Heart failure highlights in 2012–2013

Introduction

As in previous years,1 several pioneering scientific discoveries and paradigm-shifting clinical trials were published this year. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis, and treatment of heart failure (HF) that were published in 2012 or 2013. The most important clinical trials are summarized in Table 1.

Pathophysiology

Loss of functional myocardium is the major cause for cardiac dysfunction and HF. The ability to regenerate functional myocardium has therefore been considered the holy grail of cardiovascular science for decades. While initial approaches were focused on injection of undifferentiated stem cells or their progeny into diseased myocardium,13 14 the paradigm appears to have shifted towards manipulation of resident cardiac tissue instead. In 2012, remarkable progress was made in this field. First, Senyo et al. showed that pre-existing cardiomyocytes rather than resident cardiac progenitor cells are the dominant source of endogenous cardiomyocyte renewal. These findings indicate that stimulation of endogenous cardiomyocyte proliferation could result in regeneration of diseased myocardium.15 Secondly, a high-throughput screen of human microRNAs (miRNAs) identified miR-590-3p and miR-199a-3p to be potent inducers of cardiomyocyte proliferation in vitro and in vivo.16 Remarkably, forced expression of these miRNAs in cardiomyocytes after myocardial infarction was associated with almost complete recovery of cardiac viability and function. Thirdly, two independent groups convincingly demonstrated that cardiac fibroblasts can be reprogrammed into fully functional cardiomyocytes in their native environment, thereby reducing myocardial infarct size and improving cardiac function.17 18 Whether these experimental observations will translate into clinical practice remains to be established.

Another (re) emerging field of HF research is metabolic and mitochondrial dysfunction.19 Mitochondria account for ∼30% of cardiac mass and serve crucial roles in energy production, calcium handling, and cell viability.20 However, mitochondria are also an important source of cardiac pathology. For instance, Oka et al. revealed that ‘rogue’ mitochondrial DNA that escapes from mitophagy is a major source of cardiac inflammation and may cause cardiac dysfunction.21 Furthermore, several signal transduction pathways that have been implicated in cardiac pathophysiology appear to do so in part through modulation of mitochondrial function and integrity.22 23 While it is generally accepted that the failing heart is energy starved, direct evidence for this assumption is sparse. Gupta et al. tested this hypothesis by generating mice in which myocardial energy availability is increased through conditional cardiomyocyte-specific overexpression of creatine kinase (CK).24 Overexpression of CK in mice with HF resulted in marked improvement of cardiac function, but the functional improvement was rapidly lost when CK expression was normalized to control values. While these observations strongly suggest that the failing heart is energetically starved, clinical evaluation of cardiac substrate availability will be challenging. For instance, circulating levels of metabolic substrates are not correlated with exercise capacity or survival in patients with HF.25 Recent advancements in magnetic resonance spectroscopy suggest that detailed non-invasive analysis of cardiac mitochondrial respiration may become available soon.26

Co-morbidities in heart failure

In the past decade, the importance of concomitant organ dysfunction in the syndrome of HF has increasingly been recognized. Not only are co-morbidities frequently present in patients with HF, but their presence is also associated with an increased risk for death and rehospitalizations for HF. Among known co-morbidities, renal dysfunction is now a well-established and important co-morbidity. However, the prediction of deterioration of renal function in HF is still difficult. In a study of 399 acute HF patients, Collins et al. found that urinary neutrophil gelatinase-associated lipocalin (NGAL) may identify patients at risk for worsening renal function and impaired clinical outcome.27 Interestingly, data from REVERSE, a trial on cardiac resynchronization in mild HF, suggested that the presence of renal impairment is not an innocent bystander, but also hampers the ability of cardiac reverse remodelling to occur by cardiac resynchronization therapy (CRT).28 Most important data on renal function in HF in 2012 come from the CARRESS-HF trial where ultrafiltration was compared with a stepped diuretic regimen in patients who had deterioration in renal function and persistent signs of congestion.2 In CARRESS-HF, ultrafiltration showed higher increases in serum creatinine, despite similar reduction in weight. Overall, there were several potential problems in the design and execution of CARRESS-HF; there were crossovers among treatment groups, patients were not truly resistant to diuretics considering strong diuresis in the medical therapy group, and patients were allowed inotropes in the medical group, but not in the ultrafiltration group. Therefore, the interpretation of the study is difficult from a clinical perspective. For now, standard ultrafiltration therapy in these patients does not appear to be justifiable.

Anaemia is also common in HF patients, and the presence of anaemia has consistently been associated with increased morbidity and mortality in HF. However, several mechanisms may contribute to the high prevalence of anaemia in HF. Blunted erythropoietin production and reduced sensitivity of bone marrow to endogenous erythropoietin have consistently been implicated.29 30 Treatment with recombinant human erythropoietin would thus appear to be feasible. Based on two semi-large phase II clinical trials,31 32 which showed potentially promising effects on quality of life and clinical outcome, the RED-HF trial was initiated in 2006. In this double-blind, placebo-controlled trial, 2278 patients with systolic HF and mild-to-moderate anaemia were randomized to receive darbepoetin alpha or placebo for a median follow-up of 28 months.33 At baseline, the groups were well balanced,34 and the pre-specified haemoglobin target was achieved in the active treatment group. However, the incidence of the primary composite endpoint of all-cause mortality or hospitalization for worsening HF did not differ between the groups.6 There were also no significant between-group differences in any of the secondary outcomes. Instead, a slight but significant increase in the incidence of thrombo-embolic events was observed on darbepoetin alfa treatment. While these results will probably lead to the end of therapeutic exploration of erythropoietin in HF,35 this does not mean that anaemia should be dismissed as a therapeutic target altogether. For instance, correction of iron deficiency, a well-established cause of anaemia, has recently been shown to improve exercise capacity and quality of life in HF patients with or without anaemia.36 37

The incidence of diabetes is increasing, and diabetes is a common precursor of HF.38 Indeed, HF that occurs in diabetic patients is considered to result from a unique diabetes-related mechanism, which is often referred to as ‘diabetic cardiomyopathy’. Several mechanisms have been attributed as underlying diabetic heart disease,39 and specific therapeutics for this emerging cardiomyopathy are under investigation.40 The concept that diabetes inevitably propagates into diabetic cardiomyopathy was, however, challenged in 2012. In a post-hoc analysis of the ASPIRE trial, patients with diabetes were not more prone to develop left ventricular (LV) dilatation or LV systolic dysfunction.41 Moreover, long-term and detailed follow-up of Zucker diabetic rats showed that, despite severe diabetes with renal complications, these rats did not develop systolic LV dysfunction.42 Finally, antidiabetic drugs may have beneficial cardiac effects. For instance, sitagliptin, a dipeptidyl peptidase IV (DPP4), improved cardiorenal function in HF by interfering with brain natriuretic peptide (BNP) degradation.43

Cognitive impairment is a lesser known co-morbidity in HF patients. Compared with matched controls, patients with decompensated HF displayed significantly impaired cognitive function. Although cognitive performance was restored to some extent after recompensation, it did not normalize to control values.44 A history of stroke has been observed in up to 10% of patients with HF, and ∼10% of patients with acute stroke have HF.45 The latter was found to be mainly attributable to cardio-embolism secondary to atrial fibrillation (AF). The presence of HF in acute stroke was found to be predictive of clinical outcome, independent of the presence of AF. Finally, patients with chronic HF have a reduction in bone mass loss, even increased compared with age-matched controls, and this was associated with secondary hyperparathyroidism.45 Since it was also associated with clinical outcome, this highlights the need to look more closely at less frequent co-morbidities in HF, and may call for a multidisciplinary approach.

Atrial fibrillation

Atrial fibrillation and HF remain one of the most important cardiovascular problems in the 21st century. From the Framingham Heart Study it is known that individuals with both AF and HF have a worse prognosis than individuals with either condition alone.46 Since AF can beget HF and vice versa, via diverse mechanisms and potential genetic susceptibility, whether AF or HF develops first may affect prognosis. Smit et al. studied 182 consecutive AF patients hospitalized for chronic heart failure with reduced ejection fraction (HFREF).47 The majority of patients hospitalized for AF and HF consisted of patients who had developed AF first. Prognosis was worse in hospitalized patients with HF first and who subsequently developed AF. In addition, a substudy of the EVEREST trial in acute HFREF demonstrated that AF patients received less evidence-based therapies and had increased mortality and rehospitalization compared with patients in sinus rhythm.48 Thus, left ventricular ejection fraction (LVEF) does not appear to improve risk prediction for adverse prognosis in this patient population. Although interesting and novel, it is still uncertain whether AF is a marker of the progression and severity of HFREF, or whether AF is causally related to mortality in these patients.49

Beta-blockers have been shown to reduce morbidity and mortality in HF patients and are recommended as first-line therapy in all patients with HF.50 In the 2012 European Society of Cardiology (ESC) guidelines for HF, the recommendation for beta-blockers is not restricted to patients with sinus rhythm and includes all HF patients (i.e. also for those with AF), but it is unknown whether beta-blockers reduce mortality in HF patients with AF. The SENIORS investigators compared nebivolol with placebo in elderly patients with HF.51 In contrast to the overall study, nebivolol did not affect outcomes in patients with AF at baseline (738 out of the 2128 patients). Next, the BEST investigators compared the effect of bucindolol in patients with HFREF between patients in AF or in sinus rhythm.52 They observed that in both AF (303 of the 2708 patients) and sinus rhythm patients who achieved a resting heart rate ≤80 b.p.m., there were beneficial effects of bucindolol on cardiovascular mortality and hospitalizations. In patients that did not achieve a resting heart rate ≤80 b.p.m., bucindolol was not associated with improvements in outcome. A meta-analysis included four placebo-controlled, randomized beta-blocker therapy studies, which enrolled 8680 patients with HF, and 1677 of them had AF (842 treated with beta-blocker and 835 with placebo).53 In AF patients, beta-blockers did not reduce mortality and HF hospitalizations, while in sinus rhythm patients there was a significant reduction. This suggests that the effect of beta-blockers on outcome in AF patients with HF and reduced LVEF is less than that in those who have sinus rhythm. Prospective randomized controlled trials specifically aiming at HF patients with AF are eagerly awaited.

Biomarkers in heart failure

Last year was no exception to the ongoing trend on biomarker papers in cardiovascular disease. An increasing number of biomarker studies also focused on HF patients with preserved ejection fraction (HFPEF).54 55 In a small study, Santhanakrishnan et al. studied the diagnostic capability of growth differentiating factor 15 (GDF-15), N-terminal pro brain natriuretic peptide (NT-proBNP), ST2, and high sensitive troponin T.56 Their results indicated that NT-proBNP and GDF-15 were extremely accurate in distinguishing HF patients with HFREF from controls, while the ratio between NT-proBNP and GDF-15 may give some information on the difference between HFREF and HFPEF. However, discrimination between HFREF and HFPEF using any biomarker or combination was moderate at best. In another study, however, GDF-15 was able to improve reclassification of patients with possible HFREF, and was shown to outperform NT-proBNP.57 In an elegant study, GDF-15, a marker of fibrosis, was found in high concentrations in severely decompensated HF patients.58 However, this was not associated with higher myocardial messenger RNA (mRNA) levels of GDF-15. Even more strikingly, GDF-15 levels decreased strongly in a majority of patients that received a left ventricular assist device (LVAD), suggesting that activation of the profibrotic pathways may be reversible by cardiac unloading. The activity of these pathways seems to be different in men vs. women, since women experience lower levels of markers of fibrosis, inflammation, and extracellular matrix remodelling, which may be a reason for the difference in mortality rates across genders.59 A new spectrum of biomarkers is emerging in which miRNAs play a central role. Vogel et al. recently showed that either as a single biomarker, or as a combination, several miRNAs are not only dysregulated in non-ischaemic HFREF patients, but also carry important diagnostic capabilities.60

Biomarkers may also be used to differentiate between diseases that present with similar signs and symptoms but have different pathophysiology. An important example was presented by data coming from the BACH trial.61 In this substudy analysis, the authors evaluated the diagnostic capabilities of procalcitonin (PCT) in patients presenting with dyspnoea. In 1641 patients, the authors found that elevated PCT levels were strongly associated with the diagnosis of pneumonia, even in the presence of the diagnosis of obstructive lung disease or HF. PCT levels also predicted outcome, and patients had worse outcomes when they were not treated with antibiotics. Overall these findings have improved our knowledge on the pathophysiology, therapy, diagnosis, and prognosis of patients with HFREF and HFPEF.

Pharmacological therapy

Several randomized clinical trials were the subject of significant interest recently. Arguably the most important breakthrough for drug discovery came from the RELAX-AHF. In RELAX-AHF, 1161 acute HF patients were randomized to serelaxin, a recombinant form of the human vasodilatator relaxin-2, or placebo.3 Treatment with serelaxin resulted in mild improvements in dyspnoea compared with placebo. At 60 days, no differences were observed in the secondary endpoints of the study; days alive out of hospital, and cardiovascular death or readmission. Interestingly, while only administrated for 2 days, serelaxin was associated with a significant reduction of mortality up to 180 days, with curves separating from day 5 for cardiovascular death [hazard ratio (HR) 0.63, P = 0.028] and all-cause mortality (HR 0.63, P = 0.02).3 Post-hoc analyses demonstrated that serelaxin was associated with significant reductions in markers of end-organ damage,62 suggesting that serelaxin might possess organ-protective properties that may explain the post-discharge mortality benefit. It must be stressed, however, that 180-day mortality was not among the primary endpoints of the study and that the trial was not designed to address these endpoints. Thus, although the results are exciting and potentially paradigm shifting, they need to be confirmed by the replicate phase III study investigating the effect of serelaxin on cardiovascular death and other clinical outcomes that is currently ongoing (RELAX-AHF-2, NCT01870778).

Other clinical trials in acute HF that did not yield such exciting results were presented as the COMPOSE programme.63 The COMPOSE programme consisted of three randomized clinical trials that tested the efficacy of cinaciguat, a nitric oxide-independent soluble guanylate cyclase activator that produces vasodilatation. All three studies of the COMPOSE programme were terminated early due to a high incidence of adverse events. The majority of patients treated with cinaciguat developed hypotension, with no improvements in dyspnoea and cardiac index, even with low doses. Therefore, it seems unlikely that further trials including cinaciguat will be conducted in acute HF.

Another exciting new drug in clinical development is the first-in-class cardiac myosin activator omecamtiv mecarbil, which has been shown to enhance cardiac contractility without modulating adrenergic receptors or calcium transients.64 65 Previous studies reported that omecamtiv was well tolerated and had dose-dependent inotropic effects.66 67 It should be noted, however, that myocardial ischaemia occurred at higher concentrations, probably due to shortening of the diastolic period. Although the first presentation of data from the ATOMIC-AHF at the 2013 ESC congress revealed that omecamtiv did not improve dyspnoea in patients with acute HF, trends toward reduction of worsening HF were observed. Currently, omecamtiv is being investigated in chronic HF in the COSMIC-HF trial (NCT01786512). Aliskiren, a direct renin inhibitor, has been shown to have favourable neurohormonal effects in chronic HF.68 69, 70 In the ASTRONAUT study, aliskiren had no effect on mortality and HF rehospitalizations in stable acute HF patients, despite a significant reduction in NT-proBNP levels.5 The ongoing ATMOSPHERE study may provide further insights regarding the incremental value of aliskiren in the treatment of chronic HF (NCT00853658).71 72

During the late breaking clinical trial sessions of the HF meeting in Lisbon in 2013, results of the ARTS trial were presented.10 Treatment with the novel non-steroidal mineralocorticoid receptor antagonist (MRA) BAY 94-8862 in patients with systolic HF and mild to moderate chronic kidney disease was associated with a reduced incidence of hyperkalaemia or worsening renal function than spironolactone, while the reduction in NT-proBNP levels was comparable.10 These results suggest that BAY 94-8862 may be applicable in HF patients with poor renal function, in whom the prescription of current MRAs is limited. Currently, a larger phase IIb trial with BAY 94-8862, recently named as finerenone, is ongoing in patients with worsening chronic systolic HF and type 2 diabetes and/or chronic kidney disease (ARTS-HF; NCT01807221).

As previous pharmacological interventions have failed to show improvements of morbidity and mortality in HFPEF, novel and effective drugs for these patients are urgently needed. A large community-based study is underway to evaluate the prevalence, clinical characteristics, and diagnostic accuracy of current tests for HFPEF.73 Hopefully the insights obtained from this study will result in new therapeutic approaches for this devastating disease. LCZ696, a novel dual-acting angiotensin receptor and neprilysin inhibitor, is currently under investigation as a treatment for HFPEF. In PARAMOUNT, a phase II double-blind randomized controlled trial, LCZ696 was well tolerated and significantly reduced NT-proBNP levels at 12 weeks compared with valsartan. At 36 weeks, the observed difference in NT-proBNP levels was no longer significant, but improvements in New York Heart Association (NYHA) functional class and reduction in left atrial size were observed.11 However, as endpoints of PARAMOUNT were surrogate, further research is needed to evaluate the impact of LCZ696 on clinical outcomes in HFPEF. LCZ696 is currently being investigated in patients with heart failure with reduced ejection fraction (PARADIGM-HF, NCT0103522) and soon a large phase II trial will take off investigating the impact of LCZ696 on clinical outcomes in HFPEF (PARAGON-HF trial, NCT01920711).

The effect of spironolactone was investigated for the first time in HFPEF during the ALDO-DHF trial.12 Although treatment with spironolactone improved diastolic function, LVEF, LV remodelling, and NTproBNP levels, these beneficial effects were not associated with improvements in exercise capacity and symptoms. Additionally, the late breaking clinical trial, TOPCAT, recently presented at the 2013 American Heart Association Congress demonstrated that spironolactone did not resulted in a benefit for the primary composite endpoint compared with placebo. However, patients receiving spironolacton did experience fewer hospitalizations for heart failure.

Finally, the efficacy of anticoagulation in patients with systolic HF in sinus rhythm was finally disproven in the WARCEF study.9 Using an elegant double-blind, double-dummy design, >2300 patients were randomized to warfarin or placebo and followed up for a median of 3.5 years. While warfarin reduced the incidence of ischaemic stroke, the incidence of the primary composite endpoint of ischaemic stroke, intracerebral haemorrhage, or all-cause mortality was comparable between groups. The reduced risk of ischaemic stroke with warfarin was offset by an increased risk of major haemorrhage. Whether the novel oral anticoagulants will be associated with a more favourable risk–benefit ratio remains to be determined.74

Interventional treatment

Despite the absence of adequately powered randomized controlled trials, intra-aortic balloon counterpulsation (IABP) has been routinely used for haemodynamic support in patients with cardiogenic shock due to acute myocardial infarction (MI). The IABP-SHOCK 2 trial was a landmark study which investigated the effect of IABP in the setting of acute MI complicated by cardiogenic shock.4 In this trial, 600 patients expected to undergo early revascularization were randomized to IABP or no IABP (control group). The primary endpoint was 30-day all-cause mortality. Primary percutaneous coronary intervention was performed in 95.8% of all patients. The median duration of IABP support was 3 days. At 30 days, mortality was similar among patients in the IABP group and those in the control group (39.7% and 41.3%, respectively, P = 0.69). This result was consistent across all pre-defined subgroups, including different age categories, stratification according to various cardiovascular risk factors, and types and location of MI. There were also no significant differences in a number of secondary and safety endpoints, such as time to haemodynamic stabilization, length of intensive care unit stay, and rate of ischaemic or bleeding complications. In conclusion, use of IABP does not improve the prognosis of patients with cardiogenic shock during acute MI and its standard use in this clinical setting should be discouraged.

The implantation of a MitraClip is a new treatment modality for severe mitral regurgitation (MR) in patients who are inoperable or who are at high risk for conventional mitral valve surgery. The majority of patients who undergo this procedure have a functional MR (67%), a reduced systolic LV function (71%), with functional NYHA class III or IV (93%). MitraClip therapy not only reduces MR severity acutely in the majority (94%) of patients, but also leads to improvement in functional capacity in about two-thirds of patients.75 Future randomized studies in pre-specified HF populations are ongoing and will give us a more definitive answer on the additional value of MitraClip implantation in patients suffering from both HF and severe MR.76 Another percutaneous modality for MR treatment is mitral annuloplasty using a Carillon Mitral Contour System.77 This is a double anchor device positioned in the coronary sinus/great cardiac vein which plicates the periannular tissue after deployment. First results in patients treated with this procedure showed a significant reduction of MR and also reverse LV remodelling.

Recently, renal denervation emerged as a treatment option for patients with therapy-resistant hypertension. The goal of this intervention is to inhibit sympathetic activity, which beyond any doubt also plays a crucial role in the pathogenesis of HF.78 Several ongoing trials are already investigating the effects of renal denervation in both systolic and diastolic HF, and their results are expected to be published soon.

Defibrillators and resynchronization therapy

The field of cardiac devices evolves further with a shift of focus to new areas, such as treatment of HFPEF and the prevention of HF. Implantable cardioverter defibrillators (ICDs) are currently mainly utilized for primary prevention of sudden cardiac death in HF patients. After its introduction, the use of total subcutaneous ICD (S-ICD) has increased.79 A first report of real-life utilization of this device outside of clinical studies demonstrates a learning curve, with lower rates of complications in recent patients.80 How S-ICD compares with transvenous ICDs in terms of efficacy and complication rates remains to be determined.

Research on CRT is also still ongoing. This therapy seems to be as effective in a real-life population as in randomized controlled trials, although CRT-ICD seems to be superior to CRT pacemakers in terms of mortality reduction.81 Even though CRT is a relatively new treatment option, reduction of mortality persists in the long term and it is also effective in patients older than those that were usually include in randomized controlled trials.82 The exact mechanisms of reverse remodelling remain speculative, as there is no reduction of serum markers of extracellular matrix proteins.83 Non-response to CRT without reverse remodelling remains the most important problem. An important issue to target non-response might be adequate lead positioning.84 There is accumulating evidence that the region of latest mechanical activation can govern lead position. To place three ventricular leads, either two LV or two right ventricular (RV) leads, seems to be better than conventional CRT,68 whereas the position of the RV lead per se (apical or outflow tract) seems to be insignificant.85 At least in patients with preserved atrioventricular (AV) conduction, an RV lead might not be necessary at all and LV pacing only may be as effective.86

Two major trials published in 2012–2013 attempted to expand the boundaries of the current indications for CRT. The BLOCK-HF trial compared biventricular with univentricular pacing in patients with symptomatic HF (LVEF <50%) and an AV block that required pacing.7 A CRT device (with or without ICD) was implanted and patients were subsequently randomized to receive either biventricular or RV pacing. Biventricular pacing was associated with a significant reduction in the primary endpoint of time to death from any cause, an urgent care visit for HF, or a ≥15% increase in the LV end-systolic volume index. This study therefore advocates a more lenient approach towards CRT implantation in HF patients with an AV block. In the EchoCRT trial, patients with symptomatic systolic HF, a narrow QRS, but with echocardiographic evidence of LV dyssynchrony received a CRT device and were randomized to have the CRT capability turned on or off.8 In these patients, resynchronization therapy did not modulate the incidence of the primary composite outcome of death from any cause or first hospitalization for worsening HF. Remarkably, the incidence of all-cause mortality was significantly increased in the CRT group. Therefore, this study shows that CRT should not be used to treat dyssynchrony in patients with a narrow QRS.

Device therapy for HFPEF seems a potentially attractive novel target.8 Patients with HFPEF have a high incidence of sudden cardiac death, and ICD therapy for this patient group is an interesting hypothesis that still needs to be tested. In a subgroup of patients, biatrial pacing can improve diastolic filling and exercise capacity.87 88 The term atrial resynchronization therapy can be coined for this therapy and might be new in the arsenal of treatments for HFPEF and to prevent AF.89 In addition to atrial resynchronization, ventricular resynchronization can also be effective in patients with HFPEF.90 Biventricular pacing might be the preferred strategy in any patient that needs continuous ventricular pacing.7 Whether this is true for all patients remains unknown. Future studies will have to investigate predictors for worse outcome with RV pacing, such as genetic factors or functional criteria. In patients that have been made pacemaker dependent with AV junction ablation, the advantage of biventricular over RV pacing might be limited.91

Ventricular assist devices

Heart transplantation represents the standard of care for eligible NYHA class IV HF patients, and outcomes of heart transplant recipients keep improving.92 However, the limited availability of suitable donor hearts has restricted its application to <1500 patients per year in Europe. As a result, the proportion of patients with long-term ventricular assist devices (VADs) continues to increase rapidly.93 94 Starling et al. demonstrated in the post-US Food and Drug Administration-approval study that survival was 85% for the HeartMate II continuous-flow LVAD vs. 70% for other types of LVADs [79% HeartMate XVE, 21% implantable VAD (Thoratec Corporation)].95 96 Also, haemodynamic recovery, exercise tolerance, and quality of life improved at 3 months, and the improvement in quality of life was sustained up to 12 months of LVAD treatment.95 VAD therapy is now recommended in the 2012 ESC HF guidelines as bridge to transplant (class I recommendation, level of evidence B) and as destination therapy for patients not eligible for heart transplantation (class IIa recommendation, level of evidence B).50 VAD therapy has thus transformed into an established HF treatment, and studies aimed at improving VAD-associated therapy are warranted.

While ICDs are indicated for patients with advanced HF, a small number of patients will not have an ICD at the time of VAD implantation. The question that arises is whether they should receive both devices. Garan et al. published a paper on ventricular arrhythmias and ICD therapy in 94 patients with continuous-flow LVADs (77 with ICD, 17 without ICD).97 They found that patients with pre-LVAD ventricular arrhythmias were at risk of recurrent ventricular arrhythmias while receiving continuous-flow LVAD therapy and may need an ICD to minimize sustained ventricular arrhythmias. Patients without pre-LVAD ventricular arrhythmias are at low risk and may not need active ICD therapy. New developments in LVAD technology may also improve survival and quality of life. Totally implantable LVADs may reduce infection rates,97 and perhaps modulations of LVAD pump speed during exercise may improve exercise tolerance.98 Finally, end of life decisions will become inevitable in some patients, which will require cessation of LVAD therapy. Appropriate protocols for cessation of LVAD therapy need to be developed.99 Increased experience with LVAD therapy will probably contribute to improvements in the care for patients with advanced HF.

Funding

None.