In a hypertrophied heart myocytes are not only big in size, but they also have additional sarcomeres. The manner in which these sarcomeres are added depends upon the type of load being imposed on myocytes. In situation of pressure overload, sarcomeres are added in parallel, leading to increased LV wall thickness, whereas, during volume overload, they are added in series, resulting in dilation of the ventricular cavity. There are also qualitative differences in sarcomeres of hypertrophied myocytes. A great body of evidence suggest that hypertrophy of myocytes is associated with induction of a group of genes, which are usually expressed during fetal heart development. These genes include activation of β-myosin heavy chain (MHC), skeletal-α-actin, atrial natriuretic factor and the repression of α-MHC and SR-CaATPase (SERCA). These changes may be initially salutary for an overloaded heart; however, prolonged hypertrophy leads to myocyte dysfunction, which eventually results into heart failure. Results collected from animal studies have also indicated that, the loss of α-MHC content is a critical determinant of the reduced myocardial contractility during heart failure. Direct evidence in support of a causal link between the loss of α-MHC and the development of heart failure came from experiments in which the α-MHC gene was ablated. Data correlating even small decrements of α-MHC content with changes in the intrinsic contractile characteristics of the myocardium also support the idea that a critical level of α-MHC content is essential for the normal pump function of the heart.

Another possible cause of a decrease in contractile protein-function is an alteration in the expression and/or activity of regulatory proteins. In animal models of heart failure, there are changes in the myosin light chain and the troponin-tropomyosin complex. Changes in myosin light-chain isoforms have been observed in heart samples of patients subjected to increased mechanical stress, and the expression of troponin-T splice variants was found to be altered in failing human myocardium. Changes in the phosphorylation status of Troponin-I have also been suggested to be involved in the loss of contractile activity of myocytes during heart failure. Moreover, defects in sarcoplasmic reticulum Ca2+ATPase and Ca release channels have been suggested to be responsible for the contractile dysfunction of myocytes.

It has been realized that in addition to muscle gene dys-regulation, cardiomyocyte cell-death significantly contributes to loss of ventricular function in a failing heart. During increased workload, myocytes undergo a hypertrophic growth response to compensate for the increased demand. The initiating events of which are similar to those that drive cell-cycle progression in proliferating cells. A continuous growth signal in myocytes, at some point, causes cells to malfunction and leads to cell-death. As cells die, the workload on the remaining cells increases, which further aggravates this process and eventually leads to organ failure. Both in humans and animals with different cardiac disorders, including ischemic heart disease, idiopathic dilated cardiomyopathy, hypertensive heart disease, viral myocarditis, pacing-induced cardiomyopathy and different transgenic models of heart failure, myocyte cell-death has been implicated as a common cause of the cardiac pathology. However, the mechanism of cell death in a failing heart remains highly disputed. Some studies have documented a role of caspases in myocyte cell-death, however, other have disputed this notion. The activation of caspases in ischemic heart disease seems fairly accepted, but its participation in non-ischemic diseases remains controversial. Our own studies have shown that in pressure overloaded hearts PARP is not cleaved, a marker of caspase-dependent cell-death, but rather its expression is progressively increased in relation to the degree of cardiac hypertrophy, suggesting that hemodynamic-stress endangers cardiac myocytes through a mechanism that appears different from the conventional caspase-mediated apoptosis. Activation of PARP has been seen during different animal models of heart failure as well as in human failing hearts. Recent evidence suggests that prevention of cardiomyocyte cell-death by PARP-inhibition and/or by changing activity of other cell-death intermediate protects the overloaded heart from going into failure. G-protein coupled beta receptors, which have been implicated in the normal and abnormal functioning of cardiac muscle cells in response to beta-receptor signalling. These receptors and their mechanistic properties have recently been acclaimed by the Nobel committee that saw it fit to award the Nobel Prize in Chemistry for 2012 to Drs Lefkowitz and Kobilka [23].

Before we proceed to a discussion of the complex clinical manifestations of CHF, a brief discussion of the genetic factors at work in CHF is necessary for completion. Almost 20 % of patients with dilated cardiomyopathy are likely to have an inherited genetic defect. For instance, familial hypertrophic cardiomyopathy is caused by a number of gene mutations affecting beta myosin heavy chain, cardiac troponin T & I, alpha tropomyosin, myosin-binding protein C, and myosin light chains 1 and 2 [24]. In certain conditions such as Duchenne muscular dystrophy, there are definite genetic associations of an abnormal gene called dystrophin with abnormal myocardial function [25].

Heart failure is usually defined as the inability of the heart to generate an output sufficient to meet the metabolic requirements of the body. The left or right ventricles may fail individually or together. Heart failure may also occur in the face of normal systolic ventricular function.

Left heart failure presents with shortness of breath which, if severe, will occur at rest. Patients are graded on their functional capacity depending on the level of activity that induces shortness of breath. This functional classification, known as the ‘New York Heart Association (NYHA) classification,’ is widely accepted and used around the world. This functional classification is used in the assessment of patients, prognostication and in tailoring management. The classes are as follows:

Minor impairment of cardiac function may remain asymptomatic but, as compensatory mechanisms become maladaptive, the clinical features of heart failure emerge. These relate primarily to the consequences of elevated atrial pressures and reduced cardiac output, expressed as congestion and peripheral hypoperfusion respectively. Manifestations of left and right heart may occur separately, but in reality they often occur together in varying degrees, resulting in the broader syndrome of Congestive Heart Failure (CHF).

Congestive heart failure is a complex medical condition requiring therapeutic interventions at multiple levels. It is the most common cause of medical admissions in Australia, the United States, Canada and the UK. The biggest advance in the treatment of heart failure has been the establishment of ‘Heart Failure Clinics’ and heart failure groups in hospitals, serviced by people interested in investigating, understanding and managing heart failure [30].

Multi-disciplinary heart failure programs that run cardiac rehabilitation courses after myocardial infarction or cardiac surgery, have been effective in reducing heart failure related admissions [31]. Symptomatic improvement has also been noticed, along with reduced hospitalisation in patients with cardiomyopathy who attend a specialised clinic [32].

Prevention also plays a very important role. The West of Scotland Study showed that primary prevention, by advocating drug therapy with pravastatin, prevented myocardial infarction and reduced the incidence of heart failure in a population at risk [33]. The 4S Study (Scandinavian Simvastatin Survival Study) followed patients with coronary artery disease, some of whom were randomly assigned to a placebo group and some to a group treated with simvastatin. Secondary prevention in the 4S Study showed that occurrence of heart failure at 5-year follow-up was significantly higher in the placebo than in the simvastatin group [34].

Exercise programs to improve general fitness and the level of exercise tolerance have been shown to significantly improve the functional status of patients with heart failure [35]. Bed rest, which was a cornerstone of traditional therapy for CHF, is therefore no longer advocated for these patients.

Despite these improvements in treatment and prevention the effective management of heart failure continues to be a pressing concern. Before discussing my research into the utility and efficacy of ventricular containment, this next section will review current approaches to the treatment of CHF, both medical and surgical.