TAKEN ON OUR LAST DAY @ NYP SCL Pharmaceutical Science
This is my final year project (FYP) at NYP on heart failure, i always wanted to put it out into the web because i remember being so frustrated that i could not find examples/guidelines on how to write the report and basically no one except my friends would help. Yes, emphasis on the friends only, okay google too for being so amazing and helping me throughout my FYP journey.
Its pretty boring, but hopefully this serves clueless students some skeleton as to how to go about. I left out the Internship at Bristol-Myers Squibb part cause that’s more of personal reflection. Oh, and the final grade for this was A. Not a distinction but good enough!
Background on Heart Failure
Heart Failure (HF) is a physiological state in which the heart is unable to pump sufficient blood and thus reduced oxygen delivery throughout the whole body.  Usually HF is caused by other pre-existing cardiovascular conditions which results in a damaged or weakened heart. In other cases, HF may also develop if the heart muscle becomes too stiff, resulting in a lesser capacity to contract as per normal. 
There are 2 main types of HF: Diastolic dysfunction a.k.a HF preserved Ejection Fraction (HFpEF), where ventricular relaxation is impaired and systolic dysfunction a.k.a HF reduced ejection fraction (HFrEF), where ventricular contraction is impaired.  Dysfunction in either the left and/or right ventricle leads to HF.  The development of HF begins when a patient has a lowered cardiac output (CO), leading to a reduction in mean arterial pressure (MAP) and a decreased tissue perfusion. As part of the compensatory neurohormonal mechanism, reduction in MAP leads to the activation of the sympathetic nervous system (SNS) releasing catecholamine, which directly increases the heart rate and contractility. Activation of the SNS also stimulates the renin-angiotensin system which causes vasoconstriction, sodium retention and thirst. This causes an increase in stroke volume and total peripheral resistance (TPR) and thus MAP is augmented back to normal and maintaining adequate tissue perfusion. The compensatory mechanism is triggered to maintain cardiovascular homeostasis, ensuring the heart pumps sufficient blood and oxygen according to the required demand. It is identical to those that are triggered when MAP and CO are put at risk in situations like intense physical exercise or hemorrhage but unlike HF these neurohormonal mechanisms are only activated for an acute period of time instead of long term. 
Though beneficial at the start, but the long term effects of the compensatory mechanism only exacerbates HF resulting in an endless vicious cycle. This results in the patient remaining asymptomatic for a long duration, reducing the possibility of an early intervention. During the asymptomatic phase, the heart undergoes ‘remodeling’ to increase in cardiac mass due to hypertrophy of singular cardiomyocytes and extracellular matrix alterations in order to maintain functioning during cardiac stress. This ultimately becomes detrimental as the ‘remodeling’ eventually impairs contractility due to the thick myocardial wall that developed, resulting in a much less effective pumping. With the heart being put under constant chronic strain, it leads to cardiac augmentation (enlarged heart) and a gradual descent in contractility which ultimately ends in symptomatic heart failure. 
The symptoms of HF are as follows:
– Shortness of Breath, at rest, especially during physical activity and even during sleep. This is due to blood ‘backing up’ in the pulmonary veins as a result of the heart’s incapacity, thus causing fluid leakage into lungs. 
– Persistent coughing or wheezing, coughing that creates pink blood-tinged or white phlegm. This is from the fluid that has built up in the lungs. 
– Edema, swelling in the feet, ankles, legs, abdomen or weight gain. Due to slowing blood flow, blood in the veins returning to the heart backs up, building up fluid in the tissues. Affected blood flow, also reduces the kidney’s ability to eliminate water and sodium and thus retain fluid in tissues. 
– Fatigue and/or tiredness, very often when carrying out normal daily activities. This is because blood is mostly supplied to the more vital organs (heart & brain) rather than the less vital organs (muscles in extremities) as the heart can no longer meet the demands of the whole body. 
– Increased heart rate, heart palpitations, racing/throbbing heart. In effort to meet the oxygen demands, the already incapacitated heart needs to pump harder and faster, even for low energy activities such as walking. 
– Confusion & impaired thinking, causing memory loss and feelings of disorientation. Altered levels of certain substances in the blood (e.g. sodium) and cerebral hypoperfusion due to HF can cause confusion. ,
Before any tests for HF are done, the doctor will check for medical and family history, conduct a physical exam (e.g. listening of heart beats, lungs for fluid accumulation, swelling of extremities), diseases/conditions that could have caused HF (e.g. diabetes, hypertension, and coronary heart disease) and review all the symptoms to eliminate the possibility of diseases other than HF 
As recommended by the National Institute for Health and Care Excellence (NICE) , patients with suspected HF should first have a single measurement of natriuretic peptide followed by a transthoracic Doppler 2D echocardiography if positive. Natriuretic peptide testing (B‑type natriuretic peptide (BNP)) is very important in making a diagnosis for patients with suspected HF, as increased amounts of BNP is secreted by the ventricles of the heart when cardiomyocytes are excessively stretched/stressed , thus it can be used to deny the presence of HF or confirm the necessity to affirm it further with echocardiography. ,  Transthoracic Doppler 2D echocardiogram, a test that uses ultrasound waves to measure the pumping action and structure of the heart, including the heart valves, is employed when a patient has suspected HF and elevated BNP levels. The testing is carried out within 48 hours so as to allow for early diagnosis and proper management via pharmacological and non-pharmacological interventions.  A chest radiography may also be performed to determine whether the heart is enlarged or presence of pulmonary edema. 
Due to the multifactorial nature of HF, a specific prognosis heavily gravitates on the individual itself. After confirming the diagnosis in a HF patient, the prognosis is highly based on the functional class. (See table 1)  Generally, HF can be controlled with medication, diet and lifestyle management, increasing lifespan. However, the chances of a favorable outcome depletes drastically when going down the functional classes. In the Framingham study the overall survival in 8 years for all NYHA classes was 30%, compared with a 1 year mortality in classes III and IV of 34% and a 1 year mortality in class IV of over 60%.  HF usually worsens with time, and when a patient reaches class IV, hope is mostly lost as medications, other treatments and surgeries are no longer useful. A heart transplant is the only possible resort at that point. , 
Table 1. 
NEW YORK HEART ASSOCIATION (NYHA) CLASSES
Class I (no symptoms) You have no symptoms and can perform daily activities without feeling tired or short of breath.
Class II (mild symptoms) You are comfortable when resting, but moderate activity makes you tired or short of breath.
Class III (moderate symptoms) You are comfortable when resting, but even limited physical activity makes you tired or short of breath.
Class IV (severe symptoms) You are unable to do any physical activity without discomfort and experience some symptoms at rest.
It is not uncommon for HF patients to develop life-threatening complications as their disease progresses. Early detection of any associated complications allows for a bigger window of survival. Atrial fibrillation (AF) worsens HF as the heart pumping action becomes so irregular that the heart is never able to fully fill with blood to pump out, depleting oxygen-rich blood for the rest of the body. With the heart’s already weakened contractility, it only exacerbates the symptoms of HF & increases the possibility of blood clots. ,  HF and AF also predisposes the patient to Stroke, as the brain is deprived of oxygen due to decreased blood supply, leading to loss of cognitive/motor function and possibly death.  Kidney Failure, is a common condition in patients with HF as blood flow is slowed, the glomerular filtration rate drops thus reducing functioning of the kidney and ultimately, requiring dialysis.  Cardiac Cachexia is a major indicator that the patient’s HF is worsening. It is life-threatening and the patient will require nutritional supplements.  Anemia results due to lowered hemoglobin in red blood cells which only exacerbates the symptoms and the disease itself. 
g. Special needs/ Care for special group
HF patients with AF, which may have developed before or after HF, may receive an additional prescription for anticoagulants (e.g. Warfarin, Apixaban) to prevent blood from pooling and clotting which may become lodged in an artery in the brain, causing a stroke. These group of patients will also have to look out for signs of hematoma or bruising due to the increased risk of bleeding. ,  A HF patient with high cholesterol or previous myocardial infarction (MI), most likely due to a atherosclerosis plaque buildup, significantly increases chances of their HF worsening, and are usually prescribed cholesterol-lowering drugs (e.g. atorvastatin, rosuvastatin, and simvastatin) to help with their condition. ,  Geriatrics with HF are of major concern due to complications arising from comorbidities like frailty, resulting in higher susceptibility to poorer health outcomes & cognitive impairment which causes delirium and higher chances of not following treatment regimen. Stand-alone self-care is not sufficient, and thus indirectly exacerbates their disease condition. 
a. Current medication for Heart Failure and the pros & cons
Angiotensin-converting enzyme inhibitor (ACEI) e.g. Perindopril, Captopril
PROS: It improves ventricular function, patient well-being, lowers mortality and hospital admissions.  Widens blood vessels to reduce blood pressure thus improving blood flow and eases the heart’s workload. 
CONS: There is a possibility of worsening of renal function, development of chronic cough and severe dizziness which may result in falling down. 
Angiotensin II Receptor Blocker (ARB) e.g. Losartan, Candesartan
PROS: It has demonstrated an ability to regress dilated aortic root size.  It is also associated with a reduced incidence of angioedema and cough unlike ACEI. 
CONS: All of the ARBs are pregnancy category C for the first trimester and category D for the second and third trimesters, making it rather unsafe for pregnant women. 
Beta-Blockers (BB) e.g. Pindolol, Carvedilol
PROS: BB are effective in reducing further MIs or life-threatening cardiovascular diseases.  It controls the heart rate to keep it from beating too fast, protecting the heart and reduces blood pressure. 
CONS: BB though effective, are known for their side effects such as bronchospasm, fatigue, weight gain, hypotension and hyperglycemia which may precipitate individuals with a diabetic disposition. 
Diuretics e.g. Furosemide, Bumetanide
PROS: It excretes excess fluids & sodium through urination, relieves the heart’s workload and prevents the buildup of fluid in the lungs and extremities. 
CONS: Possibility of hypokalemia which can collapse the circulation and cause uremia. It does not change the prognosis of the disease. 
Aldosterone Antagonist e.g. Spironolactone, Eplerenone
PROS: It does not eliminate potassium from the body and also reduces scarring on the heart muscle. It alleviates symptoms of HF and increases lifespan of patients with low ventricular ejection fraction. 
CONS: Possibility of hyperkalemia which may cause problems. Breast tenderness/enlargement may occur with use of spironolactone. 
Calcium Channel Blocker (CCB) e.g. Amlodipine, Nisoldipine
PROS: CCB is used to treat diastolic dysfunction by slowing the heart rate, aiding in the filling of blood in the chamber by increasing the time for filling and lowering blood pressure. 
CONS: CCB (verapamil & diltiazem) is not to be used for systolic dysfunction as it reduces inotropy and seriously impairs stroke volume.  Possibility of flushing or lightheadedness. 
b. Current development of Heart Failure
I. Gene Modification
The steady decline in SERCA2a activity has been shown to be correlated with the failing of the heart. With SERCA2a activity lowered in HF, it is compensated by increasing the extrusion of Ca2+ from the cardiomyocyte into the extracellular space by NCX. The altered ratio of SERCA2a/NCX activity in HF only results in a dramatic consumption of energy during excitation-contraction coupling. Gene transfer of SERCA2a results in temporary improvement of cardiac contractility as evidenced in HF rats, whilst a chronic overexpression of SERCA2a by intracoronary delivery of AAV carrying SERCA2 has been linked to improved ventricular remodeling in a swine volume-overload model of HF and preserved systolic function. In animal studies (diseased with HF), the SERCA2a gene transfer was shown to lower the oxygen consumption for LV contractility back to the level of healthy standards, while also restoring normal systolic and diastolic functions. In summary, SERCA2a overexpression improves mortality through enhancing the mechanism of the heart. 
II. New Biological Compound
FTY-720 is a synthetic sphingosine analogue that can greatly improve existing unfavorable cardiac conditions through negative regulation of nuclear factor of activated T-cells (NFAT) activity in cardiomyocytes and lowering expression of periostin in the extracellular matrix (ECM). The research’s paradigm points towards both mechanisms working in a parallel manner to reverse hypertrophy through antihypertrophic signals by Pak1/NFAT signaling in cardiomyocytes, reduce fibrotic response via periostin action in the ECM, re-establishing the integrity of the ECM and ameliorating cardiac performance.
In the study, comparing the group receiving Transverse Aortic Constriction-only (TAC) and the TAC/FTY-720 receiving group, the latter has shown to significantly improve diminished cardiac function as substantiated by a lowered LV-end diastolic volume and end-diastolic pressure. FTY-720s’ ability to minimize cardiac hypertrophy was evident through an echocardiograph analysis, proving its benefits. 
III. New Chemical Compound
LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI), a new class of drug with dual action, combining the action of ARB-valsartan, which blocks the renin-angiotensin-aldosterone system (RAAS), and the action of Neprilysin Inhibitor (NI)-sacubitril, which retards the degradation of natriuretic peptides such as atrial and B-type natriuretic peptides (ANP, BNP). ANP and BNP promotes diuresis and natriuresis, induces vasodilation, and oppose short-term effects of volume overload by blocking the RAAS and sympathetic nervous system (SNS). The rationale behind having a dual action drug is because the inhibition of neprilysin, a neutral endopeptidase that catalyzes the degradation of ANP and BNP, will increase levels of circulating angiotensin II, a powerful vasoconstrictor, thus requiring action on the RAAS, in order for the medication to be effective. It is shown to have greatly reduced the left atrial volume and dimension and is well-tolerated with adverse effects close to those of valsartan. LCZ696 also decreased the risk of hospitalization for HF by 21% and therefore the symptoms and physical limitations of HF were also decreased. With its significant improvement in survival and rehospitalization, it has the potential to become the first line of treatment for HF. 
c. New Products on Clinical Trial
Serelaxin, an investigational new drug for acute HF is currently under phase III of a randomized, double blinded trial to study the efficacy, safety and tolerability via intravenous injection when added to standard therapy in acute HF patients.  Serelaxin is a recombinant form of human relaxin-2, a hormone produced during pregnancy and causes hemodynamic alterations in this period, like raising the blood output of the heart and blood flow in the kidney. Human-relaxin-2 indirectly initiates a chain of reactions which stimulates the production of nitric oxide (vasodilators) and inhibits angiotensin II and endothelin (vasoconstrictors) which results in vasodilation.  Subjects are either randomized to the experimental (serelaxin) arm or control (placebo) arm, where they will receive continuous intravenous infusion over 48 hours. Data has shown that serelaxin has improved dyspnea and symptoms of congestion and also lowered early AHF worsening and hospitalization length but it did not improve post-discharge remission rate. It has also shown to have a temporary positive effect on biomarkers of myocardial, renal and hepatic injury that may be associated with higher rates of survival. Generally, serelaxin has shown to be well-tolerated and effective, but further studying will be required to confirm these findings. 
Finerenone, a non-steroidal antimineralocorticoid investigational drug under phase III  controlled, randomized and double blinded clinical trial to evaluate the efficacy and safety of finerenone compared to eplerenone on morbidity and mortality in patients with chronic HF. Subjects are either randomized to the experimental (finerenone) arm or the control (eplerenone) arm for approximately 18 to 36 months.  Finerenone inhibits the effects of mineralocorticoid receptor (MR) over-stimulation by aldosterone, which builds up fluid in the body exacerbating the disease. It has demonstrated the ability to lower cardiac hypertrophy, BNP levels and proteinuria more effectively than eplerenone (steroidal mineralocorticoid-receptor antagonists) at equinatriuretic doses in preclinical studies.  In its phase II studies, it has shown to be effective in reducing cardiovascular hospitalizations and mortality most likely due to its different binding of receptor that could have resulted from a significantly higher organ protection  and all doses of finerenone were well-tolerated. Finerenone, unlike eplerenone, has a much lesser affinity to steroid hormone receptors which greatly reduces adverse effects such as gynecomastia and impotence and a much higher affinity to its targeted MR, thus increasing therapeutic benefits. 
Chymase Inhibitors (CI), an experimental drug currently under phase II, double-blinded, randomized clinical trial to investigate the safety and tolerability at different doses in patients with left ventricular dysfunction after myocardial infarction. Subjects are either randomized to the experimental (chymase inhibitor) arm at varying doses or the control (placebo) arm for 14 days.  Chymase is stored in mast cells, which also exists in the heart. Upon stimulation, the mast cells will degranulate and release chymase which promotes interstitial fibrosis by affecting collagen metabolism, promoting cardiac remodeling.  The rationale behind developing CI for treatment of HF is due to findings that suggest chymase may generate angiotensin II even after taking ACE inhibitors, so in order to improve the efficacy of ACE inhibition, chymase must also be inhibited. Long-term administration of ACE inhibitors will increase chymase activity in the heart, rendering ACE inhibitors no longer useful.  CI has been shown to significantly decreased levels of cardiac angiotensin II, responsible for enhancing collagen synthesis in cardiac fibroblasts but also TGF-B gene expression, inhibiting collagen production and preventing the differentiation of fibroblasts to myofibroblasts and lowering the deposition of collagen exert favorable cardioprotective action through suppression of fibrosis.
Reduction in remodeling of the heart muscles can ultimately help slow progression of HF. 
d. A potential direction not covered by the current clinical trial
In the RELAX-AHF-2 trial for efficacy, safety and tolerability of serelaxin when added to standard therapy in acute HF, one of its primary endpoint focuses on time to cardiovascular (CV) death during the follow-up period of 180 days.  Since the treatment is only temporary, treatment period is significantly lesser than treatments for chronic HF and it is primarily focused on treating the symptoms exhibited. Taking into consideration that the clinical trial is intended for acute HF, it may not be the most ideal to establish efficacy based on CV related deaths as an endpoint. It is rather short-sighted to only look at its immediate uses rather than justifying its benefits in the long term for acute HF patients. CV and non-CV deaths are vital determinations on the overall safety and efficacy of serelaxin and using both as an endpoint will present the benefits of serelaxin much clearer as they will not be hidden by adverse events or unexpected issues arising from unrelated situations. Therefore, it would be more suitable to look at the total deaths as a primary safety endpoint for patients with acute HF and with the large targeted sample size, results have ample room to take into account the unrelated deaths whilst maintaining statistical significance.
e. A potential intervention of the selected product that is on trial
MYDICAR (Adeno-Associate Virus Vector 1 (AAV1) carrying the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a gene)), a gene transfer therapy for patients with chronic HF, is currently under phase II clinical trials to determine its safety and feasibility. The reason behind gene transfer of SERCA2a is to ameliorate systolic and diastolic function of the failing ventricle as decreased SERCA2a is closely associated with weakened contraction of the cardiac muscle.  MYDICAR has been shown to improve HF symptoms, haemodynamics and left ventricular remodeling without serious side effects in patients with severe HF. However, 40% of patients developed antibodies against AAV1, thus rendering MYCARDIA unbeneficial. My recommendation would be to administer immunosuppressive treatments concurrently with MYDICAR, and for the long term, development of an immunosuppressive specifically for targeting antibodies against AAV1 is an eventual must to prevent the patient from suffering the side effects of long term use. Another approach, to boost SERCA2a activity, is calsequestrin 2 (CASQ2) overexpression. Calsequestrin attaches calcium within the sarcoplasmic reticulum (SR), lowering the concentration of free calcium within SR, thus reducing the workload of SERCA2a to pump against the high concentration gradient whilst maintaining a large concentration in the SR.  Thus, CASQ2 should be a target, as the joint action with MYDICAR possesses a theoretically reasonable approach in improving the efficacy.
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