The Development of Heart Failure

Systolic heart failure is characterized by enlarged ventricles that are unable to fully contract to pump enough blood into circulation to adequately perfuse tissues. The enlargement in ventricles is due to an increased end-systolic volume. If the heart is not able to sufficiently pump the expected volume of blood with each contraction, which in a normal healthy heart is 50-60%, there will be a residual volume left in the heart after every pump (Heart Healthy Women, 2012). With the next period of filling, the heart will receive the same amount of blood volume from the atria combined with that residual volume from the previous contraction. This causes the ventricles to have to dilate to accommodate this increase in volume. The dilation causes the walls of the ventricles to stretch and become thin and weak. Also the myocardium, the muscle layer of the heart, will stretch and not be able to adequately make a full and forceful enough contraction to push blood from the ventricles (Lehne, 2010).

Heart Failure is a progressive heart disease when the muscle of the heart is weakened so that it cannot pump blood as it should; the blood backs up into the blood vessels around the lungs and the other parts of the body (NHS Choice, 2015). In heart failure, the heart is not able to maintain a normal range cardiac output to meet the metabolic needs of the body (Kemp and Conte, 2012). Heart failure is a major worldwide public health problem, it is the end stage of heart disease and it could lead to high mortality. At present, heart failure is usually associated with old age, given the dramatic increase in the population of older people (ACCF/AHA, 2013). In the USA, there are about 5.7 million adults who have heart failure, about half of the people die within 5 years of diagnosis, and it costs the nation an estimated $30.7 billion each year (ACCF/AHA, 2013).

As this disease progresses and the workload of the heart is consistently increased, ventricular hypertrophy occurs. At first, the hypertrophied heart muscles will increase contractility, thus increasing cardiac output; however, as hypertrophy of the ventricular myocardial cells continues, it begins to have poor contractility, requires more oxygen to perform, and has poor circulation from the coronary arteries. This can result in heart tissue ischemia and lead into cardiac dysrhythmias (Lewis et al. 2014, 768).

Voltage gated channels are necessary components of life processes, in many organisms. One in particular, is the calcium voltage gated ion channel. Often lodged within the phospholipid bilayer, the imbalance of the calcium, or, the inside vs outside concentration, creates a gradient. The channel proteins often undergo conformations, states that which allow or block calcium ions from passing through. As ions move inside the cell, this creates a depolarization, or surge in the voltage. Clinically, this is associated with the heart and how it allows the heart to contract, which can be read in the

So what is congestive heart failure? A simple definition is the heart 's inability to pump blood to the rest of the body but it goes way beyond that. The body’s natural mechanisms try to compensate for the changes that

I am conducting biomedical research in the laboratory of cardiac physiology under the mentorship of Dr. Elizabeth Murphy. Cardiovascular disease is the major cause of death in the US; therefore, a better understanding of the mechanisms regulating cardiomyocyte death in ischemia and reperfusion injury are important. Mitochondrial calcium plays a crucial role in the normal functioning of many processes, including the regulation of cardiac biochemical pathways and mediating ischemia-reperfusion injury. The uptake of calcium into the mitochondrial matrix is regulated by the mitochondrial calcium uniporter (MCU). An endogenous enzyme, Ca2+ Calmodulin Dependent Kinase II (CaMKII) has shown to regulate cell death and have increased activity during

The major causes of diastolic heart failure are hypertension-induced myocardial hypertrophy and myocardial ischemia-induced ventricular transformation (coronary artery disease). Hypertrophy and ischemia cause a decreased ability of the myocytes to actively pump calcium from the cytosol, resulting in impaired relaxation. Some of the other causes are aortic valvular disease and cardiomyopathies. Diabetes can also lead to diastolic heart failure (Huether and McCune 2012). Other risk factors for this disease are chronic kidney disease, obstructive sleep apnea, and older age. There are two types of the heart failure: systolic heart failure and diastolic heart failure. In systolic heart failure, the left ventricle has difficulty contracting and ejecting blood into the circulation, which causes reduced left ventricular fraction. On the other hand, diastolic heart failure has a slow and delayed relaxation and increased chamber rigidity, which then causes inadequate filling of blood and

the expression of a gene for cardiac contractile proteins, causing increased protein synthesis, a reduction in arterial contractility and a reduction in atrial energy demands. There is an action potential prolongation of the Ca+ current at a cellular level, which prolongs the time taken for myocytes to contract and relax [ncbi.nlm.nih 1998].

The American Heart Association (2015) defines heart failure as a progressive condition in which the heart is incapable of pumping a sufficient amount of blood to meet the body’s requirement. Heart failure is caused by a structural or functional disorder cardiac condition that decreases the heart’s ability to eject blood (The American Heart Association, 2015; Alpert, Lavie, Agrawal, Aggarwal, & Kumar, 2014). The causes of heart failure include hypertension, arrhythmias, ischemic heart disease, valve disorders, and metabolic disorders (Nicholson, 2014). In addition, obesity has been positively correlated with heart failure, with up to 86% of obese patients being diagnosed with heart failure (Alpert et al., 2014). Heart failure affects approximately 23 million people worldwide and roughly 5.8 people are affected in the United States (Alpert et al., 2014). It is estimated that roughly 40 to 71% of people affected by heart failure have a normal or close to normal left ventricular ejection fraction (Alpert et al., 2014). The prevalence of heart failure increases with age and it is estimated that 6-10% of people over the age of 65 are affected (Kasper et al., 2015). Heart failure is a progressive disorder that is often initiated by an event that damages the heart muscle (Kasper et al., 2015). As a result, the myocardium is unable to contract as it normally would and the heart’s pumping capacity is deteriorated (Kasper et al., 2015). Although, the heart’s pumping capacity is

Heart failure is a condition where the heart is unable to pump insufficient amount of blood to supply the rest of the body. This is a consequence of ventricular remodelling. Ventricular remodelling is a term that refers to alterations in structure, shape and function of the left ventricle. (1) The activation of neuro-hormonal systems such as RAAS and the sympathetic nervous system are predominantly linked to the pathophysiology of heart failure. Therefore, interrupting this system is vital to delaying the progression of heart failure. (2)

* The type of proteins in the cell membrane that was involved in homeostatic imbalance of his heart cells were ATP. There was no ATP, so it affected the pumps in the membrane. The calcium levels rose, and it caused proteases to spill into the interior of the cell, attacking the cytoskeleton. This caused the lysosome enzymes to digest the plasma membranes and membranes of the organelles.

Pacemaker cell activity is very important for heart rate and force of contraction of the heart. There is no constant resting potential (Figure.2), it's due to a leak of Na+ ions. That leaks causes Na+ ions moves into the cell and depolarises the cells until a threshold that activate voltage gated Ca+ channels and voltage gated K+ channels.

If too much calcium builds up in the cells of the heart, they will begin to spontaneously release through the calcium channels of the heart. This leads to heart arrhythmias with a continuous alternation of long and short heart beats. A normal sinus

DAG is lipid soluble and so stays in the membrane whereas IP3 is water soluble, so it diffuses through the cytosol. This signalling pathway therefore splits into two branches with the second messengers mediating different functions [4]. On one branch is the signalling cascade downstream of IP3. The IP3 receptors are located on the lumen of the sarcoplasmic reticulum (endoplasmic reticulum out with smooth muscle cells) and when IP3 is bound they release their intracellular Ca2+ store. This release of intracellular Ca2+ increases the Ca2+ concentration in the cytosol from around 0.1 μM to 1 μM [5]. This changes the physiology of the cell, therefore Ca2+ is said to be a second messenger itself. The way in which Ca2+ signals is through the binding of proteins. The Ca2+ binding proteins transduce this signal of the cytosolic concentration of Ca2+ and these certain proteins are called mediator proteins. Such a protein is calmodulin, and is only in its active conformation when Ca2+ is bound. The increase in intracellular Ca2+ by the binding of IP3 to the IP3 receptors promotes the binding of Ca2+to calmodulin forming the Ca2+/calmodulin complex. Proteins that are members of the Ca2+/calmodulin-dependent protein kinase family (CaM kinases) are activated by Ca2+/calmodulin. It is the formation of this complex that is fundamental for muscle contraction [4]. Figure 1

While contraction in skeletal muscle is triggered by motor neurons under central control, certain cardiac muscle variants exhibit autorhythmicity. This means that that they are capable of producing their own depolarizing electrical potential. The cardiomyocytes that are capable of producing their own electrical potentials are found in what is referred to as the electrical condition system of the heart. This system is comprised of specializes cardiomyocytes that are autorhythmic and are able to conduct electrical potentials rapidly. These specialized structures include the sinoatrial node, atrioventricular node and bundle, and Purkinje fibers.