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Human heart failure is a leading cause for the mortality and morbidity worldwide. With considerable public awareness and advancements in therapeutic systems, cardiac failure still remains as a critical unsolved problem. The hillingdon heart failure study found an incidence rate of 140 per 100,00 for men and 120 per 100,000 for women in the UK. With a high proportion of elderely people in the UK population and with an improved survival rate for patients with coronary heart disease, the prevalence of population with cardiac failure is on a rise. Henceforth only with a rapid advancements that reduce the incidence of heart failure; can reduce the burden of this disorder.
Heart failure (HF) is a progressive disorder when the blood supply to the tissues is insufficient to meet their requirements. It comprises various clinical syndromes. The various common causes of heart failure are coronary heart disease, hypertension, cardiomyopathy or genetic factors. It can be categorized based on left & right heart failure, systolic vs diastolic dysfunction, low vs high output heart failure and the extent to which the function is impaired by its classification. The stages and classification of heart failure is further demonstrated in Table 1. Along with this there are certain changes that occur in the body which is depicted in figure 1. The treatment of heart failure is to stabilize the symptoms and further preventing the progression of the disease that improve the survival of the patients. Surgical approach like heart transplantation and assist device along with drug based treatments has improved the prognosis of the patients.(3) . However with limited benefits to the patients, HF still require a novel based approach to treat at the early stage.
The current mode of treatment and new emerging targets for HF will be further discussed.
Over the recent decades, molecular biologists and geneticists have identified various genes and pathways that are involved in the structure and function of heart. With the latest technologies of microarray and illumina, more genetic information respect to heart failure is unraveled. Novel genes has been identified to be mutated or epigenetically altered and few still yet in the pipeline, Targeting their function or pathway may prove to be effective for next generation treatment of HF. Cardiac gene therapy is at its earliest stage of clinical trials. It focuses on identifying the specific molecular targets and then to manipulate them at the molecular level. These novel targets and the current advancements and obstacles in this treatment of HF will be further discussed in detail. Also the different delivery systems and vectors which are vital for a successful gene transfer, that have been used the heart failure will be reviewed.
Current treatments in heart failure
Treatments should be initiated at an early stage of risk, to prevent further disease progression.
Inotropic agents where associated with higher morbidity as they increased intracellular cAMP(6).
Adrenergic receptor antagonists, inhibitors of angiotensin II and aldosterone, diuretics are the current standard treatments in HF. (5)
Input data from trial tat support Bblockr therapy
New Treatments and Targets
A new potential target would be to look at the altered Na/Ca exchange activity in HF.-(2).
P53 as new target (8)
Check for stem cell based approaches
Statin: Statin is another product under investigation for HF due to its ability to prevent disease progression. However trials has shown that rosuvastation did not affect the clinical outcome of patients with chnronic HF.
Cardiac resynchorinzation therapy: CRT has been shown to improve the survival of patients with moderate to advanced HF. A combination approach with defibrillation has shown a reduction of mortality and hospitalization. CT are ongoing and results are awaited on its cost effectiveness and efficacy.
Cardiorenal syndrome: In patients with advanced HF, renal dysfunction is a frequent complication which is poorly defined. So treatment on HF should consider this and optimize the therapy accordingly. Vasodilator therapy is the current support , while effect on Nestiritide is still under confusion. The survival and protection of renal function with new strategies like ultrafilitration, vasopressin and adenosine antagonist is unclear and further investigations are needed. (use of loop diuretics in this ) However Ultrafilitration techniques was later shown not to improve the mortality rate in cardiorenal deaths.
Dyspnoea : it's a symptom of AHF and treatment at the earliest stage has shown to reduce the mortality of hospitalized patients with AHF.
Relaxin: it affects the multiple vascular control pathway and has shown effectiveness in improving dysponea in patients and improved the mortality due to cardiorenal deaths.
Histone deacetylase inhibitors: They are of primer interest in cancer treatments, however the with therapeutic effect on HF in animal models, CT are planned to gain further datas on its efficacy.
Proportion of patients prescribed evidence-based therapy for HF on discharge from hospital; and 1-year all-cause mortality. RESULTS: Among 944 patients surviving to hospital discharge, the prescription rate of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (74.3%) and loop diuretics (85.5%) remained high over the study period, whereas that of beta-blockers and spironolactone increased (10.5% to 51.3% and 1.4% to 23.3%, respectively), and digoxin prescription decreased (38.1% to 20.7%). The temporal trends in use of beta-blockers, spironolactone and digoxin were in line with clinical trial evidence. Age >/= 75 years was a significant, negative predictor of beta-blocker and spironolactone prescription. In-hospital echocardiography, performed in 53% of patients, was associated with a significantly greater likelihood of treatment with ACE inhibitors/ARBs, beta-blockers and spironolactone. Both ACE inhibitors/ARBs and beta-blockers prescribed on discharge were associated with a lower adjusted hazard ratio (HR) for mortality at 1-year (HR, 0.71; P = 0.003; and HR, 0.68; P = 0.002, respectively). CONCLUSION: ACE inhibitors/ARBs and beta-blockers, prescribed during initial hospitalisation for HF, are associated with improved long-term survival. Therapy became more evidence based over the study period, but echocardiography, an important predictor of evidence-based therapy, was underutilised.
Renin Inhibitors: Renin angiotensisn system is a crucial regulator of systolic and diastolic HF and hence renin inhibitors target which is under investigation by several studies to prove its efficacy in HF.
Genetics of Heart failure
The prevalence of heriditray form of HF is increasing and shows the rold of mutations and alterations in various structural genes and cytoskeletal protein (9). A classic example is DMD which shows cardiac defects, and further the protein dystrophin has a low expression level towards the end stage of HF, that shows its possible role in the cardiac muscles. (9)
Due to its compact size and availability of specific gene promoters, they are comparatively much targetable than the skeletal muscles. Henceforth the future GT developments in the field of DMD will certainly prove therapeutic benefits to its use in HF.(9)
The choice of genes to be targeted is evolving with advances in research in molecular biology, physiology (10)
Prospects of Cardiac Gene therapy
The poor prognosis of HF despite new pharmacological treatments, increase the research on other novel therapeutic approaches. Angiotensin converting enzyme inhibitors, B adrenergic blockers are unable to reduce mortality due to chronic HF as it does not reverse the pathophysiology of HF. (4) No drug is yet developed to target phospholamban which is a important regulator (3) and also with failed results on drug devp for small molecular targets, the new approach will be the need of RNA and Gene based therapeutical approach (3). Gene therapy being a promising approach is a at its clinical trial stage with quite a lot other preclinical work still at the research level. The target of GT is prevent further progression of lethal arrhythimias, acute cardiac decompensaton and the end stage pump failure. (5).
The GT focuses on (1) overexpression of a target molecule; (2) alteration of the target's intracellular shuttling routes though introduction of decoy molecules; (3) loss of function approaches using dominant negative molecules or by introduction of RNA interference; (4) correcting deleterious gene mutations/deletions at the genome or primary mRNA level;or (5) installing genetically modified donor cells (stem cellsand/or differentiated cells). (5) GT targets vascular cells to stabilize plaques and induction of neoangiogenesis, prevent viable cardiomyocytes from apoptosis, preventing myocardial remodeling (by targeting fibroblasts), Targest electrophysiological abnormalities (reduce risk of arrhythmias) (5).
The requirement for an effective gene therapy and its limitations are briefed in the table. A Gene target, suitable vector and the delivery techniques are the essential elements required for an efficient GT. However , effective gene expression depends on the mode of its transfer to cardiac myocytes. Among the viral vectors, recombinant adeno viral vectors offers many advantages as mentioned in table Effective manipulation of ca2 handling proteins has been successfully shown by adenoviral gene transfer. (6)
The few other methods of delivery to achieve cardiac gene transfer include: Intracoronary catherter delivery of adenovirus, Direct injection of adenovirus into ventricular wall through epicardial approach and intramyocardial delivery using intraventricular approach. These approaches did show up regional areas of transduction. Other novel mode of delivery developed preclinically include a catheter based technique inserted into left ventricular apex and inject high concentration of adenoviral properation with aorta and pulmonary artery clamped. An ideal method however will be to tranduce the myocardium and for this the factors that influence the efficiency of the methods are: The use of crystalloid solution, High Coronory flow rate, Exposure time, virus concentration, temperature.(6)
For those patients undergoing cardiopulmonary bypass, the delivery via coronary circulation, gives a significant transgene expression in preclinical studies.(4) An ideal method of delivery will be intravenously, howeve this would be unattainable considering the large volume of blood. Also the required amount of vectors for an efficient transgene expression is not clear.(5)
Intravascular intervention theough coronary arteries, intracoronary gene delively , direct intramyocardial injection are certain other gene delivery strategies. Intracoronary gene delivery is inefficient as it requires specific unattaibnable conditions wherease direct intramyocardial injection has limited efficacy and depends on myocardial tissue accessibility.(5) . But during cardiothoracic surgery, with the accessibility of the tissue, this approach is very much appealing.(5). In future catheter based gene delivery will be of further interest. (4)
The current clinical trials on GT are targeted on SR Ca2 ATPase (5). GT for HF depends on the cause for specific condition and hence may require a combinatorial approach targeting cardiac cells and signaling pathways. (5) Targeting monogenetic cause of HF, through GT is very promising with a gene substitution therapy(3) For the inherited disease involving protein dysfunction of sarcomere, cytoskeltom, it may be feasibile to rectify the expression and further prevent HF. These includes long QT syndrome, arrhytmogenic right ventricular dysplasia, hypertrophic cardiomyopathies. (3, 5)This researchis still at its initial stage and awaiting results from clinical study. (5). To optimize the condition for a effective gene transfer still require further investigation and the need to improve the vector technology, gene delivery methods and knowledge on pathogenesis of HF.
Also recently research is in progress to the investigate the role of iRNA for the treatment of HF. They currently aims to identify the possible targets, specificity and expression patterns of the use of iRNA to develop a new class of successful RNA drugs (3). RNA intereference and micro RNA has the same theraputical benefits with the use of advancements in the vector design and delivery apporoach in the gene therapy field. (3)
Apart from this, cell based and protein based approaches are the other strategies for HF treatment.(3)
3 concepts: Gene substitution therapy for monogeneic disorders, overexpression of genes using gene transfer, Vector based approach. (3)
Gene therapy approaches in the field of DMD has led to further improvement in techniques for cardiac therapy as well (9). Rescently further developments have been seen with a succesfull delivery of sarcoglycan genes using r-AAV vectors to the heart tissue with the aid of cardiac specific gene promoters (9). This study showed an improved ventricular function and further demonstrate that gene therapy can prevent cardiomyopathy (9)
Another major concern for GT is the presence of delivery barriers involved. These barriers like avoiding antibodies and serum DNAse that degrade the DNA has to be overcome. The figure shows the barriers that has to be crossed to reach the target.
However it is also need to be considered that non target organs are not to be affected and do not evoke immune response (10) by the vectors and also it could cross the endothelial barriers in capillary wall. Lysosomal incactivation of the vectors has to be overcome for it to efficiently be uptake by the cardiomyocytes.
An appropriate mode of administration however can overcome these barriers and give effective uptake of the vectors for restricted expression at the site of interest. Retroinfusion and ultrasound mediated gene transfer are such alternatives that could bypass these barriers. (10).
Non Viral vectors
Adv: low immunogenic properties, low cost of production, low toxicity and high organ specificity
Diasdv : low transfection efficieny,
plasmid DNA is: cost effective in prod, easily leaned and made to GMP grade, low mmunogenic activity, low toxicity, water solube and heat stable.
Diasd cannot transfect effectively.
However direct delivery of vascular endothelial growth factors, hepatocyte growth factors and soncih hedgehog factors into myocardium results in safer and specific gene expression. However clinical trials results are yet to prove its efficacy.(10)
The plasmid DNA can be delivered by intra myocardial and transfection efficiency can further be improved with various compounds that form complexes with DNA. Liposomes, lipopolymers, gelation complexes and lipoproteins are few substances that transfect the heart of which liposomes when used has led to transfection of other organs.(10)
Ultrasound targeted microbubble destruction (UTMD) is a newly developed technique that could efficiently deliver at the site when the microbubbles loaded with plasmid DNA are bursted at the heart using ultrasound energies. At the preclinical stage, other transfection methods like electroporation, gene gun, or coating DNA on surgical suture showed to decrease the risk of rejection during cardiac transplants (10)
Non viral vectors due to its inablitity to integrate into genome is not able to give required long term gene expression (10)
Viral vectors : high transduction rate,
Transduction effeicinece depend on vector concentration.
The major advantage of viral vectors is the high
transduction rate. Virus-mediated gene delivery resulted in
30- to 360-fold higher levels of cardiac transduction with
adeno-associated viral or adenoviral vectors after direct
intramyocardial injections in rabbits compared to plasmid
approaches (uncomplexed and complexed) . Depending
on the vector concentration, transduction efficiencies were up
to 75% of cardiomyocytes around the needle track after direct
injection of adenoviral vectors in adult pigs . The superior
transduction efficiency of viral vectors is due to a more
efficient cellular uptake and efficient intracellular transport of
packaged DNA to the nucleus. In contrast to non-viral vectors,
viruses are taken up upon binding to specific surface receptors
and are able to escape from degradation in lysosomes [52-55].
Adenoviral vectors are the most frequently used system in
experimental and clinical gene transfer studies targeting the
heart since they enable highly efficient cardiac gene delivery
and can be produced in sufficient quantities. However,
adenoviral vectors are limited by only transient gene
expression caused by immune response against viral gene
products resulting in the clearance of transduced cells [56-58].
Non-sustained gene transfer was initially considered
With results from current preclinical and clinical trials , GT is one step closer to its application in treating heart failure.
Also severl issues regarindg the optimization of GT must have to be overcome. (9)
The viral vectors can be deliverd directly using catheters and also with availability of cardiac specific promoters, few hindrances in this area has been dealt with. (9)
Combination approach of well defined vector and delivery system will overcome the current barriers of gene transfer.(10)