Device therapies, including cardiac resynchronisation therapy (CRT) pacemakers and implantable cardioverter defibrillators (ICD), are established treatment options for patients with symptomatic heart failure due to reduced left ventricular ejection fraction (HeFREF) despite optimal medical therapy. Other novel treatments such as ultrafiltration and gene therapy may have a role in future. Here we review these other treatment options.
Cardiac resynchronisation therapy
Cardiac resynchronisation therapy (CRT) is a useful adjunct to optimal medical therapy in patients with left ventricular systolic dysfunction (LVSD) and an ejection fraction (EF) ≤35%. In clinical trials, CRT was proven to reduce both mortality and heart failure hospitalisation rates. CRT also improves symptoms, functional state and quality of life (QoL) (see section on ‘Clinical evidence base for CRT’ below).
What is CRT?
Many patients with LVSD have a delay in the electrical conduction through the heart. The electrical conduction delay is identified on a 12-lead electrocardiogram (ECG) by a widened QRS complex, often meeting criteria for bundle branch block. Over 30% of patients with LVSD have left bundle branch block (LBBB) in comparison to <1% of the general population (figure 1). Around 10% of patients with normal conduction develop new LBBB each year. Atrioventricular (AV) nodal disease, particularly first-degree heart block, is also common in LVSD.1,2
CRT pacing uses the coronary sinus as a route to access a pacing position on the left ventricle via a vein draining the left lateral wall of the heart. The hypothesis is that CRT, which paces the right ventricular (RV) apex (or septum) and LV free wall simultaneously, corrects inter-ventricular dyssynchrony (and shortens the QRS duration). It is commonly assumed that this translates to more co-ordinate LV systolic contraction.
Despite the success of CRT in clinical practice, it is not clear how CRT mediates its benefits. Much discussion has centred on the mechanical consequences of a prolonged QRS duration, particularly:
- late LV contraction relative to right ventricular contraction – inter-ventricular dyssynchrony
- unco-ordinated LV systolic contraction – intra-ventricular dyssynchrony.
Some patients with LVSD are also at high risk of ventricular arrhythmias and CRT can be combined with defibrillation therapy (CRT-D). (Implantable cardioverter defibrillators are covered below). CRT-P is the pacing element of the device alone and is used in patients for whom defibrillation therapy is not appropriate.
CRT has numerous benefits in appropriately selected patients:
- reduced mortality rate
- reduced heart failure hospitalisation rate
- improved New York Heart Association (NYHA) class
- improved six-minute walk test distance
- improved cardiopulmonary exercise testing
- improved quality of life (QoL) questionnaire scores in over two-thirds of the patients undergoing the procedure
- increased systolic arterial pressure
- improved myocardial efficiency – improved LV function without increased LV oxygen consumption
- reduced LV size and mass, and reduction in severity of mitral regurgitation
- in some patients, ‘super-responders’, LV systolic function may ‘normalise’.
However, around 20–30% of patients treated with CRT do not appear to benefit in terms of either symptomatic improvement or improvement in LV size or function. There is no universally agreed definition of ‘response’. It’s not at all clear whether a ‘non-responder’ might actually have deteriorated without the CRT (and hence ‘response’ might be failure to deteriorate), and it’s not clear if lack of clinical response translates into lack of mortality benefit from CRT.
The best predictors of response to CRT are:
- QRS complex ≥150 ms
- LBBB morphology
- non-ischaemic cardiomyopathy
- female sex
- sinus rhythm.
A brief note about mechanical dyssynchrony
The mechanisms underlying the benefit of CRT are not clear. There is no convincing evidence that any one of several measures of mechanical dyssynchrony is associated with the beneficial effects of CRT, and the latest (2014) NICE guidance on CRT has removed any reference to measuring mechanical dyssynchrony on echocardiography as part of patient selection.3
QRS morphology, rather than duration, may the important factor for predicting response and survival following CRT implantation; LBBB is associated with improved survival following CRT implantation compared to patients with non-LBBB QRS morphology.4
However, it may be that a major part of the benefit of CRT is simply to shorten the atria-ventricular delay. Old studies in patients with heart failure and a long PR interval showed that AV sequential pacing reduced mitral regurgitation and could improve some aspects of myocardial function. It may be that CRT (by pacing the left ventricle as well as the right) shortens the AV delay whilst avoiding the potentially harmful effects of RV apical pacing alone.
Patient selection for CRT
CRT is recommended for patients with severe LVSD (left ventricular ejection fraction [LVEF] ≤35%) and bundle branch block (BBB) morphology on ECG who remain symptomatic despite optimal medical therapy. There is no randomised controlled trial (RCT) evidence to support use of CRT in patients with narrow QRS complex (QRS <120 ms). It is also fundamental to note that CRT is not a replacement for medication.
The National Institute for Health and Care Excellence (NICE) provided guidance in 2014 on the use of CRT in patients with severe LVSD based on New York Heart Association (NYHA) class, QRS duration and presence of LBBB. In line with international guidance, NICE no longer stipulates that patients should be in sinus rhythm to be considered for CRT (table 1).
Table 1. NICE guidelines on treatment options with ICD or CRT for people with heart failure who have LVSD with an LVEF ≤35% (according to NYHA class, QRS duration and presence of LBBB)
|<120 milliseconds||ICD if there is a high risk of sudden cardiac death||no recommendations|
|120–140 milliseconds without LBBB||ICD||ICD||ICD||CRT-P|
|120–140 milliseconds with LBBB||ICD||CRT-D||CRT-P or CRT-D||CRT-P|
|≥150 milliseconds without LBBB||CRT-D||CRT-D||CRT-P or CRT-D||CRT-P|
|≥150 milliseconds with LBBB||CRT-D||CRT-D||CRT-P or CRT-D||CRT-P|
|Key: CRT = cardiac resynchronisation therapy; CRT-D = CRT defibrillator; CRT-P = CRT pacemaker; ICD = implantable cardiac defibrillator; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; NICE = National Institute for Health and Care Excellence; NYHA = New York Heart Association
Reproduced with kind permission from NICE3
NICE recommends CRT for patients who meet the following criteria:1
- QRS >150 ms, regardless of BBB morphology or symptoms
- QRS 120-149 ms with LBBB morphology and NYHA II symptoms or worse
- QRS 120–149 ms with non-LBBB morphology and NYHA class IV symptoms.
European Society of Cardiology (ESC) heart failure guidelines recommend a similar approach but broaden the selection criteria for patients with a QRS duration of 130–149 ms and non-LBBB morphology to include those with NYHA II and III symptoms.5
ESC guidelines also recommend CRT over right ventricular (RV) pacing for patients with heart failure with reduced ejection fraction (HeFREF) who have an indication for ventricular pacing and high degree AV block regardless of LVEF or symptoms.
If a patient with a simple pacemaker is receiving a substantial amount of RV pacing, and develops worsening heart failure symptoms despite optimal medical therapy, then an upgrade to CRT is recommended, regardless of LVEF.
How do you implant a CRT device?
A common misconception is that insertion of a CRT device is similar to that of a pacemaker used to treat bradycardia. Whilst some similarities exist there are significant and important differences in terms of the procedure itself and potential adverse effects.
A CRT device is commonly implanted under local anaesthetic and takes one to three hours. The patient may be in hospital overnight.
CRT devices have the following features:
- small battery-powered generator (about the size of a match box) containing circuitry and a battery
- leads (wires) that are placed in the heart using X-ray guidance.
The leads stay in contact with the myocardium at one end, while the other end is connected to the generator.
Insertion of the right atrial and RV leads is performed in the same way as for a pacemaker used to treat bradycardia.
The significant difference for a CRT device is placement of a lead to allow pacing of the LV. In general, a lead cannot be positioned within the LV due to the thromboembolic risk associated with a foreign body inside the systemic circulation.
The LV lead is typically placed transvenously via the coronary sinus (CS) to lie on the epicardial (outside) surface of the left heart.
The coronary sinus lies in the left AV groove, collects blood from the myocardium and drains into the right atrium through the Thebesian valve.
LV lead implantation steps
Pre-shaped guide catheters are used to access the coronary sinus (figure 2). This can prove challenging if there is significant cardiomegaly with associated tricuspid regurgitation. Furthermore, unlike the arterial circulation, the venous anatomy varies considerably from patient to patient.
After coronary sinus cannulation, contrast is injected to visualise the vessel with or without the aid of an occlusive balloon (figure 3).
LV pacing requires placement of a pacing lead down a suitable tributary of the coronary sinus, preferably in a posterolateral location. The lead may be advanced over an angioplasty guidewire into the appropriate position (figures 4 and 5).
A common problem with CRT is inadvertent phrenic nerve stimulation (PNS), which results in diaphragmatic contraction at the programmed pacing rate: a particularly unpleasant side effect. This has been overcome, to a certain degree, by the development of LV pacing leads with multiple pacing points (electrodes) that can be switched on or off electronically without the need to reposition the lead.
Once the LV lead is satisfactorily positioned, the delivery catheter needs to be removed by means of splitting whilst leaving the lead in situ (figure 6).
The majority of adverse events during CRT implantation relate to LV lead placement and include:
- failure to implant LV lead 4.5–8.5%
- coronary sinus dissection 0.5–2.1%
- cardiac perforation/tamponade 0.3–2.1%
- extracardiac stimulation/PNS 0.8–4%
- LV lead dislodgement 0.4%
- death 0.01–0.03%.
Following successful implantation, the CRT device needs to be programmed to ensure as near to 100% pacing as possible. The P wave-to-pacing stimulus interval has to be short to prevent normal LV activation via the AV node.
The device should be checked in the pacing clinic for levels of biventricular pacing (aiming for 100%), arrhythmia detection and pacing variables at set intervals.
Clinical evidence base for CRT
It is important to note that the major CRT RCTs have recruited patients with LVEF ≤35%, mainly in NYHA class II–III, in sinus rhythm with LBBB. Evidence is therefore strongest in this patient group.
Does CRT work in moderate-to-severely symptomatic patients (NYHA class III/IV)?
The COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial (n=1,520) showed a relative risk reduction (RRR) in death of 24% with a CRT-P (p=0.059) and 36% with CRT-D (p=0.003) compared to medical therapy.6
In a similar patient population, the CARE-HF (Cardiac Resynchronisation — Heart Failure) trial (n=813) compared CRT-P to medical therapy.7 The primary end point of time to death from any cause or hospitalisation for a major cardiovascular event occurred in 39% patients with CRT-P compared to 55% patients with medical therapy alone, with a significant reduction in mortality in the CRT arm versus medical therapy alone arm, 20% versus 30%, respectively (p<0.002).
CRT may even be a useful treatment for patients with advanced heart failure: one study published from a single centre found that CRT implantation in patients with severe LVSD and broad QRS complexes who are dependent on intravenous inotropic support can enable LV recovery to the point that patients are weaned off support and survive to discharge.8
Does CRT work in mildly symptomatic patients (NYHA class I/II)?
Both the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronisation Therapy) (n= 1,820, NYHA I 15%, NYHA II 85% of the trial population)9 and RAFT (Resynchronisation–Defibrillation for Ambulatory Heart Failure Trial) (n=1,798, NYHA class II 80%, NYHA III 20% of trial population)10 trials confirmed a similar reduction in heart failure events and survival benefit for CRT in patients with mild symptoms.
In both trials, more than half of the patients had heart failure due to ischaemic heart disease. The benefit of CRT was seen mainly in patients with LBBB and a QRS duration >150 ms. The number needed to treat (NNT) with CRT to gain one-life year over a period of three years is <7 and the NNT with CRT to reduce one hospitalisation is <4.
Does CRT work in patients with atrial fibrillation?
There is no evidence from RCTs that patients with atrial fibrillation (AF) benefit from CRT implantation. RAFT, the only trial recruiting a significant number of patients with AF, showed no benefit in the AF subgroup.7
The subsequent CERTIFY registry (Cardiac Resynchronisation Therapy in Atrial Fibrillation Patients Multinational Registry) compared patients in permanent AF undergoing CRT combined with either AV nodal ablation or rate-limiting medications to patients in sinus rhythm undergoing CRT (AF and AV node ablation [n=443]; AF and rate-limiting medication [n=895]; sinus rhythm [n=6,046]).11
Patients with AF and CRT who had undergone AV node ablation had a similar mortality rate to patients with CRT in sinus rhythm and lower mortality than patients with AF and CRT who were taking rate-limiting medications.9 Only one patient in RAFT had undergone AV junction ablation and it is possible that the neutral results were due to insufficient biventricular pacing in patients with AF.
For every 1% increase in biventricular pacing percentage, the risk of mortality decreases by 6–10% among patients in sinus rhythm with CRT-D.12 Biventricular pacing percentage is inversely associated with mortality in patients regardless of underlying rhythm in a large cohort study (n=36,935).13
Case series of patients with AF and LBBB suggests that CRT might be beneficial, particularly when strategies are used to maximise biventricular pacing rates, either pharmacologically or with AV node ablation.14
However, case series (whether collected together into a ‘meta-analysis’ or not) are no substitutes for clinical trials. Proper RCTs of different strategies for patients with LVSD, AF and LBBB are needed to prevent patients from being exposed to anecdote-based medicine.
Does CRT work in patients who have an indication for a conventional pacemaker but with no heart failure?
The BLOCK-HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) study (n=691, NYHA I or II, LVEF 35-50%) randomised patients who had high degree AV block to either CRT or conventional RV pacing. The primary end point of all-cause mortality, urgent heart failure visit or increase in LV end systolic volume index, occurred in 56% patients with conventional RV pacing, compared to 46% patients with a CRT device, demonstrating superiority of CRT over conventional RV pacing.15
Does CRT work in patients with narrow QRS complex?
The Echo-CRT (Echocardiography Guided Cardiac Resynchronization Therapy) study (n=1,679) recruited patients with narrow QRS complexes and echocardiographic evidence of mechanical dyssynchrony. CRT did not confer any benefit to patients with narrow QRS complexes and was stopped early for futility.16 However, the trial was not included in the NICE Assessment Group’s systematic review, hence the inclusion of patients with QRS >120 ms (rather than >130 ms as in ESC guidance) in NICE recommendations for CRT.
Does CRT work in patients with mild or moderate LVSD?
As with assessing efficacy of a new pharmacological intervention, such as an ACE inhibitor, initial trials concentrated on selective high-risk and/or highly symptomatic patient groups. This is also true of CRT. To date, no RCT has been published on the efficacy of CRT in patients with heart failure with a normal ejection fraction, or mild or moderate LVSD. Studies are currently ongoing (NCT 03338374).
Does CRT work in patients without LBBB?
An individual patient meta-analysis of all randomised controlled data of CRT (n=3,872) found that the reduction in mortality or hospitalisation with heart failure with CRT, compared to medical treatment alone, was only statistically significant in those with LBBB morphology (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.55 – 0.78) but not in patients with RBBB (HR 0.74, 95% CI 0.44–1.23) or non-specific interventricular conduction delay (HR 0.82 (0.48–1.41). However, the same analysis found that patients with longer QRS duration derived greatest benefit from CRT implantation regardless of QRS morphology. Additionally, there was a signal that CRT may be associated with greater risk of mortality or hospitalisation with heart failure in patients with QRS duration <130 ms.17
The European Society of Cardiology (ESC) and NICE subsequently attempted to distil these findings into usable clinical guidelines. The ESC guidelines recommend CRT for symptomatic patients with LBBB and QRS >130 ms (class I recommendation – ‘indicated’) but only advise consideration of CRT in patients with RBBB and QRS >130 ms (class IIb recommendation – ‘may be considered’). CRT is contraindicated in patients with QRS <130 ms.5 NICE recommend CRT for symptomatic patients with LBBB and QRS >120 ms with CRT only indicated in patients with RBBB if they have a QRS >120 ms and NYHA IV symptoms or QRS >150 ms.
Implantable cardioverter defibrillators (ICDs)
Patients with heart failure are at increased risk of life-threatening arrhythmias,18 and sudden death is a common mode of death in patients with heart failure, even amongst those with mild symptoms.19
Amiodarone may reduce the incidence of ventricular arrhythmia in patients with heart failure but has no impact on overall mortality and is often associated with a high rate of toxicity which limits its long-term use.20 Other anti-arrhythmic medications such as flecainide, dronedarone and disopyramide are contraindicated in patients with heart failure.21
ICDs reduce mortality in patients with heart failure and history of symptomatic sustained ventricular arrhythmias.22.23 Prophylactic ICD implantation also reduces sudden cardiac death24 and mortality in patients with HeFREF due to ischaemic and non-ischaemic cardiomyopathy.25,26
Patient selection and guidelines
Careful patient selection is required. Survival benefit is uncertain for patients with LVEF >35% and in patients with mild heart failure (NYHA II), the number-needed-to-treat is high (around 50 devices are required to prevent one death per year).27
Additionally, in patients with moderate or severe heart failure, a reduction in sudden death from prophylactic ICD implantation may be offset by an increase in death due to worsening heart failure.
The intent of ICD implantation is to improve survival and thus the decision to treat should be taken in the context of the patient’s prognosis and their own view of their quality of life.
ICD implantation is not recommended for patients with NYHA IV symptoms or those who are expected to die of other causes within a year.4 Patients should be counselled regarding treatment intent and complications such as inappropriate shocks.
ICDs should be deactivated in patients with deteriorating heart failure, terminal illness or those with a ‘do not attempt cardiopulmonary resuscitation (DNACPR)’ order in place. Generator changes should only be undertaken after careful reassessment of treatment aims.4
Both NICE and ESC recommend secondary prevention ICD implantation in all patients who have recovered from ventricular arrhythmias that caused haemodynamic instability.2,4
ESC guidelines currently recommend ICD implantation for primary prevention in patients with symptomatic HeFREF (NYHA II and III) and LVEF <35% despite more than three months of optimal medical therapy. NICE (table 1) also recommend primary prevention ICD implantation in asymptomatic patients with LVEF <35% and QRS >120 ms. In patients at high risk of sudden cardiac death, ICD should be considered regardless of QRS duration.2,4 Both guidelines recommend careful evaluation of prognosis before ICD implantation.
Inappropriate shocks were a common complication of ICDs (8-40%), usually triggered by AF, other supraventricular tachycardias or artefact.28 More modern programming approaches have reduced the risk of inappropriate discharge: in particular, anti-tachycardia pacing and longer delays between arrhythmia detection and ICD therapy can reduce the risk.29
Other complications of ICD implantation include:30
- lead displacement – 3.1%
- generator-related complications – 2.7%
- infection – 1.5%
- haematoma – 1.2%
- pneumothorax – 1.1%.
Unanswered questions include:
- Whether an ICD is beneficial for patients with dilated cardiomyopathy.
- The only trial designed to answer the question directly was neutral overall, with a signal that perhaps younger patients might benefit and older ones rather less so.22
- Whether an ICD confers additional benefit to a CRT device.
- ICDs appear to be most helpful in patients with prolonged QRS; in trials in which large numbers of patients in the control group (no ICD) have had a CRT (COMPANION and DANISH), the ICD does not seem to add further benefit.
More trials (as ever!) are needed.
Other device-based treatments
Invasive intra-cardiac pressure monitoring
The majority of patients admitted with heart failure have fluid retention; a consequence of increased intra-cardiac and pulmonary pressures which may be detectable on invasive monitoring several weeks before overt congestion manifests. Several implantable devices have been developed that remotely measure intra-cardiac pressures.
The CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial (2011) of the CardioMEMs device (which measures pulmonary artery pressure) is the largest RCT of such devices to date. The investigators enrolled 550 patients (average age 61 years, NYHA class III with an admission to hospital with heart failure within the preceding 12 months, ~20% of whom had an LVEF >40%) all of whom had the CardioMEMs device implanted. Patients were then assigned to either a ‘treatment’ group, in which investigators were aware of the pulmonary artery pressure, or a control group in which investigators were ‘masked’ to the pulmonary artery pressures.
Heart failure medications and diuretics were titrated based on pulmonary artery pressure (where known) and patient symptoms and signs assessed over the telephone at pre-determined intervals. There was 28% reduction in the primary end point of the rate heart failure hospitalisation after six months in the treatment group compared to the control group.31
Longer term outcomes were similarly better in the treatment group compared to the control group with reductions in heart failure hospitalisation rate (HR 0.67, 95% CI 0.55–0.80, p<0.0001), all-cause hospitalisation rate (HR 0.84, 95% CI 0.75–0.95, p=0.0003), and combined end point of death or heart failure hospitalisation rate (HR 0.77, 95% CI 0.60–0.98, p=0.03) during the 18-month randomised access period.32 However, there was no mortality benefit with continuous pulmonary artery monitoring (19% vs. 23%, p=0.23) and it is unknown whether the costs involved in implanting, monitoring and maintaining the devices are outweighed by the clinical benefit.
The MultiSENSE (Multisensor Chronic Evaluations in Ambulatory Heart Failure Patients) trial (n=900, average age 66 years, 94% NYHA II–III, median NTproBNP 754 ng/L) found that an algorithm using variables measured by pre-implanted CRT-D devices could identify patients at greater risk of heart failure related events (death, hospitalisation with heart failure, increased diuretic treatment without hospitalisation). Remote identification of patients at greater risk may allow earlier intervention that reduces the rate of adverse outcomes although this was not tested in the study.33
The HOMEOSTASIS (Hemodynamically Guided Home Self-Therapy in Severe Heart Failure Patients) trial (n=45, average age 66 years, average LVEF 32%, NYHA II-III) established the safety and potential outcome benefits of titration of heart failure medications based on readings from an implantable pressure monitor in the left atrium (HeartPOD).34 Medication changes depending on readings had been pre-programmed into the device by investigators with the broad aim of reducing or withdrawing diuretics from patients with low left atrial pressures or increasing diuretic in those with high pressures. These changes could be implemented by patients based on instructions from the device without involvement of the medical team.
LAPTOP-HF (Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study) studied the HeartPOD device in patients with HeFREF and NYHA class III symptoms. The trial was stopped early due to a high rate of procedure-related complications on insertion of the device.35 Amongst the 486 patients enrolled (out of a planned 730), titration of treatment based on left atrial pressure was associated with a 41% reduction in the risk of admission with heart failure compared to the control group (p=0.005).
One problem with the above trials, and indeed with home telemonitoring in general, is that each device produces a large volume of data, much of which is difficult to interpret remote from the clinical context. Another issue is that of the time taken to review and act upon the data generated; it is quite possible that, by the time a doctor or nurse has had a chance to review the data and make a clinical decision, the adverse event predicted (e.g. hospitalisation with heart failure) has already occurred.
Patient directed titration of heart failure medication (such as in HOMEOSTASIS and LAPTOP-HF) would ultimately bypass this step and may prove beneficial in the future. Interest in remote monitoring remains high and the advent of ‘wearable technology’ may lead to devices that can direct patients to manage their condition without the time-consuming involvement of their overstretched medical team or the risks associated with implantable devices.
Cardiac contractility modulation
A cardiac contractility modulation (CCM) device is an implantable device that delivers a low-voltage, biphasic current to the myocardium after the detection of QRS (during the ventricular refractory period). The result is to increase the strength of LV contraction without triggering a new action potential. Implantation is similar to that of a simple pacemaker with right atrial and ventricular leads.
Early studies suggest that CCM devices can improve exercise tolerance and quality of life in patients with HeFREF, NYHA class II–IV symptoms and narrow QRS (<120 ms). The technology is in its infancy, however, with no established effect on mortality or morbidity.36 More work is needed.
Recent years have seen a variety of implantable devices developed that are able to increase vagal tone by electrical stimulation of different nerve fibres with implantable devices. Increased vagal tone (activation of the parasympathetic nervous system) may be potentially beneficial for patients with heart failure in that it may counteract some of the deleterious effects of sympathetic activation.
Four different methods of neuro-modulation have been tested in patients with heart failure: spinal cord stimulation, carotid sinus nerve stimulation or baro-reflex activation therapy, cervical vagal nerve stimulation and intracardiac AV-nodal stimulation. There are few trials of note.
The DEFEAT-HF (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure) trial of implantable spinal cord stimulators (n=66, average age 61 years, average LVEF 27%) found no change in biomarkers, echocardiographic or exercise variables, functional capacity or quality of life with spinal cord stimulation compared to medical treatment.37
Conversely, the HOPE4HF (Barostim® Hope for Heart Failure) study (n=146, average age 64 years, average LVEF 24%, median NTproBNP 1,422 ng/L) found that an implantable device that stimulated the baroreceptors in the carotid sinus thus reducing sympathetic tone (and increasing parasympathetic activity) was associated with improved exercise capacity, quality of life, symptom severity and NTproBNP levels six months after implantation compared to medical therapy alone.38
The INOVATE-HF (Increase of Vagal Tone in CHF) study of a similar device in patients with HeFREF (n=707, average age 61 years, average LVEF 24%) demonstrated improvements in quality of life, symptom severity and exercise capacity but had no effect on the primary end point of mortality or heart failure hospitalisation rate, which, alongside a trend towards harm in the treatment arm, led to early termination of the study.39
More work will be required to clarify what, if any, role neuromodulation may have for patients with heart failure. While there are many devices available, the failure and early termination of the largest study to date (INOVATE-HF) may signal the beginning of the end for neuromodulation as a treatment for heart failure.40
Sleep-disordered breathing in heart failure
Sleep disordered breathing (SDB) is a description of abnormal breathing patterns during sleep, affecting up to half of patients with heart failure. The condition is associated with poor prognosis.41
There are two major types of SDB:
- obstructive (upper airway collapses but respiratory effort continues)
- central (respiratory drive ceases).
Trials investigating the treatment of SDB with adaptive servo ventilation in patients with acute (CAT-HF) and chronic heart failure (SERVE-HF) have failed to show outcome benefit.42,43 In fact, treatment with adaptive servo ventilation was associated with increased risk of all-cause and cardiovascular mortality in SERVE-HF.
The reason for the increased mortality in SERVE-HF is not clear. It appeared to be related to an increase in the risk of sudden death in the treated patients. Adaptive servo-ventilation should certainly not be used routinely for patients with central sleep apnoea, although continuous positive airways support for patients with symptomatic obstructive sleep apnoea should be considered on an individual basis.
Ultrafiltration as a treatment of venous congestion in heart failure was first investigated in the 1970s.44 It has since been the focus of RCTs to explore its possible role as an adjunct or even potential alternative to loop diuretics in patients with severe fluid retention (figure 7).
Ultrafiltration is an extracorporeal process that attempts to mimic filtration in the Bowman’s capsule. Venous blood is removed from the body and passed through a circuit with a membrane permeable to smaller molecules, such as water and electrolytes. Blood is maintained at a pressure greater than the transmembrane pressure; hydrostatic pressure forces water and solutes to cross the membrane and out of the blood. The intravascular space is then refilled with fluid from the interstitium, thus reducing congestion.
It differs from dialysis in that the latter is usually intermittent, allowing solutes – which can be larger sized molecules (e.g. toxins, lactate) – to diffuse through a semi-permeable membrane down the solute’s concentration gradient into the dialysate fluid.
Using ultrafiltration, fluids can be removed rapidly – at rates of up to 500 ml/hour (up to 9.6 litres per day) – although, in practice, 150–300 ml/hour (3.6 to 7.2 litres per day) is considered adequate. Lower rates are advised when there is RV disease or pulmonary arterial hypertension, as there is a higher risk for potential haemodynamic disturbance with high fluid removal rates.
Ultrafiltration rate should be monitored and adjusted according to clinical variables such as blood pressure. Serial haematocrit measurements can help monitor adequate refilling of the intravascular space with fluid from the interstitium.45,46
By ensuring that intravascular volume does not decrease, i.e. ultrafiltration rate (removal of fluid from the body) does not exceed plasma refilling rate (movement of fluid from tissues to bloodstream), further renin angiotensin aldosterone system activation, hypotension, and renal injury may be prevented.47 Another advantage of ultrafiltration is that more sodium can be removed (and less potassium) as compared to diuretic therapy.48
With newer machines, ultrafiltration can be performed using peripheral or central venous access. The typical treatment period may vary from 24–72 hours, mainly limited by the fact that the ultrafiltration membranes only last up to 72 hours. Diuretics are stopped during ultrafiltration. Urine output can be monitored but it is not essential to do so.
Clinical studies with ultrafiltration
The role of ultrafiltration in heart failure remains uncertain and further research is required. Ultrafiltration is expensive in terms of equipment and staff training and the economic impact of the therapy as an initial strategy for acute heart failure may limit its use.53 However, it might be that early ultrafiltration reduces length of stay for acute heart failure, which currently stands at 10–11 days in the UK. Halving length of stay would make ultrafiltration appear a very attractive alternative to conventional treatment.
The ESC guidelines recommend that ultrafiltration may be used in patients who fail to respond to diuretics or have end-stage renal failure and its complications.2
Clinical scenarios in which ultrafiltration may be indicated include:
- venous congestion resistant to high dose diuretic therapy
- oliguria refractory to fluid resuscitation
- refractory severe hyperkalaemia (>6.5 mmol/L)
- acidaema (pH <7.2)
- renal failure
- urea >25 mmol/L
- creatinine >300 μmol/L.
Patients in whom ultrafiltration is contra-indicated have:
- poor venous access
- cardiogenic shock requiring inotropic support
- advanced renal disease (consider renal replacement therapy instead such as haemofiltration or peritoneal dialysis).
Potential complications of treatment with UF are:
- venous line infection
- increased risk of haemorrhage as patients are anticoagulated with heparin haemodynamic disturbance with hypotension
- acute kidney injury.
Gene therapy as a concept
Chronic heart failure (CHF) is associated with activation of stress-signalling pathways which alter gene expression in the failing cardiomyocytes through changes in transcription factors, co-regulators and microRNAs.
The underlying trigger for these changes is, in part, chronic stimulation of beta-adrenergic receptors (β-ARs) leading to alterations in gene expression by cAMP-dependent signalling pathways.
Some of the changes in gene expression are currently being exploited as biomarkers in heart failure: for example, up-regulation of the human NPPB gene for N-terminal pro-brain natriuretic peptide (NT-proBNP). However, many of the changes to gene expression in heart failure affect functional proteins and are damaging to the heart.
Gene therapy is “the introduction or alteration of genetic material within a cell or organism with the intention of curing or treating a disease”,54 and may allow direct modification of the damaging changes to gene expression that are associated with heart failure.
In therapeutic terms, this either increases the production of a deficient protein, commonly by delivering a new copy of the relevant gene, or inhibits production of a deleterious protein, for example by interfering with ribonucleic acid (RNA).
Although there is much enthusiasm for gene therapy and much promising laboratory data, there are no convincing clinical trial data in humans as yet.
Potential targets for gene therapy
A plethora of changes occur in gene expression in heart failure affecting proteins involved in the following:
- contractile proteins (α– myosin heavy chain and β– myosin heavy chain)
- cytoskeleton (titin and tubulin)
- pro-inflammatory cytokines (TNF-α and IL-6)
- receptors (β-ARs and ryanodine receptors)
- transporters (SERCA and Na/K ATPase)
- metabolism switches from free fatty acids to carbohydrate (glucose transport [GLUT], pyruvate dehydrogenase kinase [PDK])
- ion channels (Nav1.5 and Kir)
- calcium binding proteins (calmodulin and phospholamban)
- exchangers (sodium-calcium exchanger [NCX] and sodium/proton exchangers [NHX])
- kinases (CaMKII).
Vectors and delivery systems for gene therapy
Once the therapeutic gene has been selected, an appropriate vector and delivery method is required. There are various techniques used in laboratory research (table 2) but in the small numbers of clinical trials that have been carried out, the most common vector is the adeno-associated virus and the delivery method is the antegrade intracoronary infusion without balloon occlusion.
Clinical experience of gene therapy
Numerous animal studies have targeted various genes and used a variety of vectors and delivery methods. The genes that have been successfully targeted encode for proteins involved predominantly in either calcium handling (sarcoplasmic [endoplasmic] reticulum calcium ATPase (SERCA2a), phospholamban, protein phosphatase 1, inhibitor-1, S100A1 and small ubiquitin-related modifier 1) or the β-adrenergic system (upregulation of β-ARs, inhibition of G-protein coupled receptor kinases, activation of adenyl cyclase).
Many of these laboratory studies have shown promise, but the only area that has advanced to clinical trials is one which targets the SERCA2a gene using an adeno-associated virus as the vector, delivered during an intracoronary infusion. The function of SERCA2a in the normal physiology versus heart failure state is shown in figure 8.55
Results have been disappointing: phase II trials CUPID 2 (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Patients with Cardiac Disease) and AGENT-HF (Effect of Intracoronary Administration of AAV1/SERCA2a on Ventricular Remodelling in Patients with Advanced Systolic Heart Failure) failed to show an improvement in ventricular dimensions or outcome with gene therapy that restored function of SERCA2a in patients with HeFREF.56,57
One frequently cited reason for the failure of both the CUPID 2 and AGENT-HF studies was the relatively low myocardial uptake of the viral vectors compared to the preclinical animal studies. Advancements in more ‘cardio-tropic’ vectors mean that work to find an effective genetic therapy for patients with heart failure continues.
Genetic therapies have been proposed as a potentially curative treatment for heritable causes of heart failure such as muscular dystrophy, but translating promising results in animal models into clinical trials is proving problematic.58
Finally, there is ongoing interest in ‘gene-silencing’ therapies for transthyretin (ATTR) amyloidosis, an increasingly recognised cause of heart failure with normal ejection fraction in elderly patients. Production of transthyretin occurs in the liver and can be interrupted by ribonucleic acids (RNA) specifically engineered to inhibit translation of the gene. Three such so-called ‘small interfering RNAs’ exist: revusiran, inotersen and patisiran.
Treatment with inotersen or patisiran can improve various neurological end points in patients with hereditary ATTR and polyneuropathy compared to placebo and trials are ongoing (NCT01960348).59,60 However, none of these studies had heart failure related end points and enrolment into the only study involving patients with cardiac amyloid, the ENDEAVOUR (Revusiran in Patients With Transthyretin Mediated Familial Amyloidotic Cardiomyopathy) study of revusiran, was recently halted due to safety concerns arising from the phase II extension study in which more than half of patients receiving revusiran developed peripheral neuropathy.61
Stem cell therapy
On the cellular level, heart failure is characterised by the loss of functioning myocytes. Regenerating myocardial tissue with cell therapies is a potential future treatment for heart failure. Types of cell under investigation include bone marrow mononuclear and mesenchymal stem cells, skeletal myoblasts and cardiac progenitor cells.
The field is littered with many small studies conducted in single centres with no control groups and the promising preclinical data is yet to translate into convincing benefit in phase II and III trials. Insufficient retention of the cells (delivered by injection or infusion) is a significant problem and generation of ‘new’ myocardium is yet to be demonstrated.62,63 Ventricular arrhythmia is a common adverse event in clinical trials, and the trials have only involved a very select group of patients. The safety of stem cell therapy has not yet been confirmed. Additionally, ethical issues surrounding the use of human embryonic stem cells may limit further work in the field.
Gene and stem cell therapy for heart failure in its infancy but much laboratory research supports its possible role. There are many possible genetic targets and gene therapy may become a useful treatment in heart failure. Similarly, stem cell therapy to replace dead myocardium may yet find a role in heart failure management. However, early clinical trials have been disappointing and there are still problems to overcome.
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