The Ever-advancing Nature of Medicine: New Treatments for Matters of the Heart

Why do I love the heart?

The heart was probably the first organ which we were taught about in secondary school, at probably around the same time as when I first actually began enjoying biology lessons. Coincidence? Most definitely not. I was captivated by the heart - its functions seemed so simple, yet so essential for the health of animals. As I progressed through GCSE and A level biology and into university studies, my love for cardiac biology has just grown. I have explored more intricate, fascinating details of cardiac development and functioning, and different ways in which these can go wrong. Unfortunately, in our modern society, heart disease is one of the leading causes of death and is associated with many co-morbidities including obesity and hypertension. Overall, I’ve found that developing on my very early curiosities of the heart is very satisfying and I am excited about applying my knowledge to help clinical situations.

In this blog, I will discuss some of the basic theories behind heart failure. I will then discuss how drugs are used clinically to target these theories - illustrating how scientific principles can be translated to patient-centred, clinical practice. I will also mention some of the latest clinical evidence on some of these drugs which will hopefully highlight the ever-advancing nature of medicine and provide inspiration for the future.

What is heart failure?

Heart failure can be caused by any condition which reduces the ability of the heart to provide adequate oxygenated blood to the body tissue. As of September 2018, NICE reported that there were approximately 920,000 people in the UK diagnosed with heart failure, however incidences are increasing due to a rise in obesity rates and the ageing population. Failure of the left side of the heart can lead to breathlessness due to lack of blood supplied to the peripheries, especially during exercise, and confusion due to lack of blood supply to the brain. Failure of the right side of the heart can lead to an increased venous blood pressure which can cause peripheral oedema and hypertension. Failure of both ventricles at the same time is common.

Target 1: lack of kidney action

Heart failure causes a lack of kidney perfusion, reducing the efficiency of renal functioning. This can lead to fluid overload as there is less loss of fluid through urine, and fluid overload can worsen heart failure. This is the theory behind the routine use of diuretics for treatment of generalised heart failure (NICE guidelines), including furosemide, thiazide and spironolactone.

The drug spironolactone is an aldosterone antagonist. Aldosterone usually increases the reabsorption of water by the kidney (reducing urine production) - hence spironolactone inhibits the function of aldosterone. This reduces body fluid retention. Interestingly, recent studies have suggested that spironolactone has added benefits - it appears to increase contractility of the left ventricle by reducing ventricular fibrosis. Ventricular fibrosis is caused by excess proliferation of cardiac connective tissue, which compromises the function of ventricular muscles cells and reduces ventricular contractility. In the Aldo-DHF randomised controlled trial (2013), it was found that patients with increased collagen cross-linking were more resistant to the therapeutic effects of spironolactone - which may suggest that spironolactone threatens the integrity of collagen in the ventricle connective tissue. Patients with more collagen cross-linking may have more stable collagen which is resistant to breakdown by spironolactone. This reflects the importance of personalised treatment options.

Target 2: hypertension

Lack of kidney perfusion also leads to release of renin, which converts angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II causes vasoconstriction which, as well as fluid overload, can lead to high blood pressure and forces a failing heart to work even harder to maintain peripheral perfusion. This is the theory behind the use of drugs which lower blood pressure for patients with heart failure. ACE inhibitors, eg captopril and enalapril, are the first line treatment for heart disease (NICE guidelines). By inhibiting the formation of angiotensin II, these drugs reduce peripheral vasoconstriction and hence reduce blood pressure.

However, ACE inhibitors are not tolerated in all patients. Alternative anti-hypertensive drugs recommended by NICE include angiotensin receptor blockers, eg valsartan and losartan. These also prevent peripheral vasoconstriction by blocking the action of angiotensin II.

Target 3: sympathetic nervous system

When the body is under stress, as in the case of heart failure, there is increased activation of the sympathetic nervous system. This means that there are increased concentrations of circulating adrenaline and noradrenaline. Increased adrenaline input in particular on the heart leads to an increase in heart rate. An increased heart rate can exacerbate symptoms of heart failure, as it increases the heart’s oxygen requirement, which cannot be provided by a failing heart. It can also increase the risk of cardiac arrhythmias.

Adrenaline acts on cardiac beta receptors - for this reason, drugs which act as beta receptor blockers partially block the action of adrenaline on the heart and hence are commonly prescribed for heart failure. Beta blockers include propranolol and atenolol. However, beta blockers can also further reduce cardiac contractility, hence NICE recommends that beta blockers should be avoided if patients with heart failure already have reduced cardiac contractility (heart failure with reduced ejection fraction).

Target 4: cardiac function

At the start of a cardiac muscle contraction, there is a release of calcium ions (Ca2+) into muscle cells, and removal of Ca2+ from the cells leads to muscle relaxation. In this way, cardiac muscle contractions are dependent on consistent Ca2+ cycling. In mice models with cardiac failure, there is evidence of altered Ca2+ cycling during cardiac contractions, which leads to a fall in their contractility. Irregular Ca2+ cycling can also lead to cardiac arrhythmias and irregular ventricular contractions. This can reduce the volume of blood being ejected from the heart, which can mean less oxygenated blood is supplied to the heart itself, further precipitating heart failure. Ca2+ channel blockers, eg amlodipine and verapamil can help regulate Ca2+ cycling in cardiac muscle and reduce the risk of arrhythmias. However, NICE recommends that Ca2+ channel blockers should also be avoided with patients with heart failure with reduced ejection fraction, as Ca2+ channel blockers can also reduce the contractility of cardiac muscle.

What’s next?

I have discussed some of the most common drugs which have been approved for treatment of cardiac failure and emphasised how many factors need to be considered when prescribing these drugs to individual patients. However, not all treatment options for heart failure are drug based. With emerging technology, new physical devices can be used to reduce the risk of cardiac arrhythmias. These include implantable cardioverter defibrillators and ventricular assist devices. Furthermore, cardiac gene therapy is also a field which is being researched into extensively. Finally, of course, patients are advised to follow as healthy a lifestyle as possible.