Abstract
Heart disease is a major cause of morbidity and premature mortality. Cardiomyopathy is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure–related disability. Dilated cardiomyopathy caused by mutations in A-type lamin gene (i.e., LMNA cardiomyopathy) is characterized by an increase in both myocardial mass and volume. The ventricular walls become thin and stretched, compromising cardiac contractility and ultimately resulting in poor left ventricular function. Despite current strategies to aggressively manage “LMNA cardiomyopathy,” the disorder remains a common cause of heart failure with decreased ejection fraction, and a prevalent diagnosis in individuals is referred for cardiac transplantation. Despite progress in reducing “LMNA cardiomyopathy”–related mortality, hospitalizations remain very frequent and rates of readmission continue to rise. It appears important and necessary to further increase our knowledge on the pathophysiology of “LMNA cardiomyopathy” to unveil novel molecular/cellular mechanisms to target future therapeutic approaches.
Keywords
- Dilated cardiomyopathy
- Genetics
- LMNA
- A-type lamins
- Nuclear lamina
1. Introduction
Cardiomyopathy, a major cause of morbidity and premature mortality in developed countries, is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure-related disability, which is a staggering clinical and public health problem. The mechanical component of the heart is liable for pumping blood throughout the body. The electric component, as for it, produces a rhythm for the blood to be pumped correctly. Hence, both components are tightly connected and regulated. Most common symptoms of dilated cardiomyopathy are shortness of breath, leg swelling, decreased exercise tolerance, fatigue, dizziness, coughing or wheezing, weight gain, and palpitation. Given the diversity in severity of symptoms in dilated cardiomyopathy, the disease is not always diagnosed. Cardiomyopathies are a clinically heterogeneous group of cardiac muscle disorders [1]. Cardiomyopathies have historically been broken down into several major phenotypic categories. Dilated cardiomyopathy, the most common form, is a condition where the heart muscle becomes enlarged and weakened, resulting in poor left ventricular function. Despite current strategies to aggressively manage dilated cardiomyopathy, the disorder remains a common cause of heart failure with a decrease below 45 % of ejection fraction and a referring for cardiac transplantation. Notwithstanding progress in reducing heart failure-related mortality, hospitalizations for heart failure remain very frequent and rates of readmissions continue to rise. It appears important and necessary to increase our knowledge on the pathophysiology of cardiomyopathies to unveil novel molecular/cellular mechanisms for future therapeutic approaches.
2. Inherited cardiomyopathies
While the most common cardiomyopathies are secondary to acquired conditions, many are inherited. Genetic mutations have been identified in 25–35 % of patients presenting dilated cardiomyopathy. These mutations affect genes that encode components of a wide variety of cellular compartments and pathways, including the nuclear envelope (e.g.,
3. LMNA cardiomyopathy
Among the causing genes of dilated cardiomyopathy, it has been estimated that mutations in
4. A-type nuclear lamins
The
5. Pathogenesis
Identification of disease-causing mutations in the heart has contributed to the delineation of “
The exact mechanisms by which defects in nuclear lamins cause dysregulated signaling remain to be elucidated.
6. Treatments
Advances in molecular techniques have improved the understanding of mechanisms responsible for cardiac dysfunction in “
7. Conclusion
In the past decade, there has been an extraordinary burst of researches on lamin A/C and the nuclear lamina, which has been accelerated by attempts to explain the pathogenesis of “
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