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This study used cardiovascular magnetic resonance (CMR) to evaluate whether elevated extracellular volume (ECV) was associated with mitral valve prolapse (MVP) or if elevated ECV was a consequence of remodeling independent of primary mitral regurgitation (MR) etiology.Replacement fibrosis in primary MR is more prevalent in MVP; however, data on ECV as a surrogate for diffuse interstitial fibrosis in primary MR are limited.Patients with chronic primary MR underwent comprehensive CMR phenotyping and were stratified into an MVP cohort (2 mm leaflet displacement on a 3-chamber cine CMR) and a non-MVP cohort. Factors associated with ECV and replacement fibrosis were assessed. The association of ECV and symptoms related to MR and clinical events (mitral surgery and cardiovascular death) was ascertained.A total of 424 patients with primary MR (229 with MVP and 195 non-MVP) were enrolled. Replacement fibrosis was more prevalent in the MVP cohort (34.1% vs. 6.7%; p 0.001), with bi-leaflet MVP having the strongest association with replacement fibrosis (odds ratio: 10.5; p 0.001). ECV increased with MR severity in a similar fashion for both MVP and non-MVP cohorts and was associated with MR severity but not MVP on multivariable analysis. Elevated ECV was independently associated with symptoms related to MR and clinical events.Although replacement fibrosis was more prevalent in MVP, diffuse interstitial fibrosis as inferred by ECV was associated with MR severity, regardless of primary MR etiology. ECV was independently associated with symptoms related to MR and clinical events. (DeBakey Cardiovascular Magnetic Resonance Study [DEBAKEY-CMR]; NCT04281823).

Objectives This study hypothesized that left ventricular (LV) enlargement in Barlow disease can be explained by accounting for the total volume load that consists of transvalvular mitral regurgitation (MR) and the prolapse volume. Background Barlow disease is characterized by long prolapsing mitral leaflets that can harbor a significant amount of blood—the prolapse volume—at end-systole. The LV in Barlow disease can be disproportionately enlarged relative to MR severity, leading to speculation of Barlow cardiomyopathy. Methods Cardiac magnetic resonance (CMR) was used to compare MR, prolapse volume, and heart chambers remodeling in patients with Barlow disease (bileaflet prolapse [BLP]) and in single leaflet prolapse (SLP). Results A total of 157 patients (81 with BLP, 76 with SLP) were included. Patients with SLP were older and more had hypertension. Patients with BLP had more heart failure. Indexed LV end-diastolic volume was larger in BLP despite similar transvalvular MR. However, the prolapse volume was larger in BLP, which led to larger total volume load compared with SLP. Increasing tertiles of prolapse volume and MR both led to an incremental increase in LV end-diastolic volume in BLP. Using the total volume load improved the correlation with indexed LV end-diastolic volume in the BLP group, which closely matched that of SLP. A multivariable model that incorporated the prolapse volume explained left heart chamber enlargement better than a MR-based model, independent of prolapse category. Conclusions The prolapse volume is part of the total volume load exerted on the LV during the cardiac cycle and could help explain the disproportionate LV enlargement relative to MR severity noted in Barlow disease.

Coenzyme Q10 (CoQ10) is a naturally occurring compound that is found in animals and all humans. It has a fundamental role in cellular energy production. Although it is produced in the body, tissue deficiency can occur due to medications such as statins, which inhibit the mevalonate pathway. The clinical syndromes of statin-associated muscle symptoms (SAMS) and some of the features observed in patients with heart failure (HF) may be related to blood and tissue deficiency of CoQ10. Numerous clinical trials of CoQ10 in SAMS have yielded conflicting results. Yet, the weight of evidence as reflected in meta-analyses supports the use of exogenous CoQ10 in SAMS. In patients with HF, large-scale randomized clinical trials are lacking, although one relatively contemporary trial, Q-SYMBIO, suggests an adjunctive role for CoQ10. The possibility that statin-related CoQ10 deficiency may play a role in patients with diastolic HF is an intriguing hypothesis that warrants further exploration.

Background Quantitation of tricuspid regurgitant (TR) severity can be challenging with conventional echocardiographic imaging and may be better evaluated using cardiovascular magnetic resonance (CMR). Objectives In patients with functional TR, this study sought to examine the relationship between TR volume (TRVol) and TR fraction (TRF) with all-cause mortality. Methods We examined 547 patients with functional TR using CMR to quantify TRVol and TRF. The primary outcome was all-cause mortality. Thresholds for mild, moderate, and severe TR were derived based on natural history outcome data. Results During a median follow-up of 2.6 years (interquartile range: 1.7 to 3.3 years), there were 93 deaths, with an estimated 5-year survival of 79% (95% confidence interval [CI]: 73% to 83%). After adjustment of clinical and imaging variables, including RV function, both TRF (adjusted hazard ratio [AHR] per 10% increment: 1.26; 95% CI: 1.10 to 1.45; p = 0.001) and TRVol (AHR per 10-ml increment: 1.15; 95% CI: 1.04 to 1.26; p = 0.004) were associated with mortality. Patients in the highest-risk strata of TRVol ≥45 ml or TRF ≥50% had the worst prognosis (AHR: 2.26; 95% CI: 1.36 to 3.76; p = 0.002 for TRVol and AHR: 2.60; 95% CI: 1.45 to 4.66; p = 0.001 for TRF). Conclusions This is the first study to use CMR to assess independent prognostic implications of functional TR. Both TRF and TRVol were associated with increased mortality after adjustment for clinical and imaging covariates, including right ventricular ejection fraction. A TRVol of ≥45 ml or TRF of ≥50% identified patients in the highest-risk strata for mortality. These CMR thresholds should be used for patient selection in future trials to determine if tricuspid valve intervention improves outcomes in this high-risk group.

Objective To determine the prevalence of multi-drug resistant variants among patients failing on a nucleoside reverse transcriptase inhibitor (NRTI) based regimen with a detectable viral load ≥ 1000 copies/ml among patients harboring HIV subtype A, C and D. Methods Samples were obtained from patients who were failing on an NRTI based regimen. Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off Results Analysis of the Non-nucleoside reverse transcriptase inhibitor (NNRTI) coding region revealed that the K101 and the Y181 mutations were more predominant among subtype C than subtype A and D. Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. Furthermore, the Q151M mutation complex which involves mutations in multiple domains was significantly more prominent among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex being significantly more predominant among patients harboring subtype C viruses. Even in patients with a susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that by the time they are detectable, cross resistance to other drugs has occurred in some cases.

Background Chronic aortic regurgitation (AR) can be associated with myocardial scarring. It is unknown if scarring in AR is linked to poor outcomes and whether aortic valve replacement impacts this association. We investigated the relationship of myocardial scarring to mortality in chronic AR using cardiac magnetic resonance. Methods and Results We enrolled patients with moderate or greater AR between 2009 and 2019 and performed a blinded assessment of left ventricle remodeling, AR severity, and presence and extent of myocardial scarring by late gadolinium enhancement. The primary outcome was all‐cause mortality. We followed 392 patients (median age 62 [interquartile range, 51–71] years), and 78.1% were men, and 25.8% had bicuspid valves. Median aortic valve regurgitant volume was 39 mL (interquartile range, 30–60). Myocardial scar was present in 131 (33.4%) patients. Aortic valve replacement was performed in 165 (49.1%) patients. During follow‐up, up to 10.8 years (median 32.3 months [interquartile range, 9.8–69.5]), 51 patients (13%) died. Presence of myocardial scar (hazard ratio [HR], 3.62; 95% CI, 2.06–6.36; P P P P =0.02). Among patients with myocardial scar, aortic valve replacement was independently associated with a lower risk of mortality (HR, 0.34; 95% CI, 0.12–0.97; P =0.03), even after adjustment for confounders. Conclusions In aortic regurgitation, myocardial scar is independently associated with a 2.5‐fold increase risk in mortality. Aortic valve replacement was associated with a reduction in risk of mortality in patients with scarring.

Recent studies reported left ventricular (LV) fibrosis in patients with primary mitral regurgitation (MR) thought to be principally due to mitral valve prolapse (MVP).This study sought to evaluate the prevalence, characteristics, and prognostic implications of LV fibrosis in a large cohort of primary MR patients with and without MVP using cardiovascular magnetic resonance (CMR).Patients referred for contrast CMR assessment of chronic primary MR were enrolled and underwent comprehensive assessment of cardiac remodeling, severity of MR, and LV replacement fibrosis. Primary MR patients were stratified into: an MVP group if there was2 mm mitral leaflet displacement on cine-CMR, or a non-MVP group. Patients were followed for arrhythmic events (sudden cardiac death, aborted sudden cardiac arrest, and sustained or inducible ventricular arrhythmia).A total of 356 primary MR patients (177 MVP and 179 non-MVP) were enrolled. LV fibrosis was more prevalent in the MVP group than the non-MVP group (36.7% vs. 6.7%; p 0.001). The presence of MVP had the strongest association (odds ratio: 6.82; p 0.001) with LV fibrosis even after adjustment for clinical variables, measures of cardiac remodeling, and MR severity. During follow-up (median 1,354 days), MVP patients with LV fibrosis had the highest event rate for arrhythmic events.In primary MR patients, LV fibrosis is more prevalent in MVP than non-MVP, suggesting a unique pathophysiology beyond volume overload in MVP. LV fibrosis in primary MR may represent a risk marker of arrhythmic events.

Echocardiograms are the second most frequently utilized cardiac test after electrocardiograms and are most commonly ordered by noncardiology providers. Echocardiogram reports are designed to communicate a comprehensive interpretation of cardiac function; however, it is not known how well these reports are understood by ordering providers. In order to identify gaps in understanding and target potential areas for improvement, we developed a questionnaire testing various topics reported on a standard transthoracic echocardiogram report. This questionnaire was administered to general medicine and cardiology trainees and attending physicians at 2 large academic institutions. Questionnaire response rate was 81%. There were several topics that were not well understood by general providers; these included viability of an akinetic region, pulmonary artery systolic pressure, left ventricular filling pressure, recognition of abnormal structures, and method of identifying of intracardiac thrombus. In conclusion, strategies such as improved communication techniques and adjustment of reporting format should be implemented to increase the clinical value of the echocardiogram.

Objectives The goal of this study was to evaluate the diagnostic performance of a comprehensive, multicomponent cardiac magnetic resonance (CMR) study for assessment of left atrial (LA) and left atrial appendage (LAA) thrombus. Background Pre-operative evaluation for pulmonary vein isolation (PVI) typically requires tomographic imaging to define pulmonary venous anatomy and transesophageal echocardiogram (TEE) to assess for the presence of LA/LAA thrombus. CMR is increasingly being used to define pulmonary venous anatomy before PVI. Limited data are available on the utility of a multicomponent CMR protocol in assessing LA/LAA thrombus. Methods We studied patients who underwent multicomponent CMR for evaluation of pulmonary venous anatomy before PVI and underwent TEE within 7 days. LA and LAA thrombi were evaluated by using CMR as follows: 1) cine-CMR; 2) contrast-enhanced magnetic resonance angiography; and 3) equilibrium phase delayed enhancement (DE) CMR with a long inversion time (TI) of 600 ms (long TI DE-CMR). Components of the CMR study were evaluated for diagnostic performance for detection of LA or LAA thrombus using TEE as the reference standard. Results During the study period, 261 patients were assessed. The median CHA 2 DS 2 VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 2, and 73.6% of patients were undergoing anticoagulation therapy. CMR and TEE were performed within 1.3 ± 2.3 days. LA/LAA thrombi were discovered in 9 patients (3.5%) by using TEE. Among the CMR techniques performed, long TI DE-CMR had the highest diagnostic accuracy (99.2%), sensitivity (100%), and specificity (99.2%), followed by contrast-enhanced magnetic resonance angiography (accuracy 94.3%; sensitivity 66.7%; and specificity 95.2%) and cine-CMR (accuracy 91.6%; sensitivity 66.7%; and specificity 92.5%). Conclusions In patients referred for PVI, CMR could be a single complete diagnostic study for assessment of pulmonary venous anatomy as well as presence of LA/LAA thrombi, thus reducing the number of pre-operative tests before PVI. Long TI DE-CMR has the best diagnostic performance and should be used for the detection of LA/LAA thrombi.

Grading of aortic regurgitation (AR) and mitral regurgitation (MR) is similar in the guidelines despite distinct differences in LV pathophysiology. We compared LV remodeling in AR and MR patients and evaluated optimal cutoffs for significant AR in relation to the need for aortic valve replacement (

Barlow's disease is characterized by large prolapsing leaflets that can harbor significant amount of blood - prolapse volume (PV) - at end-systole. Barlow's left ventricles (LV) can be disproportionately enlarged relative to the severity of mitral regurgitation (MR), leading to speculation of a

Mural thrombus formation on an infarcted segment of the left ventricle (LV) is a well-recognized complication of a myocardial infarction (MI). A majority of these thrombi occur within the first 30 days after an anterior ST-segment elevation myocardial infarction (STEMI) and are considered a cause of

The evaluation of ischemic heart disease is the cornerstone of clinical Cardiology. Although there are many means of ischemic evaluation, all are with their own limitations. While perfusion-based studies are highly sensitive, they lack specificity. Conversely, systolic wall motion analysis with echocardiography tends to have high specificity; however, the sensitivity may be limited by short duration of systolic abnormalities when present. With the advent of Doppler echocardiography, and more specifically tissue Doppler imaging, and strain and strain rate imaging, a more comprehensive evaluation of the left ventricular function is available, including diastole. Diastolic abnormalities in the setting of ischemia are now being studied using these new parameters and have been suggested as a reliable marker of ischemia. Exercise-induced abnormalities in diastolic parameters have improved sensitivities and specificities over traditional stress testing and persist longer than systolic abnormalities. A review of the medical literature regarding the subject will be discussed here.

The heterogeneous reaction of nitrogen dioxide (NO(2)) on fresh and coated soot surfaces has been investigated to assess its role in night-time formation of nitrous acid (HONO) in the atmosphere. Soot surfaces were prepared by incomplete combustion of propane and kerosene fuels under lean and rich flame conditions and then processed by heating to evaporate semivolatile species or by coating with pyrene, sulfuric acid, or glutaric acid. Uptake kinetics and HONO yield measurements were performed in a low-pressure fast-flow reactor coupled to a chemical ionization mass spectrometer (CIMS), using atmospheric-level NO(2) concentrations. The uptake coefficient and the HONO yield upon interaction of NO(2) with nascent soot depend on the type of fuel and combustion regime and are the highest for samples prepared using fuel rich flame. Heating the nascent soot samples before exposure to NO(2) removes the organic material from the soot backbone, leading to a significant increase in NO(2) uptake coefficient and HONO yield. Continuous exposure to NO(2) reduces the reactivity of soot because of irreversible deactivation of the surface sites. Our results support the oxidation-reduction mechanism involving adsorptive and reactive centers on soot surface where NO(2) is converted to HONO and other products. Coating of the soot surface by different materials to simulate atmospheric aging has a strong impact on its reactivity toward NO(2) and the resulting HONO production. Coating of pyrene has little effect on either reaction rate or HONO yield. Sulfuric acid coating does not alter the uptake coefficient, but significantly reduces the amount of HONO formed. Coating of glutaric acid significantly increases NO(2) uptake coefficient and HONO yield. The results of our study indicate that the reactivity and HONO generating capacity of internally mixed soot aerosol will depend on the chemical composition of the coating material and hence will vary considerably in different polluted environments.

The aim was to evaluate the safety of stress echocardiography using contrast (CE) for endocardial enhancement compared with a noncontrast (NCE) cohort in a large nonselect population. The recent Food and Drug Administration warning cited lack of data for safety regarding the use of contrast in conjunction with stress echocardiography. A detailed record review was performed for 5,069 consecutive patients who underwent stress echocardiography (58% pharmacologic, 42% exercise) during an 8-year period. Contrast use, hemodynamics, and adverse clinical and electrocardiographic events were evaluated until time of discharge from the laboratory. Contrast was administered to 2,914 patients (58%) and was higher in in-patients (66%) and during dobutamine stress (67%). Compared with the NCE group, the CE group was older (median age 61 vs 58 years) and had more depressed left ventricular ejection fraction

Objectives The purpose of this work was to assess whether the incorporation of intermediate stages during supine bicycle exercise echocardiography (BEE) improves the accuracy of detection of coronary artery disease (CAD) through the evaluation of a biphasic response. Background Exercise echocardiography allows cardiac imaging throughout exercise. Methods Exercise echocardiography was performed in 104 patients (mean age 57 ± 11 years, 37 women), 91 of whom underwent coronary angiography. The BEE protocol started at 25 W with increments of 25 W every 3-min stage. Images were digitized at rest, 25 W, 50 W, and peak exercise. Two experienced observers and 1 less experienced observer interpreted rest and peak exercise images, with and without the intermediate stages. Results Imaging during intermediate stages improved the sensitivity for detection of all individual vessel stenoses (78% vs. 58%, p 10% predicted CAD (sensitivity 94%, specificity 74%) and was more marked than changes observed from rest to peak exercise. The severity of coronary stenosis related to the double product achieved at the onset of ischemia during exercise (r = −0.61, p Conclusions During BEE, the acquisition and interpretation of intermediate stages of exercise in addition to peak exercise improves the detection of CAD and allows a better physiologic evaluation of the severity of coronary stenosis.

Echocardiography has evolved over the past 45 years from a simple M-mode tracing to an array of technologies that include two-dimensional imaging, pulsed and continuous wave spectral Doppler, color flow and tissue Doppler, and transesophageal echocardiography. Together, these modalities provide a comprehensive anatomic and functional evaluation of cardiac chambers and valves, pericardium, and ascending and descending aorta. The switch from analog to digital signal processing revolutionized the field of ultrasound, resulting in improved image resolution, smaller instrumentation that allows bedside evaluation and diagnosis of patients, and digital image storage for more accurate quantification and comparison with previous studies. It also opened the door for new advances such as harmonic imaging, automated border detection and quantification, 3-dimensional imaging, and speckle tracking. This article offers an overview of some newer developments in echocardiography and their promising applications.

Objectives We sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI). Background PG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure. Methods In an international, randomized, double-blind, placebo-controlled study, 253 patients with first ST-segment elevation MI and ejection fraction between 15% and 40% were enrolled 48 ± 24 h after MI and treated with placebo or PG-116800 for 90 days. Major efficacy end points were changes in LV volumes as determined by serial echocardiography, and clinical and safety outcomes were also collected. Results In total, 203 patients (80%) completed 90 days of treatment and had evaluable baseline and 90-day echocardiograms. The proportion of patients with anterior MI (78% vs. 81%) and primary percutaneous coronary intervention (90% vs. 91%) along with baseline LV ejection fraction (35.5% vs. 36.8%) did not differ between PG-116800-treated and placebo-treated patients. There was no difference in the change in LV end-diastolic volume index from days 0 to 90 with PG-116800 versus placebo (5.09 ± 1.45 ml/m2vs. 5.48 ± 1.41 ml/m2, p = 0.42). Changes in LV diastolic volume, LV systolic volume, LV ejection fraction, sphericity index, plus rates of death or reinfarction were not significantly improved with PG-116800. PG-116800 was well tolerated; however, there was increased incidence of arthralgia and joint stiffness without significant increase in overall musculoskeletal adverse events (21% vs. 15%, p = 0.33). Conclusions Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI.

OBJECTIVE To study whether the use of echocardiographic left ventricular (LV) wall motion index (WMI) is a dependable parameter for identifying patients with LV dysfunction to be enrolled in multicenter trials. METHODS Videotaped echocardiographic examinations from 200 randomly selected patients that were screened for inclusion into the DIAMOND-CHF and DIAMOND-MI trials were reevaluated by an external expert echocardiographer. WMI was calculated using the 16-segment LV model. RESULTS The external echocardiographer systematically found lower values of WMI than the core laboratory. The average difference in WMI was 0.18 (SD: 0.33) in the DIAMOND-CHF trial and 0.09 (SD: 0.33) in the DIAMOND-MI trial. The difference in WMI exceeded 0.33 in 34% of the patients in both trials. The cutoff value for inclusion into the DIAMOND trials was WMI < or = 1.2. There was an agreement on WMI dichotomized to below or above 1.2 in 82% of the patients in both trials (kappa coefficient 0.66 for the DIAMOND-CHF and 0.55 for the DIAMOND-MI). CONCLUSIONS Despite substantial interlaboratory variation in WMI in individual patients and a systematic lower WMI score by the external echocardiographer there was an acceptable overall agreement for identifying patients with severe impairment of LV function. This not only underscores the value of LV-WMI as a useful tool for selecting high-risk patients to be included in multicenter studies but also serves to warn against the use of rigid cutoff values for WMI in the treatment of individual patients.

Myocardial ischemia leads to changes in regional wall stress. Induction of ischemia during a treadmill exercise, although brief, may lead to transient elevation in the plasma level of B-type natriuretic peptide (BNP) from baseline levels, which could serve as a biochemical marker of myocardial ischemia.Sixty subjects (mean age 57, 41 men) undergoing myocardial single-photon emission computed tomography (SPECT) in conjunction with Bruce protocol treadmill exercise for evaluation of chest pain or screening for ischemia had their BNPs measured (Triage Biosite Test) at baseline, immediately postexercise, and 10 to 15 minutes after exercise.Of the 60 patients, 10 had ischemic perfusion defects by SPECT (mean 14%, range 5%-37%). In patients with no evidence of ischemia, median BNP level at baseline was 15.05 pg/mL (interquartile range 7-37.7), increased significantly immediately postexercise median level (34.7 pg/mL [14.9-67.6]), and decreased toward baseline levels within 10 to 15 minutes postexercise (20.3 pg/mL [8.6-48.5], analysis of variance P.001). This transient rise in BNP level during exercise was also observed in patients with ischemia but was more pronounced. Percent change in BNP level from baseline for each minute of exercise was significantly higher in patients with evidence of ischemia compared with those without (14% +/- SEM 2.3 vs 7% +/- SEM 1.2, P = .014). Patients with and without ischemia did not differ in age, exercise time, peak systolic or diastolic blood pressure, peak heart rate, or other baseline characteristics. A10% change in BNP level from rest per minute of exercise had a sensitivity of 80%, a specificity of 71%, and a negative predictive value of 92% to detect reversible ischemia by SPECT.Transient elevation in BNP occurs during treadmill exercise and is more pronounced in patients with ischemia. B-type natriuretic peptides may therefore be used in combination with treadmill exercise for the evaluation of coronary artery disease.

Cardiovascular disease is the leading cause of mortality for women in the United States. Coronary heart disease, which includes coronary atherosclerotic disease, myocardial infarction, acute coronary syndromes, and angina, is the largest subset of this mortality, with >240 000 women dying annually from the disease. Atherosclerotic coronary artery disease (CAD) is the focus of this consensus statement. Research continues to report underrecognition and underdiagnosis of CAD as contributory to high mortality rates in women. Timely and accurate diagnosis can significantly reduce CAD mortality for women; indeed, once the diagnosis is made, it does appear that current treatments are equally effective at reducing risk in both women and men. As such, noninvasive diagnostic and prognostic testing offers the potential to identify women at increased CAD risk as the basis for instituting preventive and therapeutic interventions. Nevertheless, the recent evidence-based practice program report from the Agency for Healthcare Research and Quality noted the paucity of women enrolled in diagnostic research studies. Consequently, much of the evidence supporting contemporary recommendations for noninvasive diagnostic studies in women is extrapolated from studies conducted predominantly in cohorts of middle-aged men. The majority of diagnostic and prognostic evidence in cardiac imaging in women and men has been derived from observational registries and referral populations that are affected by selection and other biases. Thus, a better understanding of the potential impact of sex differences on noninvasive cardiac testing in women may greatly improve clinical decision making. This consensus statement provides a synopsis of available evidence on the role of the exercise ECG and cardiac imaging modalities, both those in common use as well as developing technologies that may add clinical value to the diagnosis and risk assessment of the symptomatic and asymptomatic woman with suspected CAD.

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by a diverse array of cardiac phenotypes evolving over several decades. We have developed transgenic rabbits that fully recapitulate the phenotype of human HCM and provide for the opportunity to delineate the sequence of evolution of cardiac phenotypes, and thus, the pathogenesis of HCM. We determined evolution of biochemical, molecular, histological, structural and functional phenotypes at 4 age-periods in 47 beta-myosin heavy chain-glutamine (MyHC-Q)-403 transgenic rabbits. Ca(+2) sensitivity of myofibrillar ATPase activity was reduced very early and in the absence of other discernible phenotypes. Myocyte disarray also occurred early, prior to, and independent of hypertrophy and fibrosis. The latter phenotypes evolved predominantly during puberty in conjunction with activation of stress-related signaling kinases. Myocardial contraction and relaxation velocities were decreased early despite normal global cardiac function and in the absence of histological phenotype. Global cardiac function declined with aging, while left atrial size was increased along with Doppler indices of left ventricular filling pressure. Thus, Ca(+2) sensitivity of myofibrillar ATPase activity is a primary phenotype expressed early and independent of the ensuing phenotypes. Pathogenesis of myocyte disarray, which exhibits age-independent penetrance, differs from those of hypertrophy and fibrosis, which show age-dependent expression. Myocardial dysfunction is an early marker that predicts subsequent development of hypertrophy. These findings in an animal model that recapitulates the phenotype of human HCM, implicate involvement of multiple independent mechanisms in the pathogenesis of cardiac phenotypes in HCM.

Valvular regurgitation has long been recognized as an important cause of morbidity and mortality. Although the physical examination can alert the clinician to the presence of significant regurgitation, diagnostic methods are often needed to assess the severity of valvular regurgitation and remodeling of the cardiac chambers in response to the volume overload state. Echocardiography with Doppler has recently emerged as the method of choice for the noninvasive detection and evaluation of the severity and etiology of valvular regurgitation. This article offers a critical review of echocardiographic and Doppler techniques used in the evaluation of valvular regurgitation in the adult patient, and provides recommendations for the assessment of severity of valvular regurgitation based on the scientific literature and a consensus of a panel of experts. Issues of medical management and timing of surgical intervention will not be addressed in this article, as these have been recently published[1]. Valvular regurgitation or incompetence results from various etiologies including valvular degeneration, calcification, fibrosis or infection, alteration of the valvular support apparatus or dilatation of the valve annulus. These conditions cause poor apposition of the valvular leaflets or cusps, and may lead to prolapse, flail, restricted leaflet motion or valvular perforation. With the advent of Doppler techniques that are sensitive to detection of regurgitation, trivial and physiologic valvular regurgitation, even in a structurally normal valve, is now well recognized and is noted to occur frequently in right-sided valves. The following sections describe general considerations of the role of echocardiographic and Doppler techniques in the evaluation of regurgitant lesions. ### Role of Two-dimensional echocardiography Two-dimensional (2D) echocardiography allows an evaluation of the valvular structure as well as the impact of the volume overload on the cardiac chambers. Calcifications, tethering, flail motion or vegetations can be readily assessed, which can give indirect clues as to the severity of regurgitation. While …

Background— Systolic (Sa) and diastolic (Ea) myocardial velocities measured by tissue Doppler (TD) imaging (TDI) recently were shown to be decreased in subjects who have mutations causing hypertrophic cardiomyopathy (HCM) but who do not have left ventricular (LV) hypertrophy. By studying these subjects at a later date, we sought to determine whether TDI predicts the subsequent evolution of the HCM phenotype. Methods and Results— Serial 2D and Doppler echocardiography were performed in 12 subjects (age range, 17 to 51 years) with HCM-causing mutations on 2 occasions: before development of hypertrophy and 2 years later. Twelve age- and gender-matched family members without mutations were included as control subjects. In those with mutations, mean septal thickness and LV mass were 1.07±0.14 cm and 103.0±11 g at baseline, respectively, and increased to 1.30±0.36 cm and 193.0±78 g at follow-up ( P P P Conclusions— Subsequent development of HCM in subjects with initially reduced TD velocities establishes TDI as a reliable method for early identification of HCM mutation carriers.

Exercise (Ex) echocardiography has been shown to have significant prognostic power, independent of other known predictors of risk from an Ex stress test. The purpose of this study was to evaluate a risk index, incorporating echocardiographic and conventional Ex variables, for a more comprehensive risk stratification and identification of a very low-risk group. Two consecutive, mutually exclusive populations referred for treadmill Ex echocardiography with the Bruce protocol were investigated: hypothesis-generating (388 patients; 268 males; age 55 +/- 13 years) and hypothesis-testing (105 patients; 61 males age: 54 +/- 14 years).Cardiac events included cardiac death, myocardial infarction, late revascularization (90 days), hospital admission for unstable angina, and admission for heart failure. Mean follow-up in the hypothesis-generating population was 3.1 years. There were 38 cardiac events. Independent predictors of events by multivariate analysis were: Ex wall motion score index (odds ratio [OR] = 2.77/Unit; P.001); ischemic S-T depressionor = 1 mm (OR = 2.84; P =.002); and treadmill time (OR = 0.87/min; P =.037). A risk index was generated on the basis of the multivariate Cox regression model as: risk index = 1.02 (Ex wall motion score index) + 1.04 (S-T change) - 0.14 (treadmill time). The validity of this index was tested in the hypothesis-testing population. Event rates at 3 years were lowest (0%) in the lower quartile of risk index (-1.22 to -0.47), highest (29.6%) in the upper quartile (+0.66 to +2.02), and intermediate (19.2% to 15.3%) in the intermediate quartiles. The OR of the risk index for predicting cardiac events was 2.94/Unit ([95% confidence interval: 1.4 to 6.2]; P =.0043). Echocardiographic and Ex parameters are independent powerful predictors of cardiac events after treadmill stress testing. A risk index can be derived with these parameters for a more comprehensive risk stratification with Ex echocardiography.

Echocardiographic assessment of cardiac function can be quite difficult in the intensive care unit and may require transesophageal echocardiography (TEE). We therefore compared harmonic imaging alone or in combination with contrast to TEE in 32 consecutive patients in the intensive care units who were considered technically very difficult (≥50% of the 16 segments not visualized from any view). Excellent or adequate endocardial visualization was achieved in 13% of segments with fundamental imaging, 34% with harmonic imaging, and 87% with contrast (p

The American Society of Echocardiography has published guidelines relating to standards for training (and certification), performance, nomenclature and measurement, and quality improvement related to echocardiography.1-15 However, the Society has not previously made recommendations about what constitutes the core variables, ie, measurements and other elements, to be included in a transthoracic echocardiographic report. A document addressing this topic would be timely and could serve the following purposes: (1) Promote quality by defining the basic core of measurements and statements that constitute the report; (2) encourage the comparison of serial echocardiograms performed in patients at the same site or different sites; (3) improve communication by expediting development of structured report form software; and (4) facilitate multicenter research and analyses of cost-effectiveness. Because of these considerations, Dr Richard Kerber, President of the American Society of Echocardiography, appointed a task force in 1998 to develop recommendations for a standardized report for adult echocardiography.Various international societies have recently addressed this issue and recommended standards. The purpose of this report is not to define how to record a proper adult cardiac ultrasound examination or how to perform the measurements but, rather, to serve as a guideline to what measurements and descriptive items should be included. It is the hope of the Task Force that publication of this document will further our ongoing efforts to improve the overall quality of the practice of echocardiography.

Background The objective of this study was to examine the prognostic utility of cardiac magnetic resonance imaging (CMR) in patients with chronic mitral regurgitation undergoing mitral valve repair. Methods This study is a prospectively enrolled observational cohort study of 48 consecutive patients with chronic mitral regurgitation who had preoperative evaluation with CMR including delayed-enhancement CMR for assessment of myocardial fibrosis before undergoing mitral valve repair. Postoperative adverse clinical events were defined as intensive care unit readmission, needs of permanent cardiac pacemaker, and rehospitalization for cardiac reasons. Results The cohort comprised 33 (69%) men with a mean age of 61 ± 13 years and mean left ventricular ejection fraction of 0.63 ± 0.12. Preoperative myocardial fibrosis was detected in 40% of the patients. Median fibrosis was 4% (interquartile range, 2% to 10%). Mean follow-up duration was 11 months (interquartile range, 1 to 24 months). Adverse clinical events occurred in 16 patients. In multivariate analysis, the presence of myocardial fibrosis was independently associated with postoperative adverse clinical events (hazard ratio, 4.775; 95% confidence interval, 1.100 to 20.729; p = 0.037). The addition of the presence of myocardial fibrosis to the preoperative characteristics model significantly improved overall predictive performance ( p = 0.04). Conclusions The presence of preoperative myocardial fibrosis assessed with delayed-enhancement CMR was an independent predictor of increased adverse clinical outcomes in patients with chronic mitral regurgitation undergoing mitral valve repair. Our findings suggest that in this population, preoperative delayed-enhancement CMR may be of clinical utility.

OBJECTIVESThis study was designed to compare the hemodynamic efficacy of nonsurgical septal reduction therapy (NSRT) by intracoronary ethanol with standard therapy (surgical myectomy) for the treatment of hypertrophic obstructive cardiomyopathy (HOCM).BACKGROUNDNonsurgical septal reduction therapy has gained interest as a new treatment modality for patients with drug-refractory symptoms of HOCM; however, its benefits in comparison to surgery are unknown.METHODSForty-one consecutive NSRT patients at Baylor College of Medicine with one-year follow-up were compared with age- and gradient-matched septal myectomy patients at the Mayo Clinic. All patients had left ventricular outflow obstruction with a resting gradient ≥40 mm Hg and none had concomitant procedures.RESULTSThere were no baseline differences in New York Heart Association class, severity of mitral regurgitation, use of cardiac medications or exercise capacity. One death occurred during NSRT because of dissection of the left anterior descending artery. At one year, all improvements in both groups were similar. After surgical myectomy, more patients were on medications (p < 0.05) and there was a higher incidence of mild aortic regurgitation (p < 0.05). After NSRT, the incidence of pacemaker implantation for complete heart block was higher (22% vs. 2% in surgery; p = 0.02). However, seven of the nine pacemakers in the NSRT group were implanted before a modified ethanol injection technique and the use of contrast echocardiography.CONCLUSIONSNonsurgical septal reduction therapy resulted in a significantly higher incidence of complete heart block, but the risk was reduced with contrast echocardiography and slow ethanol injection. Surgical myectomy resulted in a significantly higher incidence of mild aortic regurgitation. Nonsurgical septal reduction therapy, guided by contrast echocardiography, is an effective procedure for treating patients with HOCM. The hemodynamic and functional improvements at one year are similar to those of surgical myectomy.

Background Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature. Methods and Results A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. Conclusions Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene.

Background Hypertrophic cardiomyopathy is a genetic disease characterized by cardiac hypertrophy, myocyte disarray, interstitial fibrosis, and left ventricular (LV) dysfunction. We have proposed that hypertrophy and fibrosis, the major determinants of mortality and morbidity, are potentially reversible. We tested this hypothesis in β-myosin heavy chain–Q 403 transgenic rabbits. Methods and Results We randomized 24 β-myosin heavy chain–Q 403 rabbits to treatment with either a placebo or simvastatin (5 mg · kg −1 · d −1 ) for 12 weeks and included 12 nontransgenic controls. We performed 2D and Doppler echocardiography and tissue Doppler imaging before and after treatment. Demographic data were similar among the groups. Baseline mean LV mass and interventricular septal thickness in nontransgenic, placebo, and simvastatin groups were 3.9±0.7, 6.2±2.0, and 7.5±2.1 g ( P P =0.002), respectively. Simvastatin reduced LV mass by 37%, interventricular septal thickness by 21%, and posterior wall thickness by 13%. Doppler indices of LV filling pressure were improved. Collagen volume fraction was reduced by 44% ( P Conclusions Simvastatin induced the regression of hypertrophy and fibrosis, improved cardiac function, and reduced ERK1/2 activity in the β-myosin heavy chain–Q 403 rabbits. These findings highlight the need for clinical trials to determine the effects of simvastatin on cardiac hypertrophy, fibrosis, and dysfunction in humans with hypertrophic cardiomyopathy and heart failure.

OBJECTIVES The study assessed whether end-diastolic wall thickness (EDWT), measured with echocardiography, is an important marker of myocardial viability in patients with suspected myocardial hibernation, and it compared this index to currently established diagnostic modalities of dobutamine stress echocardiography (DSE) and rest-redistribution thallium-201 (Tl-201) scintigraphy. BACKGROUND Because myocardial necrosis is associated with myocardial thinning, preserved EDWT may provide a simple index of myocardial viability that is readily available from the resting echocardiogram. METHODS Accordingly, 45 patients with stable coronary artery disease and ventricular dysfunction underwent rest 2D echocardiograms, DSE and rest-redistribution Tl-201 tomography before revascularization and a repeat resting echocardiogram ≥2 months later. RESULTS Global wall motion score index decreased from 2.38 ± 0.73 to 1.94 ± 0.82 after revascularization (p 0.6 cm had a sensitivity of 94% and specificity of 48% for recovery of function. Similarly, a Tl-201 maximal uptake of ≥60% had a sensitivity of 91% and specificity of 50%. Receiver operating characteristic curves for prediction of recovery of regional and global function were similar for EDWT and maximum Tl-201 uptake. Combination of EDWT and any contractile reserve during DSE for recovery of regional function improved the specificity to 77% without a significant loss in sensitivity (88%). CONCLUSIONS End-diastolic wall thickness is an important marker of myocardial viability in patients with suspected hibernation, and it can predict recovery of function similar to Tl-201 scintigraphy. Importantly, a simple measurement of EDWT ≤0.6 cm virtually excludes the potential for recovery of function and is a valuable adjunct to DSE in the assessment of myocardial viability.

Despite great improvements in the prevention and treatment of coronary artery disease (CAD), the prevalence of heart failure (HF) continues to rise, and CAD remains a common etiology for this disorder ([1,2][1]). This apparent paradox is partially explained by the increasing prevalence of risk

Certain mutations in genes for sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). We have developed a transgenic rabbit model for HCM caused by a common point mutation in the beta-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human beta-MyHC cDNAs were cloned 3' to a 7-kb murine beta-MyHC promoter. We injected purified transgenes into fertilized zygotes to generate two lines each of the wild-type and mutant transgenic rabbits. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in their myocardia. Mean septal thicknesses were comparable between rabbits carrying the wild type transgene and their nontransgenic littermates (NLMs) but were significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wild-type transgenic rabbits or in NLMs. Thus, cardiac expression of beta-MyHC-Q(403) in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to beta-MyHC-Q(403).

OBJECTIVESThe purpose of this study was to evaluate changes in left ventricular (LV) filling, left atrial (LA) volumes and function six months after nonsurgical septal reduction therapy (NSRT) for hypertrophic obstructive cardiomyopathy (HOCM).BACKGROUNDPatients with HOCM frequently have enlarged left atria, which predisposes them to atrial fibrillation. Nonsurgical septal reduction therapy results in significant reduction in left ventricular outflow tract (LVOT) obstruction and symptomatic improvement. However, its effect on LV passive filling volume, LA volumes and function is not yet known.METHODSThirty patients with HOCM underwent treadmill exercise testing as well as 2-dimensional and Doppler echocardiography before and six months after NSRT. Data included clinical status, exercise duration, LVOT gradient, mitral regurgitant (MR) volume, LV pre-A pressure and LA volumes. Left atrial ejection force and kinetic energy (KE) were computed noninvasively and were compared with 12 age-matched, normal subjects.RESULTSNew York Heart Association (NYHA) class was lower and exercise duration was longer (p < 0.05) six months after NSRT. The LVOT gradient, MR volume and LV pre-A pressure were all significantly reduced. HOCM patients had larger atria, which had a higher ejection force and KE, compared with normal subjects (p < 0.01). After NSRT, LV passive filling volume increased (p < 0.01), whereas LA volumes, ejection force and KE decreased (p < 0.01). Reduction in LA maximal volume was positively related to changes in LV pre-A pressure (r = 0.8, p < 0.05) and MR volume (0.4, p < 0.05). Changes in LA ejection force were positively related to changes in LA pre-A volume (r = 0.7, p < 0.01) and KE (r = 0.81, p < 0.01). The increase in exercise duration paralleled the increase in LV passive filling volume (r = 0.85, p < 0.05).CONCLUSIONSNonsurgical septal reduction therapy results in an increase in LV passive filling volume and a reduction in LA size, ejection force and KE.

Background —Idiopathic dilated cardiomyopathy, of which ≈20% of cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. It is a common cause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped by linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsible for dilated cardiomyopathy. Considerable evidence suggests desmin, a muscle-specific intermediate filament, plays a significant role in cardiac growth and development. Methods and Results —To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DNA analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of ≥2.7 cm/m 2 with an ejection fraction ≤50% in the absence of other potential causes. After amplification by polymerase chain reaction, the exons of the desmin gene were sequenced. A missense desmin mutation, Ile451Met, which cosegregates with FDCM without clinically evident skeletal muscle abnormalities, was identified in a 4-generation family but was not detected in 460 unrelated healthy individuals. Conclusions —A novel missense mutation of desmin, Ile451Met, was identified as the genetic cause of idiopathic dilated cardiomyopathy. This finding is of particular significance because this is the first mutation detected in the desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the family studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.

Background —Nonsurgical septal reduction therapy (NSRT) decreases left ventricular outflow tract (LVOT) gradient and improves symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). NSRT effects on LV/left ventricular diastolic function are currently unknown. Methods and Results —HOCM patients (n=29) had Doppler echocardiography at baseline and 6 months after NSRT to evaluate changes in LV volume, pre–A-wave pressure, early diastolic mitral annulus velocity (Ea) by tissue Doppler, and τ. At 6 months, a significant reduction in LVOT gradient (from 53.6±15 to 6±5 mm Hg; P P =0.04) and New York Health Association class (from III to I; P P P P P Conclusions —NSRT improves LV relaxation and compliance, which contributes to the symptomatic relief seen at 6 months.

Background —Doppler echocardiography is frequently used to predict filling pressures in normal sinus rhythm, but it is unknown whether it can be applied in sinus tachycardia, with merging of E and A velocities. Tissue Doppler imaging (TDI) can record the mitral annular velocity. The early diastolic velocity (E a ) behaves as a relative load-independent index of left ventricular relaxation, which corrects the influence of relaxation on the transmitral E velocity. Methods and Results —We evaluated 100 patients 64±12 years old with simultaneous Doppler and invasive hemodynamics. Mitral inflow was classified into 3 patterns: complete merging of E and A velocities (pattern A), discernible velocities with A dominance (B), or E dominance (C). The Doppler data were analyzed at the mitral valve tips for E, acceleration and deceleration times of E, and isovolumic relaxation time. In patterns B and C, the A velocity, E/A ratio, and atrial filling fraction were derived. Pulmonary venous flow velocities were also measured, and TDI was used to acquire E a and A a . Weak significant relations were observed between pulmonary capillary wedge pressure (PCWP) and sole parameters of mitral flow, pulmonary venous flow, and annular measurements. These were better for patterns A and C. E/E a ratio had the strongest relation to PCWP [ r =0.86, PCWP=1.55+1.47(E/E a )], irrespective of the pattern and ejection fraction. This equation was tested prospectively in 20 patients with sinus tachycardia. A strong relation was observed between catheter and Doppler PCWP ( r =0.91), with a mean difference of 0.4±2.8 mm Hg. Conclusions —The ratio of transmitral E velocity to E a can be used to estimate PCWP with reasonable accuracy in sinus tachycardia, even with complete merging of E and A velocities.

In 1960, mitral valve replacement was introduced as surgical treatment for mitral regurgitation (MR). Initially, this procedure was reserved for patients with New York Heart Association (NYHA) functional class III symptoms. In these patients, it was thought that the improvement in symptoms and quality of life outweighed the surgical mortality and the long-term morbidity associated with a prosthetic valve. 31 Improvements in valve design and in methods of myocardial protection coupled with development of surgical techniques for valve repair and preservation of the subvalvular apparatus have lowered surgical mortality and improved the long-term results of mitral valve surgery. Concurrent with these developments, a body of evidence has accumulated indicating the deleterious effects of left ventricular (LV) dysfunction on mortality and morbidity of patients undergoing valve replacement. Consequently the current trend is to recommend surgery earlier. Rather than wait for symptoms to progress, surgeons now commonly operate patients in NYHA functional class II, particularly if they show signs of LV dysfunction. Concerns about permanent injury to the left ventricle have prompted in some cases referral for surgery of asymptomatic patients. This article discusses the factors that may influence long-term prognosis in MR, reviews the evidence supporting earlier intervention, and provides some guidelines based, when possible, on experimental findings and at times on the author's opinion. The discussion is limited exclusively to isolated MR without stenosis or any other significant valvular lesion.