57 The future

Heart failure (HF) continues to challenge professionals in all areas of health care, yet remains one of the most rewarding medical conditions to treat. Enormous advances in pharmacological care have led to a doubling in life expectancy for patients with chronic HF; a renewed emphasis on the central haemodynamic abnormalities of HF has led to the widespread uptake of cardiac resynchronization therapy (CRT); and changes in the delivery of health care together with improved monitoring of patients have greatly increased the likelihood of patients receiving the care they need.

No textbook of cardiology is complete without a tour d’horizon considering possible new developments over the next 5–10 years: HF therapy has progressed dramatically in the last 30 years, and will continue to do so over the next 30.

The bulk of the research to date in HF has been on chronic HF, and only recently has there been a new emphasis on acute HF. The interest is driven in large part by pharmaceutical developments—new drugs need to find their niche. One difficulty with dealing with acute HF and acute HF trials has been the classification and definition of acute HF syndromes: it is important that the defining process is tightened up.

Novel vasodilator drugs being studied in acute HF include cinaciguat and relaxin.^1,2 Some new drugs share more than one mode of action: chimeric natriuretic peptides such as CD-NP have both venodilatory and natriuretic effects.^3,4 Similarly, some novel positive inotropic agents being tested in clinical trials have other properties. Isataroxime is a Na⁺,K⁺-ATPase inhibitor which increases SERCA2a activity and is both inotropic and lusitropic.⁵ Urocortins also exhibit powerful inotropic and lusitropic effects.⁶ There are novel myocardial protection agents in development. Adenosine regulators such as acadesine have anti-ischaemic effects and ameleriorate glucose uptake and free fatty acid oxidation, thereby increasing ATP synthesis.⁷ We will see many clinical trials of these novel agents reporting in the next few years.

Therapy for acute HF will become much more evidence-based: the traditional treatments will be subjected to clinical trials, and newer agents being developed and reaching market will have their roles defined. Making sure the right drugs are tested in appropriate populations may be a challenge. For example, the vaptans need to be tested in HF patients with hyponatraemia, endothelin antagonists in HF patients with pulmonary hypertension, and tumour necrosis factor (TNF) antagonists in HF patients with a raised TNF.

The neurohormonal explanation for the pathophysiology of chronic HF and its progression led to the modern treatment regime of angiotensin converting enzyme (ACE) inhibition, β-blockade, and aldosterone antagonism. However, a limit does seem to have been reached: essentially neutral results of trials testing the addition of further neurohormonal antagonists, such as endothelin antagonists (bosentan) and combined ACE/neutral endopeptidase inhibitors (omapatrilat), suggest that any further interference with neurohormones may cause trouble.

Controversies still remain as to which is the better ‘triple therapy’: should patients on ACE inhibitor plus β-blocker be offered either an angiotensin receptor antagonist or an aldosterone antagonist? The question is unlikely to be answered directly, but there will be new data on aldosterone antagonists, particularly eplerenone, in the next few years.

Other developments in the neurohormonal field include the combination of the angiotensin receptor blocker (ARB) valsartan and a neutral endopeptidase (NEP) inhibitor in a single molecule. The NEP inhibitor increases the concentrations of natriuretic peptides in the circulation by preventing their breakdown. Clinical trials are under way.

Moving away from the neurohormonal field, other agents attracting interest include myosin ATPase activators. These drugs potentially improve myocardial contractility by accelerating the productive phosphate-release step of the crossbridge cycle.⁸ They prolong stroke volume, improving the energy efficiency of the contractile apparatus rather than by increasing dP/dt (and hence increasing myocardial oxygen demand) as conventional inotropes do. Clinical studies are at an early stage.

Some lines of evidence suggest that the failing heart is starved of energy.^9,10 For example, a major change in advancing HF is depletion of phosphocreatine.¹¹ Such changes lead to the suggestion that therapy directed at cardiac metabolism may have a role. One possible target is to modulate the substrates used for energy production. Fatty acids are the dominant fuel for myocytes (at least in some circumstances) and whereas, weight for weight, oxidation of fatty acids produces more ATP than oxidation of glucose, it takes more oxygen per mole of ATP produced to oxidize lipid.

Perhexiline and etomoxir both inhibit carnitine palmitoyltransferases (CPT) 1, the enzyme responsible for transporting fatty acids into mitochondria. Trimetazidine inhibits fatty acid oxidation. The use of such agents results in a shift towards predominant glucose metabolism, and small-scale clinical studies have suggested that they may have a role in HF therapy.¹²–¹⁴ Other metabolic approaches include modifying insulin and glucose metabolism with metformin.

Metabolic manipulation is at an early stage of development and larger-scale clinical trials with hard endpoints are now needed.

An important part of HF management will be the individualizing of treatment. The present practice of trying to give all treatments to all patients may not last. Clear examples of the trend include treating only those with iron deficiency with intravenous iron, and only those with left bundle branch block with a CRT device.

If knowledge of the human genome is to make an impact in ‘ordinary’ medicine, then it will be in trying to select the appropriate therapies for the right patients. Genome-wide association studies of, for example, genetic loci associated with hypertension,¹⁵ hold the promise that individually targeted medication regimes will eventually be possible. However, the most promising single genetic polymorphism area widely researched so far has perhaps been the insertion/deletion polymorphism in the gene coding for angiotensin converting enzyme and its relation to the risk of ischaemic heart disease: conflicting results have not led to any advance in therapy.¹⁶

It is unlikely that the answer will be so simple as to depend on a single polymorphism in a single gene: individual enzymes and gene products function only in relation to other enzymes and gene products. A particular polymorphism might have different effects in different environments. Chains of potentially polymorphic enzymes lead to the production of the different active neurohormones, as well as to potentially polymorphic receptors and then polymorphisms in downstream signalling pathway enzymes; in addition, there are polymorphisms in the enzymes responsible for breaking down the neurohormones.¹⁷

Nevertheless, despite these complications, it is possible that an individual patient presenting with HF in the future might be genotyped rapidly, and specific therapy targeted to that person’s individual genetic make-up will be used.¹⁸ Perhaps the first area where an individualized approach might be practicable is in those cases of familial cardiomyopathy with a single-gene defect underlying HF.

The biggest changes with implantable devices will be in patient selection. As with pharmacological therapy, the selection of patients for device therapy is very broad brush at present; for patients receiving a CRT device, only about two-thirds experience a sustained symptomatic benefit, and for patients with an implantable cardioverter-defibrillator (ICD), only a small proportion ever receives an appropriate shock.

Studies already under way will expand and refine the selection criteria for CRT, and address whether (and which) patients in atrial fibrillation or with narrow QRS complexes might benefit. There will be important refinements in technique, allowing careful selection of which potential lead position creates the greatest benefit, and allowing easier positioning of the left ventricular lead in that position.

For ICDs, the indications are likely to narrow markedly as new methods will make the assessment of which patients are at greatest risk of ventricular tachyarrhythmia more precise. The technology will continue to improve: new pacemakers are being developed with a total volume of only 1 cm³, and miniaturization of defibrillators will follow. The burden of an ICD for the patients will thereby decrease, and perhaps incidentally save money for pressed health care systems.

Other developments include the possibility of using devices as neural stimulators: for example, a stimulator positioned in the neck can be used to produce vagal simulation to the heart, thereby redressing the sympathovagal imbalance of chronic HF (see Fig. 57.1).^19,20

Ever more sophisticated monitoring of patients is becoming possible (see Chapter 56). As more and more patients have devices implanted, the remote and, importantly, automatic, monitoring of patients will become widespread. On-board ‘add-ons’ already in use can now measure variables such as activity level and intrathoracic impedance, and newer devices capable of monitoring mixed venous oxygen saturation and even left atrial pressure are being developed. Remote programming of the devices is also possible.

Simplification of telemonitoring equipment is also moving apace. Home telemonitoring can be burdensome, and newer devices simply attached to the skin as patches can detect changes in cutaneous impedance, heart rate, and rhythm and transmit information to the centre using wireless technology via a mobile phone.

CRT improves the mechanical function of the heart without the cost of positive inotropic drug therapy (see Chapter 48). Its success has refocused attention on the underlying mechanics of HF, rather than the secondary effects of neurohormonal activation. Advances in left ventricular assist device (LVAD) therapy make long-term survival with a device implanted as ‘destination therapy’ a present reality,²¹ and the technology will continue to advance. Currently, the source of greatest morbidity with LVADs is drive-line infection, and efforts are being made to have fully implantable systems with internal batteries (see Chapter 51).

Inevitably, devices that can be implanted percutaneously are already being assessed,²² and will become more reliable, and easier to insert. Their widespread use might not only tide patients over an initial episode of cardiogenic shock, but become in turn destination therapy for some patients.

If such devices actually become sufficiently reliable and cheap, it holds out the possibility that the HF syndrome might even become a thing of the past.

The possibility of using pluripotent stem cells to replace damaged organs is very appealing, and has been suggested for a range of conditions including chronic HF. Initial reports were extremely enthusiastic: small, noncontrolled, nonrandomized studies from enthusiasts were reported as showing improvements in many clinical variables. Some patients have heard enough to come to clinic and demand stem cell therapy, convinced that some dramatic intervention may be possible.

There are many potential hurdles to an effective stem cell therapy: which stem cells to use, how to deliver them, and the timing of delivery (Box 57.1). Other remaining problems include that of persuading implanted cardiomyocytes to remain in the heart, and persuading those that do remain to continue to function. In some situations, fewer than 1% of transplanted cells survive.²⁶

Clinical trial results have not provided compelling evidence for the use of stem cells as yet. The most promising overall concept appears to be the use of intracoronary injections of mesenchymal stem cells in patients with HF due to coronary artery disease. A meta-analysis of 18 randomized and nonrandomized trials including 999 patients found that stem cell treatment improved left ventricular ejection fraction by 3.7%, with small decreases in scar size and left ventricular volume. Whether such a small benefit translates into a clinical benefit is not at all clear.

A final possibility for cell therapy is the possibility of persuading surviving differentiated cardiac myocytes to divide and replace damaged cells. There is some evidence that cardiac cells can divide,²⁷

and recruiting the patient’s native cells is obviously attractive. One possible source of appropriate cells is cardiac progenitor cells isolated from endomyocardial biopsies. A trial, CADUCEUS,²⁸ is under way to assess whether the cells help in clinical practice.

For the moment, despite much promise, stem cell therapy for chronic HF is a rather distant dream. Testing of new strategies should surely only take place with in the context of carefully controlled clinical trials to avoid the overdramatizing of results that subsequently prove illusory.

Writing from the perspective of physicians in the developed world, it is all too easy to think of chronic HF as a problem controllable with medication, and the major challenge being delivery of care. For much of the world’s population, access to health care is a major challenge, and the high-technology world of Westernized medicine is not practical. However, it is in the developing nations that HF is increasing in incidence and prevalence. The greatest intervention that can be made to help potential patients with HF is to prevent their getting HF in the first place.

As with other great health care advances in the past (such as the control of infectious disease with improvements in sanitation and the development of vaccination), the greatest impact is in the arena of public health. As ischaemic heart disease will continue to be the commonest cause of HF, tobacco control is perhaps the single most important measure to prevent HF.²⁹ Other measures, such as the widespread availability of a ‘polypill’ treating other risk factors for heart disease (antihypertensives, a statin, aspirin)³⁰ may have something to offer, but the long struggle to be free of tobacco remains perhaps the biggest single challenge for HF.^31,32