Heart Failure

Heart failure is a major public health problem worldwide. In the United States alone, nearly 5 million Americans have been diagnosed with heart failure, and 550, 000 new cases are being diagnosed each year. The number of deaths attributed to the disease has increased significantly in the past 35 years.

Although, heart failure is significantly more prevalent in older people, people of all ages can be affected by this disease. Heart failure is often a chronic condition which is characterized by the inability of the heart to pump enough blood to the lungs and the rest of the body. Consequently, the metabolic demands of the body are not met. Heart failure can result either from systolic dysfunction, as a result of inadequate pumping activity, or from diastolic dysfunction, which is due to impaired relaxation and thus improper blood filling.

The manifestations of these dysfunctions are the symptoms associated with heart failure. Due to insufficient supply of blood, and thus oxygen and nutrients, the patients feel tired and fatigued. Furthermore, blood coming into the heart can back up and cause fluid accumulation in the lungs as well as in other parts of the body, such as the legs, causing edema and congestion. This lung congestion is also the cause of shortness of breath, or dyspnea, that these patients experience. These patients also exhibit increased heart rates since, as a compensatory mechanism, the heart pumps out blood at a faster rate in an attempt to meet body blood demands. Other symptoms associated with heart failure also include nausea, loss of appetite and impaired thinking.
Although there is currently no cure for heart failure, other than heart transplantation, there exist a variety of treatments that can improve the quality of life of the patients. Such treatments include lifestyle changes, surgery and medication. However, these therapies aim at treating the symptoms of the disease rather than the subcellular mechanisms, which underly the etiology of heart failure in the cardiomyocyte and may lead to cardiac dysfunction and pathological remodeling. It has been suggested that abnormal Ca2+ handling in the heart is a central player in the progression of heart failure. At the myocyte level, hallmarks of heart failure include depressed contractility, decreased peak systolic Ca2+, increased diastolic Ca2+, reduced Ca2+ transport into the sarcoplasmic reticulum and depressed SR Ca2+ load. Several SR Ca2+ regulatory proteins have been suggested to be involved in the progression of this deteriorating disease. For example, altered levels of SERCA 2a, as well as alterations in its regulation by the phosphoprotein phospholamban, have been suggested to be key players in heart failure. Therefore, the approach of our lab is to use genetically altered mouse models to elucidate the function of such important players in Ca2+ homeostasis, not only in cardiac physiology but also during pathophysiological states. More specifically, our lab utilizes methodology to either increase the levels of expression of these proteins of interest using transgenesis or to decrease their expression levels using gene-targeting. Furthermore, mouse models expressing altered forms of these proteins (e.g. constitutively phosphorylated forms) are also powerful tools, which our lab uses to study the role of these proteins in heart failure. This knowledge of the underlying molecular defects may allow for the development of better therapeutic agents for treating heart failure.

Houser et al, 2000.

Regulation of Intracellular Ca2+ in Non-Failing and Failing Human Myocardium. The upper panel depicts the differences in the action potential (AP) waveshape and cytosolic free Ca2+ [Ca2+] i between non-failing (NF) and failing (HF) human ventricular myocytes. The lower panels depict the potential subcellular alterations in HF that cause abnormal [Ca2+] i transients. The gray level represents the [Ca2+] i. In diastole the [Ca2+] i is similar in NF and HF myocytes. However, SR Ca loading (depicted by the blue level in the SR) is smaller in the failing myocyte. Also note the difference in the density and location of Ca regulatory proteins in the NF v HF myocytes. Peak systolic [Ca2+] i during the early AP plateau phase is lower than normal in the failing myocyte because SR Ca release is smaller and Ca efflux via forward-mode NCX is greater than normal. SR Ca release is also reduced in the failing myocyte because of defective EC coupling. During the late phase of the AP plateau[Ca2+] i is greater than normal in the failing myocyte because the prolonged AP duration promotes reverse-mode NCX (Ca influx) and SR uptake is slower than normal. Repolarisation of the membrane potential is required for full recovery of diastolic Ca2+ in failing myocytes.