The 50-Year History, Controversy, and Clinical Implications of Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota 55407, USA.
Journal of the American College of Cardiology (Impact Factor: 16.5). 08/2009; 54(3):191-200. DOI: 10.1016/j.jacc.2008.11.069
Source: PubMed


Dynamic obstruction to left ventricular (LV) outflow was recognized from the earliest (50 years ago) clinical descriptions of hypertrophic cardiomyopathy (HCM) and has proved to be a complex phenomenon unique in many respects, as well as arguably the most visible and well-known pathophysiologic component of this heterogeneous disease. Over the past 5 decades, the clinical significance attributable to dynamic LV outflow tract gradients in HCM has triggered a periodic and instructive debate. Nevertheless, only recently has evidence emerged from observational analyses in large patient cohorts that unequivocally supports subaortic pressure gradients (and obstruction) both as true impedance to LV outflow and independent determinants of disabling exertional symptoms and cardiovascular mortality. Furthermore, abolition of subaortic gradients by surgical myectomy (or percutaneous alcohol septal ablation) results in profound and consistent symptomatic benefit and restoration of quality of life, with myectomy providing a long-term survival similar to that observed in the general population. These findings resolve the long-festering controversy over the existence of obstruction in HCM and whether outflow gradients are clinically important elements of this complex disease. These data also underscore the important principle, particularly relevant to clinical practice, that heart failure due to LV outflow obstruction in HCM is mechanically reversible and amenable to invasive septal reduction therapy. Finally, the recent observation that the vast majority of patients with HCM have the propensity to develop outflow obstruction (either at rest or with exercise) underscores a return to the characterization of HCM in 1960 as a predominantly obstructive disease.

Full-text preview

Available from:
  • Source
    • "Obstruction is highly variable and is influenced by a number of physiological situations [7]. The presence of LVOTG was, in the " preechocardiographic " era, an essential feature of patients with HCM [8]. LVOTG therefore became also the first target of therapeutic efforts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Nonpharmacological treatment of patients with hypertrophic obstructive cardiomyopathy (HOCM) comprises surgical myectomy (SME), alcohol septal ablation (ASA), and dual-chamber (DDD) pacing. The aim of the study was to compare the long-term effect of DDD pacing and ASA in symptomatic HOCM patients. Patients and methods: We evaluated retrospective data from three cardiocenters; there were 24 patients treated with DDD pacing included and 52 treated with ASA followed for 101 ± 49 and 87 ± 23 months, respectively. Results: In the group treated with DDD pacing, the left ventricle outflow tract gradient (LVOTG) decreased from 82 ± 44 mmHg to 21 ± 21 mmHg, and NYHA class improved from 2.7 ± 0.5 to 2.1 ± 0.6 (both P < 0.001). In the ASA-treated group, a decline in LVOTG from 73 ± 38 mmHg to 24 ± 26 mmHg and reduction in NYHA class from 2.8 ± 0.5 to 1.7 ± 0.8 were observed (both P < 0.001). The LVOTG change was similar in both groups (P = 0.264), and symptoms were more affected by ASA (P = 0.001). Conclusion: ASA and DDD pacing were similarly effective in reducing LVOTG. The symptoms improvement was more expressed in patients treated with ASA.
    Full-text · Article · Nov 2013 · The Scientific World Journal
  • Source
    • "The prognosis is by no means easier, since the severity of the disease varies even between direct relatives. It has been observed that the presence of a given mutation can correspond to a benign manifestation in one individual and result in SCD in another (Maron et al. 2009, Alcalai et al. 2008). Fig. 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Enrichment analysis is well established in the field of transcriptomics, where it is used to identify relevant biological features that characterize a set of genes obtained in an experiment. This article proposes the application of enrichment analysis as a first step in a disease prognosis methodology, in particular of diseases with a strong genetic component. With this analysis the objective is to identify clinical and biological features that characterize groups of patients with a common disease, and that can be used to distinguish between groups of patients associated with disease-related events. Data mining methodologies can then be used to exploit those features, and assist medical doctors in the evaluation of the patients in respect to their predisposition for a specific event. In this work the disease hypertrophic cardiomyopathy (HCM) is used as a case-study, as a first test to assess the feasibility of the application of an enrichment analysis to disease prognosis. To perform this assessment, two groups of patients have been considered: patients that have suffered a sudden cardiac death episode and patients that have not. The results presented were obtained with genetic data and the Gene Ontology, in two enrichment analyses: an enrichment profiling aiming at characterizing a group of patients (e.g. that suffered a disease-related event) based on their mutations; and a differential enrichment aiming at identifying differentiating features between a sub-group of patients and all the patients with the disease. These analyses correspond to an adaptation of the standard enrichment analysis, since multiple sets of genes are being considered, one for each patient. The preliminary results are promising, as the sets of terms obtained reflect the current knowledge about the gene functions commonly altered in HCM patients, thus allowing their characterization. Nevertheless, some factors need to be taken into consideration before the full potential of the enrichment analysis in the prognosis methodology can be evaluated. One of such factors is the need to test the enrichment analysis with clinical data, in addition to genetic data, since both types of data are expected to be necessary for prognosis purposes.
    Full-text · Article · Oct 2013 · Journal of Biomedical Semantics
  • Source
    • "Ulteriormente surgieron una gran cantidad de reportes de estudios histopatológicos, aparte de una serie de complicaciones adicionales, revelando la compleja heterogeneidad clínica de esta enfermedad ; complejidad ésta que persiste aún hoy en día (Ommen , 2011). En años recientes se inició una nueva etapa en el estudio de la MCH que incluyeron las técnicas genéticas (Jarcho et al., 1989, ver revisión en Maron et al., 2012) y de ecocardiografía (Botstein et al., 1980, Maron et al., 2009). Luego, con el auge del estudio del genoma humano, se detectó la primera mutación en el gen que codifica para la miosina cardíaca (MYH7), como causante de la MCH en una familia afectada (Geisterfer-Lowrance et al., 1990). "
    [Show abstract] [Hide abstract]
    ABSTRACT: RE PORT OF A NEW MUTATION (Val748Leu) ASSOCIATED WITH HYPERTROPHIC MIOCARDIOPATHY LOCATED IN THE C5 DOMAIN OF THE CARDIAC MYOSIN BINDING PROTEIN-C (cMyBP-C) Hypertophic miocardiopathy (HMC) is a primary hearth disease mainly characterized by left ventricle hypertrophy, its most serious consequence being sudden death. It has been associated to sarcomeric protein mutations, cardiac β-myosin and the cardiac myosin binding protein-C (cMyBP-C) being the most affected. Since until now, only clinical diagnostic of HCM has been performed in Venezuela, it was decided to study it at the genetic level. In collaboration with the Asociación Cardiovascular Centro Occidental (ASCARDIO), blood samples from clinically diagnosed HCM patients living in Lara state, Venezuela, were analyzed. Following informed consent, genomic DNA was isolated from each patient and control, the exons that conform three of ther genes associated with HCM (MYBPC3, MYH7, MYL2) were amplified by PCR and sequenced to detect possible mutations. A new mutation found: a substitution G>C (Val748Leu) in exon 24 of the MYBPC3 gene. Utilizing the atomic structure of the central C5 (PDB 1GXE) domain of the human cardiac isoform of cMyBP-C, the mutation was localized in the F chain of the C5 domain of cMyBP-C. This location could specifically affect the establishment of the FG contact, which is considered as the initial step in the C5 domain folding. Therefore, we propose that the alteration of such folding could be associated with HCM, contributing to the observed clinical phenotype.
    Full-text · Article · Sep 2013 · Interciencia
Show more