Iron Overload and Myocardial Restriction

Heart failure still remains the main cause of death in β-thalassemia, despite the progress, which was made by intensification of iron chelation therapy. Iron myocardial deposition, due to regular blood transfusions, can cause congestive heart failure as a result of left- or right-sided heart failure combined with left ventricular myocardial restriction. Regular and intense chelation therapy has improved quality of life and survival by decreasing secondary hemochromatosis. However, heart failure has not been prevented despite the intensification of iron chelation therapy.             Acute myocarditis in β-thalassemia major has been reported to contribute to heart failure in addition to iron overloading. However, apart from myocarditis which may lead to immune mediated chronic left ventricular dysfunction and failure, other factors acting through immunologic or genetically defined mechanisms might also affect the development of left sided heart failure. Multiple transfusions represent a repetitive antigenic stimulus together with iron chelation therapy itself. In this brief overview, the pathogenetic mechanisms of myocardial involvement and heart failure in β-thalassemia major are discussed

Ischemic preconditioning: Protection against myocardial necrosis and apoptosis

The phenomenon of ischemic preconditioning has been recognized as one of the most potent mechanisms to protect against myocardial ischemic injury. In experimental animals and humans, a brief period of ischemia has been shown to protect the heart from more prolonged episodes of ischemia, reducing infarct size, attenuating the incidence, and severity of reperfusion-induced arrhythmias, and preventing endothelial cell dysfunction. Although the exact mechanism of ischemic preconditioning remains obscure, several reports indicate that this phenomenon may be a form of receptor-mediated cardiac protection and that the underlying intracellular signal transduction pathways involve activation of a number of protein kinases, including protein kinase C, and mitochondrial KATP channels. Apoptosis, a genetically programmed form of cell death, has been associated with cardiomyocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. While ischemic preconditioning significantly reduces DNA fragmentation and apoptotic myocyte death associated with ischemia-reperfusion, the potential mechanisms underlying this effect have not been fully clarified. A comprehensive understanding of these mechanisms and application to clinical scenarios will provide new directions in research and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury

The pathophysiological relationship and clinical significance of left atrial function and left ventricular diastolic dysfunction in beta-thalassemia major

Iron deposition in combination with inflammatory and immunogenetic factors is involved in the pathophysiology of cardiac dysfunction in -thalassemia major. We investigated the mechanical and endocrine function of the left atrium and ventricle to identify early signs of dysfunction. We studied 90 patients (mean age: 29 +/- 11 years) with -thalassemia and normal left ventricular function and 90 age and sex-matched healthy controls. Patients and controls underwent a thorough cardiac echocardiographic study and measurements of the b-type (NT-proBNP) and atrial natriuretic peptides (proANP). Patients underwent 24-hr Holter recordings for arrhythmia monitoring. In the patient group, atria were affected early during the course of the disease, prior to diastolic and systolic left ventricular dysfunction. The E/Eratio (E Doppler mitral fast inflow to the corresponding tissue Doppler E) continually increased with age (P<0.05) and reached levels indicating left ventricular diastolic dysfunction (E/E>15) in the third decade whereas indexes of active and passive atrial function decreased gradually throughout life. In controls, the E/E ratio continually increased with age but with later (fifth decade) appearance of diastolic dysfunction and a compensatory increase in atrial active function. Both natriuretic peptides were significantly increased in patients compared to controls (558 +/- 141 and 2,580 +/- 1,830 fmol/mL for NT-proBNP and proANP versus 332 +/- 106 and 1,331 +/- 1,134 fmol/mL, respectively). Atrial fibrillation was found in a subgroup of 23 (26%) patients, older in age with mild diastolic function and enlarged, depressed atria. In conclusion, atrial mechanical depression seems to be a very early sign of cardiac damage. It may become echocardiographically evident even before diastolic and systolic dysfunction and is associated to supraventricular arrhythmias. Am. J. Hematol. 89:13-18, 2014. (c) 2013 Wiley Periodicals, Inc

Ventricular long-axis contraction as an earlier predictor of outcome in asymptomatic aortic regurgitation

The long-term prognostic significance of left ventricular (LV) long-axis contraction was investigated prospectively in 65 consecutive patients aged 58 +/- 15 years with asymptomatic aortic regurgitation, normal LV ejection fraction at rest, and no coronary artery or aortic root disease. A complete transthoracic echocardiographic study was performed at baseline and 12 months later. In 24 of 65 patients with peak systolic wave velocity at the lateral mitral annulus (LatS) <9 cm/s, LV diameter (p <0.01), volume (p <= 0.01), mass (p <0.001), and end-systolic wall stress (p <0.001) significantly increased after 12 months, whereas LV shortening and ejection fraction (p = 0.001) and tissue Doppler right ventricular peak systolic wave velocity (p <0.05) decreased significantly. In patients with peak systolic wave velocity at the lateral mitral annulus 2:9 cm/s, none of these parameters was significantly affected during follow-up. Aortic valve replacement was performed in 6 of 24 patients (25%) with peak systolic wave velocity at the lateral mitral annulus <9 cm/s and none with peak systolic wave velocity at the lateral mitral annulus 2:9 cm/s. In patients with peak systolic wave velocity at the lateral mitral annulus <9 cm/s, a cut-off value of 6.25 cm/s predicted aortic valve replacement within the next year with 97% sensitivity and 83% specificity. In conclusion, ventricular long-axis contraction seems to be a reliable indicator for outcome prediction in patients with asymptomatic aortic regurgitation. (c) 2007 Elsevier Inc. All rights reserved

Carvedilol improves left atrial and left ventricular function and reserve in dilated cardiomyopathy after 1 year of treatment

Background: The aim of this study was to evaluate the effects of carvedilol therapy on left atrial (LA) function in patients with heart failure from nonischemic dilated cardiomyopathy. Methods and Results: Thirty-five patients (42.4 +/- 13.5 years) in New York Heart Association functional Class II-III have been studied. A low-dose (20 mu g.kg.min) echo-dobutamine study has been performed, before and 12 months after carvedilol therapy. Twelve months after carvedilol therapy, a significant improvement in LA and left ventricular (LV) function was observed. To investigate the beneficial effects of carvedilol, patients were separated into 2 groups according to the presence of pretreatment LV contractile reserve (CR) (ejection fraction [EF] increases > 20% after dobutamine infusion): Group A consisted of 18 patients with CR and Group B of 17 patients without CR. After carvedilol treatment, both the LV and LA function were improved in group A (P < .01 for all). However, in group B, only the LA function was significantly improved (left atrial ejection volume increased from 10.4 +/- 3 mL to 15.4 +/- 6.7, P < .01 and LA ejection fraction from 19.6 +/- 45.3% to 29.4 +/- 12.5%, P < .01), whereas the LV contractile reserve has partially reappeared (EF from 29.9 +/- 4.5% at baseline, increased after dobutamine infusion to 35.8 +/- 6.8%, P < .0001). Conclusions: In conclusion, carvedilol therapy is associated with improvement in both LV and LA functions in nonischemic dilated cardiomyopathy. In a subgroup of these patients, carvedilol may act differently on LV and LA function

Multimarker approach in cardiovascular risk prediction

Various biomarkers express different pathways and pathophysiologic mechanisms of cardiovascular disease, such as inflammation, oxidative stress, myocardial injury, activation of the neurohormonal pathways, myocardial stress and renal function. Current thinking supports the notion that the combination of these biomarkers could increase their diagnostic and prognostic value. The multimarker approach offers benefits since it increases the diagnostic and prognostic information and may help in the design of a strategy for prevention or management of cardiovascular diseases. The purpose of the current review is to describe the characteristics of promising biomarkers which have shown an important additive value in the assessment of cardiovascular risk. Also, an extended reference is made regarding studies that address the prognostic value of multimarker models in the settings of primary prevention of cardiovascular disease and secondary prevention for patients with acute coronary syndromes, chronic coronary artery disease and heart failure

Neurocardiogenic mechanisms of unexplained syncope in idiopathic dilated cardiomyopathy

Syncope in patients with advanced heart failure is a sign of poor prognosis. The cause of syncope in patients with dilated cardiomyopathy (DC) is not fully recognized and may remain elusive even after standardized evaluation. The purpose of the present study was to examine the implication of neurally mediated mechanisms in the pathophysiology of syncopal episodes in patients with DC. Twenty-six patients (21 men, 5 women; mean age 59 +/- 2 years, range 38 to 79) with DC and left ventricular ejection fractions <= 40% were included in the study. Thirteen patients with unexplained syncope or presyncope and a control group of 13 patients without unexplained syncope underwent head-up tilt tests with clomipramine challenge. The 2 groups were matched with regard to age, gender, and left ventricular ejection fractions, and there were no major differences in terms of medication. Heart rate variability analysis, and plethysmography of forearm flow were performed during the tilt tests. Blood samples were also drawn for catecholamine measurements. In the group with histories of unexplained syncope, the head-up tilt test results were positive in 11 patients (84.6%). Sympathetic and parasympathetic heart rate indexes were markedly stimulated, while catecholamine concentrations and blood flow changes indicated sympathetic withdrawal during tilting. In the control group, the head-up tilt test results were negative in 12 patients (92.3%). In conclusion, neurally mediated mechanisms seem to be implicated in the pathophysiology of syncope in patients with DC and should therefore be considered in the differential diagnosis of syncopal episodes of unexplained origin. (c) 2007 Elsevier Inc. All rights reserved