Elsevier

Heart Failure Clinics

Volume 4, Issue 1, January 2008, Pages 13-21
Heart Failure Clinics

Molecular Basis of Diastolic Dysfunction

https://doi.org/10.1016/j.hfc.2007.10.007Get rights and content

Diastolic dysfunction is characterized by prolonged relaxation, increased filling pressure, decreased contraction velocity, and reduced cardiac output. Phenotypical features of diastolic dysfunction can be observed at the level of the isolated myocyte. This article reviews the cellular mechanisms that control relaxation at the level of the myocyte in the healthy situation and discusses the alterations that can affect physiologic function during disease. It focuses specifically on the mechanisms that regulate intracellular calcium handling, and the response of the myofilaments to calcium, including the changes in these components that can contribute to diastolic dysfunction.

Section snippets

What causes abnormal muscle relaxation?

It has long been recognized that both structural and biochemical changes within the myocytes are responsible for impaired relaxation of the ventricle. It has been very challenging, however, to pinpoint which of these cause diastolic dysfunction and which actually are compensatory factors that are adaptive in failing muscle. The heart is a complex organ, in both architecture and geometry. There are multitudes of differences both in architecture and composition between endocardium and epicardium,

The role of sarcoplasmic reticulum calcium++ transport in muscle relaxation

The sarcoplasmic reticulum (SR) calcium++ (Ca2+) transport plays a central role in regulating both cardiac muscle contraction and relaxation. The cardiac SR is an intracellular membrane network that surrounds the contractile machinery. It serves as a Ca2+ store for Ca2+ release and also actively maintains cytosolic Ca2+ concentration during contraction/relaxation of the muscle [5], [6], [7]. SR function is coordinated by a set of Ca2+-handling proteins localized in the T-tubule and SR membrane.

Dynamic regulation of SERCA pump expression and its role in muscle contractility

SERCA2a is the major isoform expressed in the adult atria and ventricles, whereas its alternate isoform, SERCA2b, is expressed at low levels in the heart at all stages [9], [12], [21], [22]. The SERCA pump is localized in the longitudinal SR and is the most abundant protein in the SR membrane, representing about 40% of total SR protein. The expression levels of SERCA2a are not uniform throughout the heart: there are chamber-specific differences in the expression levels of SERCA pump. In

Regulation of SERCA pump activity by the phosphoprotein phospholamban

PLB is a 52–amino acid phosphoprotein and interacts with the SERCA pump in a dynamic manner during the contraction relaxation cycle of the heart. PLB is responsible for mediating the β-adrenergic responses in the heart. It has been well documented that phosphorylation of PLB at serine 16 and threonine 17 by the kinases protein kinase A (PKA) and calcium-calmodulin kinase II (CaMKII), respectively, can increase SERCA pump activity [13], [14], [17], [35], [36], [37] and Ca2+ transport and

Abnormal calcium homeostasis and diastolic dysfunction in failing hearts

Contractile dysfunction in end-stage human heart failure has been attributed to both depressed myofilament Ca2+ sensitivity and altered calcium handling. In particular Ca2+ transients are decreased [40], [41]. Smaller amplitude of Ca2+ transients could be caused either by lower fractional SR Ca2+ release or by lower SR Ca2+ content. A decreased Ca2+ store could be caused by reduced SR Ca2+ uptake or increased Ca2+ leak during diastole (Fig. 1) [42]. Decreases in SR Ca2+-ATPase gene and protein

SERCA pump level impacts both muscle contraction and relaxation rates

To understand the significance of alterations in SERCA pump expression on myocardial contractility, transgenic mouse and rat models that express higher levels of SERCA pump were developed. Transgenic overexpression of SERCA2a or SERCA1a in the heart demonstrated that SERCA pump can be overexpressed in the heart, resulting in increased Ca2+ transport and contractility [11], [12], [61], [62], [63], [64]. Overexpression of the skeletal muscle isoform SERCA1a in the mouse heart results in a net

Role of myofilament proteins in diastolic dysfunction

Myofilament properties play a central role in the governing of cardiac relaxation. It is undisputed that the intracellular calcium concentration must decline to facilitate and initiate relaxation. The actual rate at which healthy myocardium relaxes is regulated predominantly by myofilament properties. The peak of the calcium transient amplitude generally is reached long before the peak of force development, and once force development starts to decline, the calcium concentration is already near

The role of cytoskeleton and extracellular matrix

In addition to alterations in calcium handling and myofilament properties, a multitude of changes occur in the failing myocyte, and it often is difficult to distinguish whether these changes are causative or compensatory adaptations of the failing heart. Among structural alterations, changes in cardiac myocyte cytoskeleton and extracellular matrix have been implicated as potential underlying causes of diastolic dysfunction [79], [80], [81], [82]. Cooper and colleagues [3], [83], [84] have

Therapeutic strategies to treat diastolic dysfunction

There are only limited therapeutic approaches to treat diastolic dysfunction, and most of these are already in use, albeit with limited success, to treat patients who have heart failure. This section discusses nonpharmacologic approaches to restore contractility of the heart using gene-transfer methods. Recent studies have focused on restoring SERCA pump activity, either by adenoviral-mediated gene transfer of SERCA2a or by inhibiting PLB. Adenoviral gene transfer into cardiac myocytes showed

Summary

Diastolic dysfunction is a complex disease, and it is difficult to pinpoint a single cause or a causative mechanism to be targeted. Diastolic dysfunction is also a progressive disease and could be compounded by other pathologic conditions. Despite significant advances in the understanding of basic cellular mechanisms regulating relaxation, many hurdles remain to the development of efficient therapeutic approaches to combat diastolic dysfunction.

Acknowledgment

The authors thank Carolyn Rutter for editorial assistance, and Dr. Sandor Gyorke for providing the template for Fig. 1.

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    MP is supported by NIH R01 grants HL64140 and NIH HL 088555. PMLJ is supported by NIH R01 HL73816, NIH K02 HL83957, and by an Established Investigator Award from the American Heart Association.

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