Grace Casaclang-Verzosa

Structural and Functional Remodeling of the Left Atrium: Clinical and Therapeutic Implications for Atrial Fibrillation

Left atrial (LA) structural and functional remodeling reflects a spectrum of pathophysiological changes that have occurred in response to specific stressors. These changes include alterations at the levels of ionic channels, cellular energy balance, neurohormonal expression, inflammatory response, and physiologic adaptations. There is convincing evidence demonstrating an important pathophysiological association between LA remodeling and atrial fibrillation (AF). Measures that will prevent, attenuate, or halt these processes of LA remodeling may have a major public health impact with respect to the epidemic of AF. In this review, we describe the mechanisms involved in LA remodeling and highlight the existing and potential therapeutic options for its reversal, and implications for AF development.

Left Atrial Reservoir Function as a Potent Marker for First Atrial Fibrillation or Flutter in Persons ≥ 65 Years of Age

The aim of this prospective study was to evaluate the incremental value of left atrial (LA) function for the prediction of risk for first atrial fibrillation (AF) or atrial flutter. Maximum and minimum LA volumes were quantitated by echocardiography in 574 adults (mean age 74 +/- 6 years, 52% men) without a history or evidence of atrial arrhythmia. During a mean follow-up period of 1.9 +/- 1.2 years, 30 subjects (5.2%) developed electrocardiographically confirmed AF or atrial flutter. Subjects with new AF or atrial flutter had lower LA reservoir function, as measured by total LA emptying fraction (38% vs 49%, p <0.0001) and higher maximum LA volumes (47 vs 40 ml/m(2), p = 0.005). An increase in age-adjusted risk for AF or atrial flutter was evident when the cohort was stratified according to medians of LA emptying fraction (< or =49%: hazard ratio 6.5, p = 0.001) and LA volume (> or =38 ml/m(2): hazard ratio 2.0, p = 0.07), with the risk being highest for subjects with concomitant LA emptying fractions < or =49% and LA volume > or =38 ml/m(2) (hazard ratio 9.3, p = 0.003). LA emptying fraction (p = 0.002) was associated with risk for first AF or atrial flutter after adjusting for baseline clinical risk factors for AF or atrial flutter, left ventricular ejection fraction, diastolic function grade, and LA volume. In conclusion, reduced LA reservoir function markedly increases the propensity for first AF or atrial flutter, independent of LA volume, left ventricular function, and clinical risk factors.

Infiltrative Cardiovascular Diseases: Cardiomyopathies That Look Alike

Infiltrative cardiomyopathies are characterized by the deposition of abnormal substances that cause the ventricular walls to become progressively rigid, thereby impeding ventricular filling. Some infiltrative cardiac diseases increase ventricular wall thickness, while others cause chamber enlargement with secondary wall thinning. Increased wall thickness, small ventricular volume, and occasional dynamic left ventricular outflow obstruction (e.g., amyloidosis) can outwardly appear similar to conditions with true myocyte hypertrophy (e.g., hypertrophic cardiomyopathy, hypertensive heart disease). Likewise, infiltrative disease that presents with a dilated left ventricle with global or regional wall motion abnormalities and aneurysm formation (e.g., sarcoidosis) may mimic ischemic cardiomyopathy. Low-voltage QRS complex was the sine qua non of infiltrative cardiomyopathy (i.e., cardiac amyloid). However, low-voltage QRS complex is not a uniform finding with the infiltrative cardiomyopathies. The clinical presentation, along with functional and morphologic features, often provides enough insight to establish a working diagnosis. In most circumstances, however, tissue or serologic evaluation is needed to validate or clarify the cardiac diagnosis and institute appropriate therapy.

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF+ cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

Quarterly Focus Issue: Heart FailureState-of-the-Art PaperInfiltrative Cardiovascular Diseases: Cardiomyopathies That Look Alike

Infiltrative cardiomyopathies are characterized by the deposition of abnormal substances that cause the ventricular walls to become progressively rigid, thereby impeding ventricular filling. Some infiltrative cardiac diseases increase ventricular wall thickness, while others cause chamber enlargement with secondary wall thinning. Increased wall thickness, small ventricular volume, and occasional dynamic left ventricular outflow obstruction (e.g., amyloidosis) can outwardly appear similar to conditions with true myocyte hypertrophy (e.g., hypertrophic cardiomyopathy, hypertensive heart disease). Likewise, infiltrative disease that presents with a dilated left ventricle with global or regional wall motion abnormalities and aneurysm formation (e.g., sarcoidosis) may mimic ischemic cardiomyopathy. Low-voltage QRS complex was the sine qua non of infiltrative cardiomyopathy (i.e., cardiac amyloid). However, low-voltage QRS complex is not a uniform finding with the infiltrative cardiomyopathies. The clinical presentation, along with functional and morphologic features, often provides enough insight to establish a working diagnosis. In most circumstances, however, tissue or serologic evaluation is needed to validate or clarify the cardiac diagnosis and institute appropriate therapy.

E/Ea is the major determinant of pulmonary artery pressure in moderate to severe aortic stenosis.

OBJECTIVE Our aim was to determine echocardiographic Doppler predictors of pulmonary artery systolic pressure (PASP) in patients with moderate to severe aortic stenosis (AS). METHODS In this retrospective study of 50 patients with moderate to severe AS, the determinants of PASP were analyzed. RESULTS Aortic valve area was 0.84 +/- 0.3 cm(2), with mean gradient of 55 +/- 16 mm Hg, mean ejection fraction (EF) of 60 +/- 13%, mean PASP of 37 +/- 15 mm Hg, and mean E/Ea of 14 +/- 6. aortic valve area and mean gradient did not predict degree of PASP and were not associated with EF and diastolic parameters. LV mass index (P = .0005), E velocity (P = .006), E/Ea (P < .0001), and EF (P < .0001) were univariately significantly associated with PASP. By multivariate analysis, E/Ea independently predicted PASP (P = .0001). CONCLUSION Our findings suggest that in moderate to severe AS, diastolic function, not AS severity, determines PASP. Superimposed diastolic dysfunction likely contributes to clinical symptoms of moderate to severe AS.

Frequency and Predictors of Urgent Coronary Angiography in Patients With Acute Pericarditis

OBJECTIVES To determine the frequency of urgent coronary angiography in patients with acute pericarditis and to examine clinical characteristics associated with coronary angiography. PATIENTS AND METHODS This is a retrospective analysis of all incident cases of acute viral or idiopathic pericarditis evaluated at Mayo Clinics site in Rochester, MN, between January 1, 2000, and December 31, 2006. The main outcome measures were use of urgent coronary angiography and rate of concomitant coronary artery disease in patients with pericarditis. RESULTS There were 238 patients with a final diagnosis of acute pericarditis (mean age, 47.7±17.9 years; 157 [66.0%] were male). On the initial electrocardiogram, 146 patients (61.3%) had ST-segment elevation, and 92 (38.7%) had no ST-segment elevation. Coronary angiography was performed in 40 patients (16.8% of all patients); the frequency was 5-fold higher among those with ST-segment elevation (24.7% vs 4.3%; P P =.05). Characteristics associated with a higher likelihood of coronary angiography included typical anginal chest pain, ST-segment elevation, previous percutaneous coronary intervention, elevated troponin T values, diaphoresis, and male sex. Coronary angiography revealed concomitant mild to moderate coronary artery disease in 14 (35.0%) of the 40 patients who underwent this procedure. CONCLUSION Urgent coronary angiography is commonly performed in patients with acute pericarditis, particularly those with ST-segment elevation, typical myocardial infarction symptoms, and elevated troponin T values. Coronary artery disease was present angiographically in one-third of patients undergoing the procedure. Although patients with ST-segment elevation myocardial infarction must receive prompt reperfusion, clinicians must also consider the diagnosis of pericarditis to avoid unneeded coronary angiography.

Diastolic dysfunction and left atrial enlargement as contributing factors to functional mitral regurgitation in dilated cardiomyopathy: data from the Acorn trial.

BACKGROUND Functional mitral regurgitation (MR) is commonly seen in dilated cardiomyopathy (DCM), which may result from left ventricular (LV) dilatation and alteration in the geometric relationship of mitral valve apparatus. However, not all patients with DCM show significant MR and left atrial (LA) enlargement. The aim of this study was to assess responsible factors for developing mitral valve regurgitation. METHODS Of 300 patients enrolled in the Acorn trial, baseline echocardiography studies were available in 288, of whom 144 were excluded because of a variety of reasons. Echocardiographic data were examined for the remaining 144 patients in sinus rhythm with DCM, but without organic mitral valve disease and ischemic heart disease. Mitral regurgitation was assessed by color-flow imaging. All echocardiographic parameters were indexed to body surface area. RESULTS Of 144 patients, 87 had MR grade > or =2 (group 1) and 57 had MR grade 0 or +1 (group 2). Group 1 had larger tenting area, tenting height, tethering distance, LA volume index, and mitral annular area than group 2 (all P < .001); LV volume index and ejection fraction were similar between groups. The major determinant of MR severity was tenting area (r = 0.49, P < .001), and this was best related to mitral annular area (r = 0.85, P < .001). Mitral annular area was most strongly associated with LA volume (r = 0.56, P < .001). In addition, LA volume index was highly correlated with LV diastolic dysfunction (r = 0.58, P < .001), both in total and in group 2 only. CONCLUSIONS For patients with DCM in the Acorn trial, MR severity was associated with LA volume and mitral annular area but not with LV volume. Mitral annular area and LA volume were closely related, even in patients without significant MR. These findings suggest that LA enlargement caused by advanced diastolic dysfunction may contribute to causing significant MR by augmenting mitral annular dilatation in DCM.

17α-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17&agr;-estradiol (17&agr;-E2), a naturally occurring enantiomer of 17&bgr;-estradiol (17&bgr;-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17&agr;-E2 could alleviate age-related metabolic dysfunction and inflammation. 17&agr;-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17&agr;-E2 on nutrient-sensing pathways in visceral adipose tissue. 17&agr;-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17&agr;-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17&agr;-E2. 17&agr;-E2 increased AMPK&agr; and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17&agr;-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects.

C-Reactive Protein, Left Atrial Volume, and Atrial Fibrillation: A Prospective Study in High-Risk Elderly

Background: The data regarding the interrelationships of high‐sensitive C‐reactive protein (CRP), left atrial (LA) volume, and atrial fibrillation (AF) are sparse. Additionally, while LA volume has been shown to be useful for prediction of AF in low‐to‐moderate risk populations, its predictive value in clinically high‐risk populations is unknown. Methods: SAFHIRE (Study of Atrial Fibrillation in High Risk Elderly) is an ongoing prospective study of the pathophysiology of first AF in persons aged ≥65 years with ≥2 other AF risk factors [systemic hypertension, proven coronary artery disease, heart failure (HF), diabetes]. Participants are followed annually, and undergo an interview, physical examination, blood work, electrocardiogram, and echocardiogram assessment. Results: Of 800 participants, mean age of 74 ± 6 years, 34 developed first AF over 1.7± 0.9 years. A history of systemic hypertension and proven coronary artery disease was present in 97% and 78%, respectively. CRP was unrelated to LA volume on univariable or multivariable analyses (P > 0.10), and not predictive of first AF on univariable or multivariable models (all P > 0.10). Indexed LA volume was an independent predictor of first AF (unadjusted P< 0.0001; age and sex adjusted P = 0.0006; adjusted for multiple factors, HR 1.3/5 ml per m2, 95% CI, 1.09 to 1.48, P = 0.001). Conclusion: In this elderly population at high clinical risk for the development of first AF, CRP was unrelated to LA volume and nonpredictive of first AF, while indexed LA volume was incremental to clinical risk factors for the prediction of first AF. (ECHOCARDIOGRAPHY 2010;27:394‐399)