Thomas R. Kimball

ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: Summary article: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (ACC/AHA/ASE committee to update the 1997 guidelines for the clinical application of echocardiography)

The previous guideline for the use of echocardiography was published in March 1997. Since that time, there have been significant advances in the technology of echocardiography and growth in its clinical use and in the scientific evidence leading to recommendations for its proper use. Each section has been reviewed and updated in evidence tables, and where appropriate, changes have been made in recommendations. A new section on the use of intraoperative transesophageal echocardiography (TEE) is being added to update the guidelines published by the American Society of Anesthesiologists and the Society of Cardiovascular Anesthesiologists. There are extensive revisions, especially of the sections on ischemic heart disease; congestive heart failure, cardiomyopathy, and assessment of left ventricular (LV) function; and screening and echocardiography in the critically ill. There are new tables of evidence and extensive revisions in the ischemic heart disease evidence tables. Because of space limitations, only those sections and evidence tables with new recommendations will be printed in this summary article. Where there are minimal changes in a recommendation grouping, such as a change from Class IIa to Class I, only that change will be printed, not the entire set of recommendations. Advances for which the clinical applications are still being investigated, such as the use of myocardial contrast agents and three-dimensional echocardiography, will not be discussed. The original recommendations of the 1997 guideline are based on a Medline search of the English literature from 1990 to May 1995. The original search yielded more than 3000 references, which the committee reviewed. For this guideline update, literature searching was conducted in Medline, EMBASE, Best Evidence, and the Cochrane Library for English-language meta-analyses and systematic reviews from 1995 through September 2001. Further searching was conducted for new clinical trials on the following topics: echocardiography in adult congenital heart disease, echocardiography for evaluation …

The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice

Members of the mitogen‐activated protein kinase (MAPK) cascade such as extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac‐restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus‐infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation. MEK1 transgenic mice and MEK1 adenovirus‐infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1–ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptotsis.

Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy

Abstract— Calcineurin (PP2B) is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through the dephosphorylation and translocation of nuclear factor of activated T cell (NFAT) transcription factors. Whereas calcineurin-NFAT signaling has been implicated in regulating the hypertrophic growth of the myocardium, considerable controversy persists as to its role in maintaining versus initiating hypertrophy, its role in pathological versus physiological hypertrophy, and its role in heart failure. To address these issues, NFAT-luciferase reporter transgenic mice were generated and characterized. These mice showed robust and calcineurin-specific activation in the heart that was inhibited with cyclosporin A. In the adult heart, NFAT-luciferase activity was upregulated in a delayed, but sustained manner throughout eight weeks of pathological cardiac hypertrophy induced by pressure-overload, or more dramatically following myocardial infarction-induced heart failure. In contrast, physiological hypertrophy as produced in two separate models of exercise training failed to show significant calcineurin-NFAT coupling in the heart at multiple time points, despite measurable increases in heart to body weight ratios. Moreover, stimulation of hypertrophy with growth hormone–insulin-like growth factor-1 (GH-IGF-1) failed to activate calcineurin-NFAT signaling in the heart or in culture, despite hypertrophy, activation of Akt, and activation of p70 S6K. Calcineurin A&bgr; gene–targeted mice also showed a normal hypertrophic response after GH-IGF-1 infusion. Lastly, exercise- or GH-IGF-1–induced cardiac growth failed to show induction of hypertrophic marker gene expression compared with pressure-overloaded animals. Although a direct cause-and-effect relationship between NFAT-luciferase activity and pathological hypertrophy was not proven here, our results support the hypothesis that separable signaling pathways regulate pathological versus physiological hypertrophic growth of the myocardium, with calcineurin-NFAT potentially serving a regulatory role that is more specialized for maladaptive hypertrophy and heart failure.

ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography

This document was approved by the American College of Cardiology Foundation Board of Trustees in May 2003, by the American Heart Association Science Advisory and Coordinating Committee in May 2003, and by the American Society of Echocardiography Board of Directors in May 2003. When citing this document, the American College of Cardiology, American Heart Association, and American Society of Echocardiography request that the following citation format be used: Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, Douglas PS, Faxon DP, Gillam LD, Kimball TR, Kussmaul WG, Pearlman AS, Philbrick JT, Rakowski H, Thys DM. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). 2003. American College of Cardiology Web Site. Available at: www.acc.org/clinical/guidelines/echo/index.pdf. This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), the American Heart Association (www.americanheart.org), and the American Society of Echocardiography (www.asecho.org). Single copies of this document are available by calling 1800-253-4636 or writing the American College of Cardiology Foundation, Resource Center, at 9111 Old Georgetown Road, Bethesda, MD 20814-1699. Ask for reprint number 71-0264. To obtain a reprint of the Summary Article published in the September 3, 2003 issue of the Journal of the American College of Cardiology, the September 2, 2003 issue of Circulation, and the October 2003 issue of the Journal of the American Society of Echocardiography, ask for reprint number 71-0263. To purchase bulk reprints (spec© 2003 by the American College of Cardiology Foundation and the American Heart Association, Inc.

TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II

Angiotensin II (Ang II), a potent hypertrophic stimulus, causes significant increases in TGFb1 gene expression. However, it is not known whether there is a causal relationship between increased levels of TGF-beta1 and cardiac hypertrophy. Echocardiographic analysis revealed that TGF-beta1-deficient mice subjected to chronic subpressor doses of Ang II had no significant change in left ventricular (LV) mass and percent fractional shortening during Ang II treatment. In contrast, Ang II-treated wild-type mice showed a >20% increase in LV mass and impaired cardiac function. Cardiomyocyte cross-sectional area was also markedly increased in Ang II-treated wild-type mice but unchanged in Ang II-treated TGF-beta1-deficient mice. No significant levels of fibrosis, mitotic growth, or cytokine infiltration were detected in Ang II-treated mice. Atrial natriuretic factor expression was approximately 6-fold elevated in Ang II-treated wild-type, but not TGF-beta1-deficient mice. However, the alpha- to beta-myosin heavy chain switch did not occur in Ang II-treated mice, indicating that isoform switching is not obligatorily coupled with hypertrophy or TGF-beta1. The Ang II effect on hypertrophy was shown not to result from stimulation of the endogenous renin-angiotensis system. These results indicate that TGF-beta1 is an important mediator of the hypertrophic growth response of the heart to Ang II.

American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography

UNLABELLED ACCREDITATION STATEMENT: The American Society of Echocardiography (ASE) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASE designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.trade mark Physicians should only claim credit commensurate with the extent of their participation in the activity. The American Registry of Diagnostic Medical Sonographers and Cardiovascular Credentialing International recognize the ASEs certificates and have agreed to honor the credit hours toward their registry requirements for sonographers. The ASE is committed to resolving all conflict-of-interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated. TARGET AUDIENCE This activity is designed for all cardiovascular physicians, cardiac sonographers, and nurses with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, sonographers, and other medical professionals having a specific interest in contrast echocardiography may be included. OBJECTIVES Upon completing this activity, participants will be able to: 1. Demonstrate an increased knowledge of the applications for contrast echocardiography and their impact on cardiac diagnosis. 2. Differentiate the available ultrasound contrast agents and ultrasound equipment imaging features to optimize their use. 3. Recognize the indications, benefits, and safety of ultrasound contrast agents, acknowledging the recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information. 4. Identify specific patient populations that represent potential candidates for the use of contrast agents, to enable cost-effective clinical diagnosis. 5. Incorporate effective teamwork strategies for the implementation of contrast agents in the echocardiography laboratory and establish guidelines for contrast use. 6. Use contrast enhancement for endocardial border delineation and left ventricular opacification in rest and stress echocardiography and unique patient care environments in which echocardiographic image acquisition is frequently challenging, including intensive care units (ICUs) and emergency departments. 7. Effectively use contrast echocardiography for the diagnosis of intracardiac and extracardiac abnormalities, including the identification of complications of acute myocardial infarction. 8. Assess the common pitfalls in contrast imaging and use stepwise, guideline-based contrast equipment setup and contrast agent administration techniques to optimize image acquisition.

Left Ventricular Geometry and Severe Left Ventricular Hypertrophy in Children and Adolescents With Essential Hypertension

BACKGROUND Left ventricular (LV) hypertrophy has been established as an independent risk factor for cardiovascular disease in adults. Recent research has refined this relationship by determining a cutpoint of 51 g/m(2.7) for LV mass index indicative of increased risk and defining LV geometric patterns that are associated with increased risk. The purpose of this study was to evaluate severe LV hypertrophy and LV geometry in children and adolescents with essential hypertension. METHODS AND RESULTS A cross-sectional study of young patients (n=130) with persistent blood pressure elevation above the 90th percentile was conducted. Nineteen patients (14%) had LV mass greater than the 99th percentile; 11 of these were also above the adult cutpoint of 51 g/m(2.7). Males, subjects with greater body mass index, and those who had lower heart rate at maximum exercise were at significantly (P<.05) higher risk of severe LV hypertrophy. In addition, 22 patients (17%) had concentric LV hypertrophy, a geometric pattern that is associated with increased risk of cardiovascular disease in adults. Seven patients had LV mass index above the cutpoint and concentric hypertrophy. No consistent significant determinants of LV geometry were identified in these children and adolescents with hypertension. CONCLUSIONS Severe LV hypertrophy and abnormal LV geometry are relatively prevalent in young patients with essential hypertension. These findings suggest that these patients may be at risk for future cardiovascular disease and underscore the importance of recognition and treatment of blood pressure elevation in children and adolescents. Weight loss is an important component of therapy in young patients with essential hypertension who are overweight.

GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation

Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-&bgr; superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene–targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.

Age-Specific Reference Intervals for Indexed Left Ventricular Mass in Children

BACKGROUND In older children, one of the standards for indexing left ventricular mass (LVM) is height raised to an exponential power of 2.7. The purpose of this study was to establish a normal value for the pediatric age group and to determine how, if at all, LVM/height(2.7) varies in children. METHODS M-mode echocardiography was performed in 2,273 nonobese, healthy children (1,267 boys, 1,006 girls; age range 0-18 years). Curves were constructed for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th quantiles of LVM/height(2.7). RESULTS In children aged > 9 years, median LVM/height(2.7) ranged from 27 to 32 g/m(2.7) and had little variation with age. However, in those aged < 9 years, LVM/height(2.7) varied significantly, and percentiles for newborns and infants were approximately double the levels for older children and adolescents: the 95th percentile ranged from 80 g/m(2.7) for newborns to 40 g/m(2.7) for 11-year-olds. CONCLUSION For patients aged > 9 years, quantiles of LVM/height(2.7) vary little, and values > 40 g/m(2.7) in girls and > 45 g/m(2.7) in boys can be considered abnormal (ie, > 95th percentile). However, for patients aged < 9 years, the index varies with age, and therefore, measured LVM/height(2.7) must be compared with percentile curves, which are provided. This variation in LVM/height(2.7) in younger children indicates that a better indexing method is needed for this age group. Nevertheless, these data are valuable in that they provide normal values with which patient data can be compared.

Stroke volume and cardiac output in normotensive children and adults. Assessment of relations with body size and impact of overweight.

BACKGROUND Relations between organs and body size are not linear but rather follow allometric (growth) relations characterized by their powers (exponents). METHODS AND RESULTS Stroke volume (SV) by M-mode echocardiography was related to height, weight, body surface area (BSA), and ideal BSA (derived from ideal body weight for given height) in 970 normotensive individuals (1 day to 85 years old; 426 < 18 years old; 204 overweight to obese; 426 female). In normal-weight children, adults, and the entire population, SV was related by allometric relations to BSA (power = 0.82 to 1.19), body weight (power = 0.57 to 0.71), and height (power = 1.45 to 2.04) (all P < .0001). Relations of cardiac output to measures of body size had lower allometric powers than those for SV in the entire population (0.41 for body weight, 0.62 for BSA, and 1.16 for height). In overweight adults, observed SVs were 17% greater than predicted for ideal BSA, a difference that was approximated by normalization of SV for height to age-specific allometric powers. Similarly, observed cardiac output was 19% greater than predicted for ideal BSA, a difference that was accurately detected by use of cardiac output/height to age-specific allometric powers but not of BSA to the first power. CONCLUSIONS Indices of SV and cardiac output for BSA are pertinent when the effect of obesity needs to be removed, because these indices obscure the impact of obesity. To detect the effect of obesity on LV pump function, normalization of SV and cardiac output for ideal BSA or for height to its age-specific allometric power should be practiced.