigments having blue and UV sensitivity.

A Framework for Systematic Characterization of the Mitral Valve by Real-Time Three-Dimensional Transesophageal Echocardiography

Because of the complex anatomy of the mitral valve, detailed imaging is a challenge. Transesophageal echocardiography (TEE) using two-dimensional echocardiography provides the backbone for the structural evaluation of the mitral valve. Interventional and surgical procedures on the mitral valve demand precise and sophisticated imaging for guidance and support. Three-dimensional (3D) transthoracic echocardiography and 3D transesophageal echocardiography (TEE) are now being used with increasing frequency to provide more comprehensive evaluations of the structure and function of the mitral valve complex. In this review, the authors present a framework for the application of 3D TEE in the evaluation of patients with structural or functional mitral valve disease, outline an examination protocol, and address the advantages and limitations of the current platform for 3D TEE. Real-time 3D TEE has the real potential to become the main imaging tool for the guidance of surgical and interventional procedures on the mitral valve. Although 3D TEE provides impressive images of the mitral valve, it now must be demonstrated, through scientific studies, that these beautiful images add clinical value to the management of patients with mitral valve disease.

Molecular basis for ultraviolet vision in invertebrates.

Invertebrates are sensitive to a broad spectrum of light that ranges from UV to red. Color sensitivity in the UV plays an important role in foraging, navigation, and mate selection in both flying and terrestrial invertebrate animals. Here, we show that a single amino acid polymorphism is responsible for invertebrate UV vision. This residue (UV: lysine vs blue:asparagine or glutamate) corresponds to amino acid position glycine 90 (G90) in bovine rhodopsin, a site affected in autosomal dominant human congenital night blindness. Introduction of the positively charged lysine in invertebrates is likely to deprotonate the Schiff base chromophore and produce an UV visual pigment. This same position is responsible for regulating UV versus blue sensitivity in several bird species, suggesting that UV vision has arisen independently in invertebrate and vertebrate lineages by a similar molecular mechanism.

Odortypes and MHC peptides: complementary chemosignals of MHC haplotype?

The olfactory and immune systems must perform optimally in the task of recognizing thousands of molecules to ensure survival. A particularly intriguing link between these systems is that animals can smell differences in the major histocompatibility complex (MHC), a cluster of highly polymorphic genes found on human chromosome 6 and mouse chromosome 17. Two different sets of compounds found in urine have been postulated to convey information on MHC haplotype: volatile compounds (odortypes) and MHC peptides. Here we argue for complementary roles for these chemosignals.

From the top down: flexible reading of a fragmented odor map

Animals that depend on smell for communication and survival extract multiple pieces of information from a single complex odor. Mice can collect information on sex, genotype, health and dietary status from urine scent marks, a stimulus made up of hundreds of molecules. This ability is all the more remarkable considering that natural odors are encountered against varying olfactory backgrounds; the olfactory system must therefore provide some mechanism for extracting the most relevant information. Here we discuss recent data indicating that the readout of olfactory input by mitral cells in the olfactory bulb can be modified by behavioral context. We speculate that the olfactory cortex plays a key role in tuning the readout of olfactory information from the olfactory bulb.

Induction of ectopic taste buds by SHH reveals the competency and plasticity of adult lingual epithelium.

Taste buds are assemblies of elongated epithelial cells, which are innervated by gustatory nerves that transmit taste information to the brain stem. Taste cells are continuously renewed throughout life via proliferation of epithelial progenitors, but the molecular regulation of this process remains unknown. During embryogenesis, sonic hedgehog (SHH) negatively regulates taste bud patterning, such that inhibition of SHH causes the formation of more and larger taste bud primordia, including in regions of the tongue normally devoid of taste buds. Here, using a Cre-lox system to drive constitutive expression of SHH, we identify the effects of SHH on the lingual epithelium of adult mice. We show that misexpression of SHH transforms lingual epithelial cell fate, such that daughter cells of lingual epithelial progenitors form cell type-replete, onion-shaped taste buds, rather than non-taste, pseudostratified epithelium. These SHH-induced ectopic taste buds are found in regions of the adult tongue previously thought incapable of generating taste organs. The ectopic buds are composed of all taste cell types, including support cells and detectors of sweet, bitter, umami, salt and sour, and recapitulate the molecular differentiation process of endogenous taste buds. In contrast to the well-established nerve dependence of endogenous taste buds, however, ectopic taste buds form independently of both gustatory and somatosensory innervation. As innervation is required for SHH expression by endogenous taste buds, our data suggest that SHH can replace the need for innervation to drive the entire program of taste bud differentiation.