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JCI - ECM remodeling in hypertensive heart

Jun 01, 2018

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    9/24/2014 JCI - ECM remodeling in hypertensive heart disease

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    9/24/2014 JCI - ECM remodeling in hypertensive heart disease

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    secondary to HHD are the relatively highly prevalent

    LV hypertrophy and cardiac fibrosis, caused by

    changes in the local and systemic neurohormonal

    environment. The fibrotic state is marked by changes in

    the balance between MMPs and their inhibitors, which

    alter the composition of the ECM. Importantly, the

    fibrotic ECM impairs cardiomyocyte function. Recent

    research suggests that therapies targeting theexpression, synthesis, or activation of the enzymes

    responsible for ECM homeostasis might represent

    novel opportunities to modify the natural progression of

    HHD.

    Background

    There is an epidemic of heart failure in the United

    States. The three major causes of heart failure are

    hypertensive heart disease (HHD), ischemic heart

    disease associated with prior myocardial infarction(s),

    and idiopathic dilated cardiomyopathy. Because the

    prevalence of hypertension is increasing globally, heart

    failure secondary to HHD will soon become the most

    common cause of heart failure. Heart failure is clinically

    defined by its signs (e.g., peripheral edema, increased

    heart size, and a third heart sound) and symptoms (e.g.,

    shortness of breath, fatigue, orthopnea, and paroxysmalnocturnal dyspnea). It has become clear that heart

    failure can clinically present with predominantly

    diastolic or systolic dysfunction or both. Patients with

    heart failure secondary to HHD frequently begin their

    clinical course with only symptoms of diastolic heart

    failure (in particular, shortness of breath with exertion)

    but frequently progress to combined diastolic and

    systolic heart failure. The major difference between

    HHD and other causes of heart failure can be

    represented by the manner in which geometricremodeling of the LV occurs (Figure 1). Patients with

    HHD usually present with LV hypertrophy (LVH) but

    have a normal-sized LV chamber and preserved

    systolic function (ejection fraction greater than 50%).

    By contrast, patients with heart failure secondary to

    ischemia or idiopathic cardiomyopathy usually have an

    enlarged, dilated LV chamber and more frequently also

    have RV enlargement (1, 2).

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    Figure 1

    Schematic representation of changes in the cardiac

    chambers of an individual with HHD compared with

    idiopathic or ischemic cardiomyopathy. The main

    difference between HHD and the other two main

    causes of heart failure (ischemic heart disease

    associated with prior myocardial infarction[s] and

    idiopathic dilated cardiomyopathy) is the nature of the

    geometric remodeling of the LV chamber. Patients with

    HHD usually present with LVH but with a normal-sized

    LV chamber and preserved systolic function. By

    contrast, patients with heart failure secondary to

    ischemia or idiopathic cardiomyopathy usually have an

    enlarged, dilated LV chamber and more frequently also

    have RV enlargement.

    Pathologic features of hearts from patients with heartfailure include cardiomyocyte hypertrophy and death

    and tissue fibrosis and scarring. Fibrosis seems to be

    more widespread in HHD than in other causes of heart

    failure. It is found throughout the heart, including the

    anterior, posterior, and lateral walls of the LV; the

    interventricular septum; and even the RV. Because of

    fibrosis, the classic finding in HHD is increased

    myocardial stiffness, especially during diastole.

    Although fibrosis contributes to stiffness, it is the quality

    of the ECM, not the quantity, that is most important.

    Importantly, fibrosis disrupts the coordination of

    myocardial excitation-contraction coupling in both

    systole and diastole. In the healthy heart,

    cardiomyocytes are connected together in an electrical

    synctium that permits a temporally coupled contraction.

    Transmission of the systolic contraction is facilitated by

    a scaffold of type I and type III fibrillar collagens,

    which are the major components of the cardiac ECM.

    Following contraction, there is an active relaxationprocess during diastole. Weber and Shirwany (3) have

    noted that the tensile strength of type I collagen is

    similar to that of steel, making it obvious that the ECM

    is the major determinant of myocardial stiffness during

    diastole.

    Alterations in HHD that contribute to disease pathology

    other than those in the ECM include changes in the

    number and function of other resident cells, myocardial

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    9/24/2014 JCI - ECM remodeling in hypertensive heart disease

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    apoptosis, and changes in calcium handling associated

    with impaired relaxation. Importantly, there are also

    substantial changes in the peripheral vasculature

    (especially resistance vessels) that impair cardiac

    function. Little and colleagues (4) showed that patients

    who present with pulmonary edema with preserved

    systolic function have HHD characterized by severe

    peripheral vascular stiffness. The impaired properties ofthe aorta and resistance arterioles (the dominant

    determinants of vascular tone and pressure) contribute

    importantly to cardiac dysfunction in HHD. However,

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