REVIEW
European Journal of Heart Failure (2014) 16, 122–132 doi:10.1002/ejhf.43
Heart failure highlights in 2012–2013 Licette C. Y. Liu, Kevin Damman, Eric Lipsic, Alexander H. Maass, Michiel Rienstra, and B. Daan Westenbrink* The Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Received 21 October 2013; revised 4 November 2013; accepted 8 November 2013 ; online publish-ahead-of-print 26 December 2013
Heart failure has become the cardiovascular epidemic of the century. The European Journal of Heart Failure is dedicated to the advancement of knowledge in the field of heart failure management. In 2012 and 2013, several pioneering scientific discoveries and paradigm-shifting clinical trials have been published. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis, and treatment of heart failure that were published during this period. All relevant research areas are discussed, including pathophysiology, co-morbidities, arrhythmias, biomarkers, clinical trials, and device therapy, including left ventricular assist devices.
.......................................................................................................... Heart failure • Highlights 2012/13 • Pathophysiology • Co-morbidities • Atrial fibrillation • Biomarkers • Pharmacological therapy • Interventional treatment • CRT • Assist devices
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
..................................................................................
Keywords
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
*Corresponding author. Tel.: +31 50 361 6161, Fax: +31 50 361 1347, Email: [email protected]
© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology
© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology
ASTRONAUT
Gheorghiade et al. March, 2013
RED-HF
SHOCK2
Thiele et al. August, 2012
Chronic heart failure Swedberg et al. March, 2013
RELAX-AHF
CARRESS-HF
Teerlink et al. January, 2013
Acute heart failure Bart et al. December, 2012
Multicentre, double-blind, placebo-controlled, phase III
Multicentre, double-blind, placebo-controlled phase III
Multicentre, prospective open label, phase III
Multicentre, prospective, double-blind, placebo-controlled, phase II/III
Prospective, randomized, controlled phase III
Systolic heart failure patients with anaemia
Hospitalized patients, stabilized after an acute heart failure episode
1615
2278
Cardiogenic shock complicating an acute myocardial infarction
Acute decompensated heart failure patients
1161
600
Acute decompensated heart failure patients
188
To evaluate whether treatment with darbepoetin alfa improves clinical outcomes
To investigate the effect of in-hospital initiation of aliskiren, on top of current background heart failure therapy
Determine the efficacy of intra-aortic balloon counterpulsation
To assess the effect of serelaxin on dyspnoea relief and clinical outcomes
Compare safety and efficacy of ultrafiltration with diuretic-based congestion relief
Primary endpoints Composite of all-cause mortality or hospitalizations for worsening heart failure
Primary endpoints Efficacy: 30-day all-cause mortality Safety: bleeding, peripheral complications, sepsis, and stroke Primary endpoints Cardiovascular death or rehospitalization for heart failure
Primary endpoint Dyspnoea improvement
Primary endpoints Δ Serum Creatinine Δ Weight
No between-group differences in the primary outcomes. Thrombo-embolic events were more frequent in the darbepoetin alfa group.
Aliskiren did not improve clinical outcomes.
Ultrafiltration resulted in higher increases in serum creatinine, despite similar reductions in weight. The incidence of serious adverse events was also higher in the ultrafiltration group. Serelaxin slightly improved dyspnoea over placebo. Mortality at 180 days was lower in the serelaxin group (RELAX-AHF was not designed to evaluate this endpoint). No between-group differences in efficacy or safety endpoints.
6
5
4
3
2
Author and Acronym Study design n Study population Aims Endpoints Main results References publication date .........................................................................................................................................................................................
Table 1 Major clinical trials published in 2012–2013
Heart failure highlights in 2012–2013
123
PARAMOUNT
ALDO-DHF
Solomon et al. October, 2012
Edelmann et al. February, 2013
WARCEF
Homma et al. May, 2012
ARTS
EchoCRT
Ruschitzka et al. September, 2013
Pitt et al. May, 2013
BLOCK-HF
Curtis et al. April, 2013
Multicentre, placebocontrolled, double-blind, parallel-group, phase II
Parallel-group, double-blind phase II
Multicentre, parallel-group, double-blind phase II
Prospective, multicentre, double-blind, double dummy, phase III
Prospective, multicentre, double-blind phase III
Prospective, multicentre, double-blind phase III
422
301
457
2305
809
691
Patients with heart failure with preserved ejection fraction
Patients with heart failure with preserved ejection fraction
Chronic systolic heart failure patients
Systolic heart failure patients in sinus rhythm
Systolic heart failure patients with indication for ventricular pacing due to atrioventricular block Stable NYHA class III or IV heart failure, LVEF < 35%, QRS 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,
128
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
........................................................................................................................................................................
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 twothirds 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.
L.C.Y. Liu et al.
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
European Journal of Heart Failure (2014) 16, 122–132 doi:10.1002/ejhf.43
Heart failure highlights in 2012–2013 Licette C. Y. Liu, Kevin Damman, Eric Lipsic, Alexander H. Maass, Michiel Rienstra, and B. Daan Westenbrink* The Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Received 21 October 2013; revised 4 November 2013; accepted 8 November 2013 ; online publish-ahead-of-print 26 December 2013
Heart failure has become the cardiovascular epidemic of the century. The European Journal of Heart Failure is dedicated to the advancement of knowledge in the field of heart failure management. In 2012 and 2013, several pioneering scientific discoveries and paradigm-shifting clinical trials have been published. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis, and treatment of heart failure that were published during this period. All relevant research areas are discussed, including pathophysiology, co-morbidities, arrhythmias, biomarkers, clinical trials, and device therapy, including left ventricular assist devices.
.......................................................................................................... Heart failure • Highlights 2012/13 • Pathophysiology • Co-morbidities • Atrial fibrillation • Biomarkers • Pharmacological therapy • Interventional treatment • CRT • Assist devices
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
..................................................................................
Keywords
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
*Corresponding author. Tel.: +31 50 361 6161, Fax: +31 50 361 1347, Email: [email protected]
© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology
© 2013 The Authors European Journal of Heart Failure © 2013 European Society of Cardiology
ASTRONAUT
Gheorghiade et al. March, 2013
RED-HF
SHOCK2
Thiele et al. August, 2012
Chronic heart failure Swedberg et al. March, 2013
RELAX-AHF
CARRESS-HF
Teerlink et al. January, 2013
Acute heart failure Bart et al. December, 2012
Multicentre, double-blind, placebo-controlled, phase III
Multicentre, double-blind, placebo-controlled phase III
Multicentre, prospective open label, phase III
Multicentre, prospective, double-blind, placebo-controlled, phase II/III
Prospective, randomized, controlled phase III
Systolic heart failure patients with anaemia
Hospitalized patients, stabilized after an acute heart failure episode
1615
2278
Cardiogenic shock complicating an acute myocardial infarction
Acute decompensated heart failure patients
1161
600
Acute decompensated heart failure patients
188
To evaluate whether treatment with darbepoetin alfa improves clinical outcomes
To investigate the effect of in-hospital initiation of aliskiren, on top of current background heart failure therapy
Determine the efficacy of intra-aortic balloon counterpulsation
To assess the effect of serelaxin on dyspnoea relief and clinical outcomes
Compare safety and efficacy of ultrafiltration with diuretic-based congestion relief
Primary endpoints Composite of all-cause mortality or hospitalizations for worsening heart failure
Primary endpoints Efficacy: 30-day all-cause mortality Safety: bleeding, peripheral complications, sepsis, and stroke Primary endpoints Cardiovascular death or rehospitalization for heart failure
Primary endpoint Dyspnoea improvement
Primary endpoints Δ Serum Creatinine Δ Weight
No between-group differences in the primary outcomes. Thrombo-embolic events were more frequent in the darbepoetin alfa group.
Aliskiren did not improve clinical outcomes.
Ultrafiltration resulted in higher increases in serum creatinine, despite similar reductions in weight. The incidence of serious adverse events was also higher in the ultrafiltration group. Serelaxin slightly improved dyspnoea over placebo. Mortality at 180 days was lower in the serelaxin group (RELAX-AHF was not designed to evaluate this endpoint). No between-group differences in efficacy or safety endpoints.
6
5
4
3
2
Author and Acronym Study design n Study population Aims Endpoints Main results References publication date .........................................................................................................................................................................................
Table 1 Major clinical trials published in 2012–2013
Heart failure highlights in 2012–2013
123
PARAMOUNT
ALDO-DHF
Solomon et al. October, 2012
Edelmann et al. February, 2013
WARCEF
Homma et al. May, 2012
ARTS
EchoCRT
Ruschitzka et al. September, 2013
Pitt et al. May, 2013
BLOCK-HF
Curtis et al. April, 2013
Multicentre, placebocontrolled, double-blind, parallel-group, phase II
Parallel-group, double-blind phase II
Multicentre, parallel-group, double-blind phase II
Prospective, multicentre, double-blind, double dummy, phase III
Prospective, multicentre, double-blind phase III
Prospective, multicentre, double-blind phase III
422
301
457
2305
809
691
Patients with heart failure with preserved ejection fraction
Patients with heart failure with preserved ejection fraction
Chronic systolic heart failure patients
Systolic heart failure patients in sinus rhythm
Systolic heart failure patients with indication for ventricular pacing due to atrioventricular block Stable NYHA class III or IV heart failure, LVEF < 35%, QRS 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,
128
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
........................................................................................................................................................................
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 twothirds 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.
L.C.Y. Liu et al.
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
