UROLOGY
ENDOCRINOLOGY
CLINICAL ONCOLOGY
NEPHROLOGY
CARDIOLOGY
NEUROLOGY
GASTROENTEROLOGY & HEPATOLOGY
RHEUMATOLOGY
A DECADE IN
MEDICINE
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Nature Reviews Cardiology
1 acutecoronarysyndromes | Successes and future objectives in acute coronary syndrome
Frans Van de Werf
3 arrhythmias | Cardiac fibrillation—challenges and evolving solutions Stanley Nattel
5 cardiomyopathies | Cardiomyopathy on the move Magdi H. Yacoub
6 dyslipidaemia | Resurgence of targets and compounds to treat dyslipidaemia John J. P. Kastelein
8 heartfailure | 10 Years of progress in HF research—what have we learned? Henry Krum
10 hypertension | The past decade in hypertension—facts, hopes, and hypes Thomas Unger
12 peripheralvasculardisease | 10 Years of breakthroughs in peripheral vascular disease
Mark A. Creager
14 valvulardisease | Current perspectives on treatment of valvular heart disease Friedrich W. Mohr
The articles included in A Decade in Medicine were originally
published online and in the November 2014 or November 2015
issues of the eight clinical Nature Reviews journals. To celebrate
the 10
thanniversary of the launch of these journals, the editors
commissioned international experts to write short essays
highlighting the key papers that made the biggest contribution
to their field in the past decade. Between them, the clinical
Nature Reviews journals published 47 articles, which are collated
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Daniel J. Sargent and Edward L. Korn
18 targetedtherapy | Successes, toxicities and challenges in solid tumours
Joel W. Neal and George W. Sledge
19 haematologicalcancer | Advances in biology and therapy S. Vincent Rajkumar and Philippe Moreau
21 cancerimmunotherapy | Entering the mainstream of cancer treatment
Steven A. Rosenberg
23 genomics | A decade of discovery in cancer genomics Kenneth Offit
25 fundingincancerresearch | National Cancer Institute awards —a work in progress
Tito Fojo and Paraskevi Giannakakou
Nature Reviews Endocrinology
28 bone| Great strides made but still further to go Ian R. Reid
29 thyroiddisease| The endocrinology of thyroid disease from 2005 to 2015
P. Reed Larsen
31 type2diabetesmellitus| At the centre of things Guang Ning
33 paediatricendocrinology| New genes, new therapies Mehul T. Dattani
35 reproductiveendocrinology| Understanding reproductive endocrine disorders
Ursula B. Kaiser
Nature Reviews Gastroenterology & Hepatology
37 hcv| Hepatitis C therapy—a fast and competitive raceStefan Zeuzem
38 hepatocellularcarcinoma| HCC—subtypes, stratification and sorafenib
Gregory J. Gores
40 gutmicrobiota| The gut microbiota era marches on Francisco Guarner
42 fgids| ‘Functional’ gastrointestinal disorders—a paradigm shift Nicholas J. Talley
43 pancreaticdiseases| Advances in understanding and care of pancreatic diseases
Randall E. Brand
45 ibd| IBD—genes, bacteria and new therapeutic strategies Jean-Frederic Colombel
Nature Reviews Nephrology
48 glomerulardisease| The glomerulus reveals some secrets Agnes B. Fogo
50 geneticsofkidneydiseases| Genetic dissection of kidney disorders
Friedhelm Hildebrandt
51 acutekidneyinjury| Acute kidney injury—a decade of progress Rinaldo Bellomo
54 renaltransplantation| A spectrum of advances in renal transplantation
Bruce Kaplan
Nature Reviews Neurology
57 dementia| A decade of discovery and disappointment in dementia research
John R. Hodges
58 multiplesclerosis| New drugs and personalized medicine for multiple sclerosis
Paul M. Matthews
60 epilepsy| Edging toward breakthroughs in epilepsy diagnostics and care
Daniel H. Lowenstein
62 movementdisorders| Tracking the pathogenesis of movement disorders
Oksana Suchowersky
63 stroke| Progress in acute ischaemic stroke treatment and prevention
Jose G. Romano and Ralph L. Sacco
65 migraine| Incredible progress for an era of better migraine care Peter J. Goadsby
67 cnsinfections| Major advances against a moving target of CNS infections
Lisa F. P. Ng and Tom Solomon
Nature Reviews Rheumatology
69 translationalrheumatology| Ten years after: rheumatology research from bench to bedside
Nunzio Bottini and Gary S. Firestein
71 paediatricrheumatology| A field on the move Seza Ozen
72 technology| Technological advances transforming rheumatology William H. Robinson and Rong Mao
74 clinicalrheumatology| 10 years of therapeutic advances in the rheumatic diseases
John D. Isaacs
Nature Reviews Urology
77 bladdercancer| International progress: from cytology to genomics James C. Costello and Dan Theodorescu
79 imaging| A decade in image-guided prostate biopsy Baris Turkbey and Peter L. Choyke
81 urinaryincontinence| Advances in female urology and voiding dysfunction
Marisa M. Clifton and Howard B. Goldman
82 kidneycancer| Discoveries, therapies and opportunities W. Marston Linehan and Christopher J. Ricketts
84 sexualdysfunction| Post-RP erectile dysfunction—therapies for the next decade
Emmanuel Weyne and Maarten Albersen
86 prostatecancer| A decade of progress in detection and treatment Behfar Ehdaie and Peter T. Scardino
CARDIOLOGY
DECADE IN REVIEW—ACUTE CORONARY SYNDROMESSuccesses and future objectives in acute
coronary syndrome
Frans Van de Werf
The past decade has seen considerable advances in the treatment of acute coronary syndromes (ACS),
particularly in the search for improved antithrombotic therapies. Despite these successes, however, renewed
efforts are needed to improve long-term outcomes after ACS by reducing recurrent ischaemic events and
lowering the risk of bleeding complications.
Van de Werf, F. Nat. Rev. Cardiol. 11, 624–625 (2014); published online 2 September 2014; doi:10.1038/nrcardio.2014.129
By 10 years ago, aspirin and clopidogrel therapy for 1 year was already the standard treatment for all patients with acute coro-nary syndrome (ACS), despite the benefit of this dual antiplatelet therapy never having been formally studied in patients with ST-segment elevation myocardial infarction (STEMI). Without a doubt, the majority of clinical studies in ACS per-formed in the past decade have focused on attempts to find more efficacious and safer antithrombotic treatments than aspirin and clopidogrel dual antiplatelet therapy. The most successful trial in this regard was PLATO,1 which showed significantly
improved outcomes (including recurrent myocardial infarction, stent thrombosis, death from vascular causes, and even all-cause mortality) with ticagrelor, a new oral, reversible, direct-acting P2Y purino-receptor 12 (P2Y12) antagonist, when
com-pared with clopidogrel; the study included patients with either STEMI or non-STEMI (NSTEMI). Pleiotropic actions, such as increased adenosine plasma concentrations, were suggested to have contributed to the beneficial effect of ticagrelor. The overall excess spontaneous bleeding rate with this new, more powerful agent was small, but the trend towards an increased risk of intra-cranial haemorrhage observed in this study was a concern.
One of the possible reasons why newer P2Y12 antagonists, such as cangrelor,
pra-sugrel, and ticagrelor, are superior to clopi dogrel in large clinical trials is the existence of genetic variants of hepatic cytochrome P450 (CYP) enzymes respon-sible for converting clopidogrel to its active metabolite. Several studies have shown that
carriers of an allele that resulted in reduced CYP function had lower levels of the active metabolite and higher rates of major cardio-vascular events. As such, carriers of CYP loss-of-function variants who are receiving clopidogrel are likely to be especially at risk of stent thrombosis. The concerns about interindividual variability in the anti platelet effect of clopidogrel have led to a number of studies aimed at monitoring platelet function and adjusting treatment accord-ingly. Surprisingly, in one of the largest randomized studies, which included 2,440 patients scheduled for coronary stenting (of whom 657 had NSTEMI), no improve-ment in clinical outcomes at 1 year was observed with platelet-function monitor-ing and treatment adjustments as compared with standard treatment without monitor-ing.2 Genetic testing and platelet-function
monitoring have not become routine tests in patients taking clopidogrel.
Bivalirudin has replaced heparin in many hospitals, especially for patients undergo-ing primary percutaneous coronary inter-vention (PCI), owing mainly to the results of the HORIZONS-AMI study.3 This trial
showed significantly reduced bleeding rates and decreased 30-day mortality with biva-lirudin alone when compared with heparin plus a glycoprotein (GP) IIb/IIIa (integ-rin αIIbβ3) antagonist.3 However, the benefit
of bivalirudin for primary PCI was chal-lenged by the results of a single-centre
trial (HEAT-PPCI4),in which GP IIb/IIIa
antagonists were used only for bailout (bivalirudin versus heparin): fewer ischae-mic events occurred with heparin than with bivalirudin and, surprisingly (in contrast to all previous trials), no reduction in bleeding complications was found with bivalirudin. Whether these data should change practice and whether a new, large multicentre trial is needed is currently a matter of hot debate.
Despite the progress made with anti-thrombotic therapy and revascularization in the early phase of an ACS, recurrent ischaemic events and long-term mortal-ity remain high. One explanation could be that dual antiplatelet therapy consisting of aspirin and clopidogrel does not provide sufficient long-term protection against recurrent thrombotic events. In two large studies,5,6 an additional antithrombotic
agent was tested in combination with aspirin and clopidogrel: vorapaxar, an antagonist of the thrombin receptor PAR-1 (protease-activate d receptor 1), was used in the TRA 2P trial,5 and rivaroxaban, a
direct oral inhibitor of fac tor Xa, was used in ATLAS-2.6 Although increased bleeding
rates were observed in both studies (and the TRA 2P study even had to be stopped prematurely in the subgroup of patients with a history of stroke, owing to an excess rate of intra cranial haemorrhage), selected populations did benefit from adding a third antithrombotic drug. In the group of >17,000 patients with a previous myo-cardial infarction, addition of vorapaxar reduced the risk of cardiovascular death, myo cardial infarction, or stroke—at the cost of an increased risk of moderate or severe bleeding, but without a significant
‘‘
…recurrent ischaemic
events and long-term mortality
remain high
increase in intra cranial haemorrhage.5 In
ATLAS-2,6 low-dose rivaroxaban (2.5 mg
twice daily) also significantly reduced the risk of the composite end point of cardio-vascular death, myocardial infarction, and stroke and, surprisingly, also reduced rates of stent thrombosis and death from any cause. Whether these agents are also beneficial and safe when, for instance, ticagrelor or pra sugrel is used in combina-tion with aspirin, is unknown. Similarly, whether aspirin can be dropped if a new P2Y12 antagonist is given in combination
with vorapaxar or low-dose rivaroxaban remains to be determined. New studies of simplified antithrombotic regimens that are underway or in the planning phase should take into account the possible benefits and risks of new a ntithrombotic combinations (Figure 1).
A number of trials to study the optimal timing of angiography and revascularization in patients with NSTEMI yielded discord-ant results. In the TIMACS trial,7 >3,000
patients with ACS were randomly assigned to either routine early intervention or delayed intervention (either <24 h or >36 h after treatment assignment, respectively). In the total population, a nonsignificant
15% reduction in the composite end point of death, myocardial infarction, or stroke was observed when comparing early versus delayed treatment. However, in line with other studies, early intervention in high-risk patients led to a significant 35% reduc-tion in the risk of death, new myocardial infarction, or stroke when compared with delayed intervention.7
The use of increasingly powerful anti-thrombotic agents has raised concern about bleeding. Major bleeding complica-tions are indeed common, and most occur at the vascular access site. In the RIVAL trial,8 >7,000 patients with ACS,
includ-ing almost 2,000 patients with STEMI, were randomly allocated to either radial or femoral access. Overall, a lower rate of local vascular complications was observed with the radial approach than with femoral access. Remarkably, patients with STEMI had better clinical outcomes (includ-ing reduced mortality) when treated via radial access, suggesting that this approach might be particularly preferable in patients with STEMI.8
Data from all registries show that, in patients with STEMI, door-to-balloon times have declined significantly over the past 10 years. The implementation of emer-gency medical systems based on a network of hospitals with various levels of technol-ogy connected by an efficient ambulance system has reduced pre-PCI delays in many places.9 How ever, in a large US study of
almost 100,000 patients with STEMI, in-hospital mortality remained unchanged despite significant improvement in door-to-balloon times, indicating that other components of the total ischaemic time need to be targeted.9 Administration of a
fibrinolytic agent to patients who cannot undergo timely PCI is a strategy that might be incorporated into prehospital care. In the STREAM trial10 of ~2,000 patients
presenting with early STEMI, pre hospital administration of tenecteplase (half the normal dose in elderly individuals) to patients who could not undergo PCI within 1 h resulted in rates of the composite end point of death, shock, congestive heart failure, or recurrent infarction at 30 days that were similar to those in patients receiv-ing standard primary PCI. Emergency coronary angiography on arrival in the PCI hospital could be avoided in almost two-thirds of patients treated with tenecte-plase.10 This strategy needs to be further
explored in patients with long transport times, especially elderly patients.
In summary, 30-day mortality after ACS has decreased remarkably in all age cate gories in the past decade, thanks to improved antithrombotic treatment and early revascularization. As a consequence, profound changes in the epidemiology of ACS have also taken place: more patients with ACS survive the initial event and go on to develop recurrent ischaemic events, heart failure, atrial fibrillation, or non-cardiac diseases (such as cancer), and are dying at an older age. In the future, more attention will have to be paid to the long-term care of patients after ACS, of which antithrombotic agents will remain an important component.
Department of Cardiovascular Sciences, University of Leuven, Herestraat 49, B‑3000 Leuven, Belgium.
Acknowledgements
I thank all my colleagues on both sides of the Atlantic with whom I was able to collaborate in performing important clinical trials that have improved the treatment of patients with acute coronary syndrome.
Competing interests
F.V.d.W. declares that he has received research grants and fees for participating in advisory boards, data and safety monitoring boards, and speaking activities from AstraZeneca, Boehringer Ingelheim, Merck, and The Medicines Company.
1. Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N. Engl. J. Med. 361, 1045–1057 (2009).
2. Collet, J. P. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting.
N. Engl. J. Med. 367, 2100–2109 (2012).
3. Stone, G. W. et al. Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358, 2218–2230 (2008).
4. Shahzad, A. et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial.
Lancet http://dx.doi.org/10.1016/S0140-6736(14)60924-7.
5. Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl.
J. Med. 366, 1404–1413 (2012).
6. Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366, 9–19 (2012).
7. Mehta, S. R. et al. Early versus delayed invasive intervention in acute coronary syndromes.
N. Engl. J. Med. 360, 2165–2175 (2009).
8. Jolly, S. S. et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.
Lancet 377, 1409–1420 (2011).
9. Menees, D. S. et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N. Engl. J. Med. 369, 901–909 (2013). 10. Armstrong, P. W. et al. Fibrinolysis or primary
PCI in ST-segment elevation myocardial infarction. N. Engl. J. Med. 368, 1379–1387 (2013). Risk of thrombosis Haemor rhagic risk Standard antithrombotic treatment PLATO1 and subgroups
of TRA 2P5 or ATLAS-26
Range of possible results of a simplified antithrombotic regimen
No option
Figure 1 | The balance of risks in treatment
of acute coronary syndrome. Patients with acute coronary syndrome receive therapies aimed at reducing the risk of thrombosis, but antithrombotic treatments carry an increased risk of bleeding complications. New therapeutic approaches should minimize the possibility of thrombotic events while keeping haemorrhagic risk at acceptable levels, or even reduce the risk when compared with current treatment.
‘‘
…use of increasingly powerful
anti thrombotic agents has raised
concern about bleeding
DECADE IN REVIEW—ARRHYTHMIAS
Cardiac fibrillation—challenges
and evolving solutions
Stanley Nattel
Cardiac rhythm disorders, or ‘arrhythmias’, are major sources of
morbidity and mortality, and have been challenging to treat because
classic pharmacological therapies are often ineffective and sometimes
dangerous. In the past decade, groundbreaking developments have
revolutionized the management of arrhythmias and prepared the
groundwork for new advances in the future.
Nattel, S. Nat. Rev. Cardiol. 11, 626–627 (2014); published online 9 September 2014; doi:10.1038/nrcardio.2014.133
At the onset of the 2000s, effective and definitive therapies were available for most types of cardiac arrhythmia. However, two common and important rhythm disorders remained major therapeutic challenges —sudden cardiac death (SCD) and atrial fibrillation (AF). SCD typically occurs owing to a chaotic, disorganized rhythm, ‘ventricular fibrillation’, which renders effective heart pumping impossible and causes death if not effectively managed within minutes of onset (Figure 1). AF resembles ventricular fibrillation in being a totally disorganized rhythm, but AF affects the atria, which are not essential for car diac pumping (Figure 1). AF causes problems by firing the heart at an inappropriately rapid rate, leading to a range of symptoms and, in extreme cases, heart muscle weak-ening that leads to heart failure. In addi-tion, the ineffec tive pump ing action of the atria allows blood clots to form in the stagnant atrial blood pool. These clots can propagate to the brain and cause strokes. Consequently, AF is a major cause of strokes, particularly in the elderly. Work dur ing the past decade has greatly improved our ability to prevent and manage both SCD and AF, and enabled further progress in the future.
Towards the end of the 20th century, the
use of implantable devices to detect and rapidly terminate ventricular tachyarrhyth-mias that might otherwise lead to SCD had become widespread. However, their effec-tiveness in reducing mortality was unclear. Despite preventing SCD, such devices might not actually reduce mortality, particularly if SCD constitutes a small portion of the overall mortality, and if device-related com plications can themselves increase the likeli hood of death. An important milestone was a study by Bardy and colleagues, who
compared the effects of amiodarone (the most effective antiarrhythmic drug) with an implantable cardioverter– defibrillator (ICD), or placebo in patients with sys-tolic heart failure, who are known to be at high risk of SCD.1 Amiodarone did not
reduce all-cause mortality during a median 45.5-month follow-up period compared with placebo; however, ICD-therapy signifi-cantly reduced all-cause mortality (by 23%;
P = 0.007).1 These findings established ICDs
as a potentially life-saving intervention in patients at increased risk of SCD.
Whereas some patients at increased risk of SCD are easily identified, the majority of these arrhythmias occur in individuals with out known high-risk factors. More work is, therefore, needed to understand the factors leading to SCD and thereby effectively identify at-risk individuals. An important contribution was provided by Haïssaguerre et al. who showed that
a speci fic electrocardiographic variant (known as early repolarization) is much more common in individuals resuscitated after SCD than in a matched control popu-lation.2 This study led to extensive clinical
and basic science investigations into the underlying mechanisms and clini cal impor-tance of early repolarization. The early repolarization pattern is a common electro-cardiographic variant in otherwise normal individuals, particularly young, physically-active men, so distinguishing between the common benign early- repolarization pat-tern and early repolarization associated with increased SCD risk is an important challenge. The combination of electro-cardio graphic ‘J-waves’ (an elevated junc-tion between the end of the QRS and the onset of the ST-segment) and a horizontal or descending ST-segment is associated with increased risk of SCD. How ever, no early repolarization pattern alone (in the absence of malignant arrhythmias) is pres-ently sufficient to warrant prophylactic therapy (such as an ICD) to prevent SCD.
A further major advance in understand-ing the pathophysiology of SCD was the dem onstration by Itzhaki and colleagues that skin fibroblasts from patients with an inher ited SCD syndrome can be trans-formed into induced pluripotent stem cells, and then differentiated into cardiomyo-cytes that reproduce the cardiac electrical dysfunction under lying SCD risk.3 This
work establishes a novel technique to aid the understanding of SCD pathophysio-logy in individual patients and might ulti-mately lead to patient-specific medical and biological therapies.
Figure 1 | Major advances in arrhythmia research during the past decade. The rate of impulse
transmission through the AVN determines the ventricular response rate during atrial fibrillation, and is the target of rate-control therapy. Abbreviations: AVN, atrioventricular node; IPSC, induced pluripotent stem cell; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Atrial fibrillation Ventricular fibrillation Implanted defibrillator prevents death1 Early repolarization: a novel cause2
IPSCs for pathophysiology and therapy3 Prevention by risk-factor reduction10 Novel anticoagulants prevent stroke9 Mechanism-directed ablation8 Drug therapy complications in high-risk patients6
Lenient versus strict rate control5
Rate control as good as rhythm control in heart failure4
Ablation as initial therapy7 RA LA RV LV AVN
Two potential approaches to manag-ing AF exist: leavmanag-ing the patient in AF, but controlling the ventricular response rate (known as rate control); and keeping the patient out of AF, generally with the use of antiarrhythmic drugs (known as rhythm control). AF is a particularly important risk factor for death and complications in patients with heart failure, so rhythm control would be expected to be of maximal value in these individuals. This hypothesis was tested in a prospective, randomized trial by Roy et al. who found that an effec-tive rhythm-control strategy had no bene-ficial effects on cardiac function, survival, or physical function in patients with heart failure and AF.4
Despite the value of rate control in con-trolling adverse consequences of AF, the parameters characterizing optimum rate control are largely unknown. Van Gelder and collea gues compared a ‘lenient’ rate-control strat egy (resting heart rate <110 bpm) with a ‘strict’ strategy (resting heart rate <80 bpm; exercise heart rate <110 bpm).5 The lenient strategy was as
effec tive in preventing adverse effects and easier to achieve than strict rate control. A further assessment of pharmaco logical management of patients handled by rate control was performed by Connolly and colleagues.6 Based on previous work
sug-gesting that the antiarrhythmia drug dronedarone reduces cardiac mortality and stroke rate in patients with AF, and that this effect might be independent of maintaining sinus rhythm, these investiga-tors administered dronedarone or placebo to patients with permanent AF and markers of increased risk. Instead of improving outcomes, dronedarone increased rates of heart failure, stroke, and cardiovas-cular death.6 This study reinforced
con-cerns about the risks of antiarrhythmic agents in patients with AF at high risk of cardiovascul ar complications.
Given the concerns about antiarrhyth-mic drugs and continual improvements in technology, ablation procedures have assumed an increasingly important role in the treatment of AF over the past 10 years. Although cardiac ablations have generally
been reserved for patients who did not respond to at least one antiarrhythmic drug, ablation as first-line therapy in AF has been given increasing consideration. Cosedis Nielsen et al. compared antiar-rhythmic drugs with radiofrequency ablation as an initial therapy for paroxys-mal AF.7 Ablation reduced the recurrence
rate of symptomatic AF (from 16% to 7%), but the primary end point (AF burden) was not significantly affected.7 This result
sug-gests that antiarrhythmic drugs still have a role in the management of AF. How ever, encouraging developments in abla tion technology have been made. Many fail-ures of ablation techniques are suspected to be owing to procedures that do not target patient-specific pathophysiology. Narayan et al. have developed a method using intra-atrial basket-catheter arrays and complex mathematical algorithms to identify and target patient-specific mecha-nisms of AF.8 Comparing their method
with conventional ablation approaches in a multicentre, prospective, randomized trial, the investigators noted substantial improvements in AF prevention: patients undergoing mechanism-directed ablation showed much greater maintenance of sinus rhythm compared with those undergoing standard procedures (77.8% versus 38.5%;
P = 0.001).8
Stroke is the most important compli-cation of AF. Effective orally adminis-tered anticoagulation drugs can prevent AF-related stroke, but until the approval of dabigatran by the European Medicines Agency in 2008, the only medications avail able for this indication were vitamin-K antagonists, which have a very narrow toxic- to-therapeutic win dow. A number of direct-acting oral anticoagulants, including the thrombin-inhibitor dabigatran, and the factor-Xa antagonists apixaban, edoxaban, and rivaroxaban, were developed in the past decade. The first to be studied, dabigatran, was demonstrated in a large, multicentre, placebo-controlled trial to be at least as effective and safer than warfarin for stroke prevention in patients with AF.9 Similar
findings were subsequently published for the other direct-acting oral anticoagulants, which have had a major and growing effect on AF management.
Ultimately, the best approach to AF man-agement would be to prevent the arrhyth-mia from occurring in the first place. An exciting proof-of-principle was provided by Abed et al. who compared aggressive weight- management intervention with
lifestyle advice (control group) in a rand-omized study of patients with AF who were overweight.10 In addition to a substantial
(19%) reduction in body mass, the interven-tion group showed significant reducinterven-tions compared with the control group in scores for AF frequency (3.4 versus 0.7; P <0.001), duration (5.0 versus 0.8; P <0.001), and symptoms (8.4 versus 1.7; P <0.001).10 This
study will motivate further investiga tion of factors and mechanisms that pro mote AF, as well as public-health measures for AF prevention.
In the past decade, the management and understanding of cardiac arrhythmias have been greatly advanced. The groundwork has now been laid for important further de velopments in the near future.
Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street East, Montreal, QC H1T 1C8, Canada.
stanley.nattel@icm‑mhi.org
Acknowledgements
S.N. is funded by the Canadian Institutes of Health Research (6957 and 44365) and the Heart and Stroke Foundation of Canada.
Competing interests
S.N. declares no competing interests. 1. Bardy, G. H. et al. Amiodarone or an
implantable cardioverter-defibrillator for congestive heart failure. N. Engl. J. Med. 352, 225–237 (2005).
2. Haïssaguerre, M. et al. Sudden cardiac arrest associated with early repolarization. N. Engl. J.
Med. 358, 2016–2023 (2008).
3. Itzhaki, I. et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471, 225–229 (2011).
4. Roy, D. et al. Rhythm control versus rate control for atrial fibrillation and heart failure N. Engl. J.
Med. 358, 2667–2677 (2008).
5. Van Gelder, I. C. et al. Lenient versus strict rate control in patients with atrial fibrillation. N. Engl.
J. Med. 362, 1363–1373 (2010).
6. Connolly, S. J. et al. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 365, 2268–2276 (2011).
7. Cosedis Nielsen, J. et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N. Engl. J. Med. 367, 1587–1595 (2012).
8. Narayan, S. M. et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J. Am. Coll. Cardiol. 60, 628–636 (2012).
9. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).
10. Abed, H. S. et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 310, 2050–2060 (2013).
‘‘
In the past decade, the
management and understanding
of cardiac arrhythmias have been
greatly advanced
DECADE IN REVIEW—CARDIOMYOPATHIES
Cardiomyopathy on the move
Magdi H. Yacoub
Since Wallace Brigden first used the term ‘cardiomyopathy’ in 1952,
this group of diseases has continued to attract the interest of clinicians,
researchers, and importantly, patients. The past decade has seen a
substantial accumulation of knowledge relating to various cardiomyopathies,
which has partially lifted the mystery surrounding this topic.
Yacoub, M. H. Nat. Rev. Cardiol. 11, 628–629 (2014); published online 30 September 2014; doi:10.1038/nrcardio.2014.157
The current definition of cardiomyo pathy, suggested by the ESC and now widely accepted worldwide, is a collection of “myo-cardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hyper-tension, valvular or congenital heart disease sufficient to cause the observed myo cardial abnormality”.1 This definition excludes
channelopathies, which do not lead to structural changes in the myocardium. The phenotypic classification proposed by John Goodwin in 1961 of hypertrophic cardio-myopathy (HCM), dilated cardiocardio-myopathy (DCM), and restrictive cardiomyopathy has withstood the test of time, with the addition of arrhythmogenic, non compaction, and Takotsubo (also known as acute broken heart syndrome) cardiomyopathies. Although clinically useful, this classification does not consider the cause or molecular mechanisms responsible for the disease.
In the past decade, the realization that a familial link for DCM is more frequent than originally thought led to the discovery of a large number of mutations in genes encod-ing proteins involved in various functions of the myocardium, particularly the sarcomere (Figure 1). One example is the gene that encodes titin (TTN), which has an impor-tant role in cardiac function, but the sheer length of the gene and molecule it encodes (the titin protein is ~1 μm long and spans half a sarcomere) has inhibited attempts to sequence it completely. Next-generation sequencing approaches have been used to identify mutations in the gene that result in a truncated molecule in 14% of patients with DCM, which increased to 27% when parallel-capture next-generation sequenc-ing was used.2 These findings have
sub-stantially increased the number (up to 70%) of patients with DCM who have a known genetic mutation, and established
TTN as the gene most-commonly
associ-ated with DCM. This development will
further stimulate studies to determine the worldwide distribution of disease-causing mutations, their possible determinants, and importantly, the u nderlying biological mechanisms responsible.
Inheritance of DCM or HCM can be autosomal dominant, X-linked, and occa-sionally, autosomal recessive. However, the incidence of these diseases in the popula-tion is grossly underestimated, has low penetrance, and low expressivity (that is,
low severity within a single family). The development and availability of large genetic databases, which include phenotypically-defined populations of different ethnic origin, such as the 1000 Genomes Project and the Exome Sequencing Project, has enabled researchers to identify a discrep-ancy between the prevalence of potential disease-causing variants and the estimated prevalence of the disease.3,4 One
explana-tion for this discrepancy might be that the cardiomyopathy phenotype is affected by modifier genes (protective or otherwise), epigenetics, or environmental factors that have yet to be identified.5 The
increas-ing use of next-generation sequencincreas-ing has enabled simultaneous, more efficient, and cost-effective detection of mutations in a large number of genes.2 This development,
and formal population studies to determine the true prevalence of the disease in different populations, might provide some answers to these seemingly complex issues.
Myocardial interstitial and focal fibro-sis are hallmarks of HCM pathology that
Sarcomere TTN TNNT2TPM1 TNNC1TNNI3 MYBPC3 ACTC1 MYL2/3 MYH6 MYH7 DCM HCM ARVC LV noncompaction cardiomyopathy a b c d DES DSC2 DSG2 PKP2 JUP DSP Cytoplasm Sarcolemma Desmosome MIB1 TFs NOTCH1 NICD NICD JAG1
Figure 1 | Genetic mechanisms of cardiomyopathies. a | Mutations in TTN and other genes
encoding sarcomeric proteins have been shown to cause HCM (yellow stars). b | Similarly, mutations in genes encoding either sarcomeric or desmosomal proteins have been linked with DCM (pink stars). c | Mutations in genes encoding desmosomal proteins have also been implicated in the pathogenesis of ARVC (green stars). d | Mutations involved in the NOTCH1 signalling pathway are thought to underlie LV noncompaction cardiomyopathy (blue stars). Abbreviations: ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LV, left ventricular; NICD1, NOTCH1 intracellular domain; TF, transcription factor. Permission for inset panels from parts a–c obtained from NPG © Hershberger, R. E. et al. Nat. Rev. Cardiol. 10, 531–547 (2013).
contribute to the impaired diastolic and sys-tolic function observed in patients with this disease. The exact molecular mechanisms responsible for interstitial fibrosis remain unknown, with a unifying hypothesis invok-ing developmental biology beinvok-ing proposed.6
Investigators using comprehensive transcrip-tional RNA analysis of cardio myocytes and nonmyocytes from two animal models of HCM identified several changes in expres-sion of profibrotic genes in nonmyocytes, which preceded myocardial hypertrophy.7
The investigators then prevented patho-logical myocardial remodelling with allele-specifi c silencing of mutant transcripts to target profibrotic molecules. This study has important mechanistic and therapeutic implications with regard to p reventing or reversing fibrosis in HCM.
Studies designed to improve our under-standing of how genetic mutations are translated into a clinical phenotype have employed a wide spectrum of tools in the past decade. These have included molecu-lar modelling,8 structural and molecular
biology, biochemistry and pharmacology, as well as biophysics. Coppini and colleagues used patch clamping to compare the electro-mechanical properties of 26 myectomy samples from patients with HCM with control tissue.9 The HCM specimens had
abnormalities in the late sodium current, which were corrected by administration of ranolazine, an inhibitor of the late sodium channels.9 Aside from its value in
under-standing the pathophysiology of the disease, this study has stimulated the development of a clinical trial using ranolazine for the treatment of HCM.9
The initial discovery that mutations in genes encoding sarcomeric proteins, such as myosin heavy chains, can cause DCM and HCM (Figure 1) has raised the hope that such diseases might be prevented or cured with strategies to counteract the molecular abnormality. Progress towards this goal is slowly being made. For example, in 2013, a study involving allele-specific, gene-mediated RNA interference in the cardio myocytes of a mouse model of HCM resulted in partial ‘silencing’ of the mutated molecule.10 This approach was sufficient to
prevent the mice from developing the HCM phenotype. The discovery of genetic cell engineering, without the use of viral vectors, might provide effective ways of using such strategies in humans with cardiomyo-pathy, in the future. The past 10 years have seen a rapidly accelerating rate of research into the mechanisms and treatment of
cardiomyopathy, which has markedly enhanced our understanding and manage-ment of the disease, and is poised to deliver much more in the coming decade.
Qatar Cardiovascular Research Center, PO Box 5825, Doha, Qatar.
Competing interests
The author declares no competing interests. 1. Cecchi, F., Tomberli, B. & Olivotto, I. Clinical and
molecular classification of cardiomyopathies.
Glob. Cardiol. Sci. Pract. 2012, 4 (2012).
2. Herman, D. S. et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 366, 619–628 (2012).
3. Golbus, J. R. et al. Population-based variation in cardiomyopathy genes. Circ. Cardiovasc. Genet. 5, 391–399 (2012).
4. Pan, S. et al. Cardiac structure and sarcomeric genes associated with cardiomyopathy exhibit
marked intolerance of genetic variation.
Circ. Cardiovasc. Genet. 5, 602–610 (2012).
5. Kalozoumi, G., Tzimas, C. & Sanoudou, D. The expanding role of epigenetics. Glob. Cardiol.
Sci. Pract. 2012, 7 (2012).
6. Olivotto, I. et al. Developmental origins of hypertrophic cardiomyopathy phenotypes: a unifying hypothesis. Nat. Rev. Cardiol. 6, 317–321 (2009).
7. Teekakirikul, P. et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β.
J. Clin. Invest. 120, 3520–3529 (2010).
8. Gaendrarao, P. et al. Molecular modeling of disease causing mutations in domain C1 of cMyBP-C. PLoS ONE 8, e59206 (2013). 9. Coppini, R. et al. Late sodium current inhibition
reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 127, 575–584 (2013).
10. Jiang, J. et al. Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science 342, 111–114 (2013).
DECADE IN REVIEW—DYSLIPIDAEMIA
Resurgence of targets and
compounds to treat dyslipidaemia
John J. P. Kastelein
Over the past decade, we have witnessed the unparalleled success of statins
to treat dyslipidaemia. Target identification by Mendelian randomization,
human monoclonal antibodies, gene therapy, RNA-based targets, and
atherogenic lipoproteins other than LDL cholesterol have fuelled intense
development efforts that might bear fruit in the very near future.
Kastelein, J. J. P. Nat. Rev. Cardiol. 11, 629–631 (2014); published online 9 September 2014; doi:10.1038/nrcardio.2014.132
When Terje Pedersen first presented the results of the Scandinavian Simvastatin Survival Study at the AHA Scientific Sessions on 16 November 1994 in Dallas, TX, USA, he probably did not realize that the study would initiate a global revolu-tion in statin therapy. Today, statins are the most widely prescribed class of drugs, and although the results of this study were presented 20 years ago, no other drug has since been shown to have any additional benefit for patients with dyslipidaemia. Inhibitors of phospholipases, cholesteryl ester transfer protein (CETP), and cho-lesterol absorption, as well as agonists of peroxisome pr oliferator-activated receptor, thyroxin receptor, and nicotinic acid have either been toxic or not provided a beneficial outcome for patients. However, not all dis-coveries in the past decade for the therapeu-tic control of dyslipidaemia can be claimed by statins. In 2003, Boileau and colleagues mapped a locus associated with familial
hyper cholesterolaemia in the gene encod-ing proprotein convertase s ubtilisin/kexin type 9 (PCSK9). As with the Scandinavian Simvastatin Survival Study, Boileau et al. could not have foreseen that their discov-ery would develop into the currently most exciting class of lipid-lowering drugs— monoclonal antibodies against circulating PCSK9. These two discoveries have led to an unprecedented number of developments in the field of dyslipidaemia in the past decade.
In 2004, the authors of two papers first established the clinical importance of statins in the treatment of cardio vascular disease, which turned the hypothesis that ‘lower LDL cholesterol is better’ into a core prin-ciple. In the PROVE-IT study,1 Cannon and
co-workers convincingly demonstrated that 80 mg of atorvastatin was superior to 40 mg of pravastatin in outcome parameters includ-ing death, myocardial infarction, u nstable angina, and revascularization (a 16% risk reduction in favour or atorvasta tin;
P = 0.005), when administered shortly after
an acute coronary syndrome (ACS).1 This
study transformed care for patients with ACS; 80 mg of atorvastatin straight after an ACS episode has now become routine clinical practice in coronary care units in most countries. This strategy has saved innumer able lives of patients with coronary artery disease (CAD) and protected them against recurrent events.
In the TNT study,2 also published in 2004,
LaRosa and colleagues demonstrated that 80 mg was superior to 10 mg of atorva statin for treating patients with stable CAD. High-dose atorvastatin reduced the primary end point (occurrence of a major cardiovascular event) by 22% compared with the lower dose of the drug (P <0.001).2 This study has also
enabled many secondary analyses that aid our understanding of renal function during statin therapy, the clinical safety of low LDL-cholesterol levels, and that a reduction in adverse clinical outcomes is independent of almost any baseline patient characteris-tic, including LDL-cholesterol level itself. These ‘statin principles’ were extended into the realm of primary prevention in 2008 in the JUPITER trial.3 Ridker et al. selected
patients with an elevated C-reactive protein level (measured by high-sensitivity assay), but who were free from CAD, and demon-strated that a daily dose of 20 mg rosuvasta-tin robustly reduced the incidence of major adverse cardio vascular events by 44% com-pared with placebo (P <0.00001).3 Again,
efficacy was observed in all subgroups, including men and women, the elderly and young, tobacco smokers and nonsmokers, and those with or without metabolic syn-drome. More importantly, the JUPITER trial3 results highlighted the link between
inflammation, dyslipidaemia, and athero-sclerotic vascular disease, which has led to the current development of selective anti-inflammatory strategies in outcome trials by the same research group.
In two papers published in 2006 and 2008, respectively, investigators applied advanced molecular biology techniques to the study of lipid control.4,5 In the first
study, mRNA inhibition by subcutane-ously administered small oligonucleotides against apolipo protein B-100 (apoB-100) lowered the levels of all atherogenic lipo-proteins in human volunteers with mild dyslipidaemia.4 These results have led to
the development of small inhibitory RNAs, mRNA inhibitors, and locked nucleic acid inhibitors that target angiopoietin-related protein 3, apoB-100, apolipoprotein C-III
(apoC-III), apolipoprotein(a) [apo(a)], and PCSK9, and which have all reached phase I and further clinical studies. These devel-opments are just the beginning, and many more will come in the next decade. In the second paper, which garnered little atten-tion when first published, Stroes and col-leagues performed the first proof-of-concept study of gene therapy for dys lipidaemia. Alipogene tiparvovec increases the removal of postprandial chylo microns, the particles known to cause the acute and potentially lethal haemor rhagic pancreatitis associ-ated with the chylo micro naemia syndrome. Alipogene tiparvovec (commercially known as Glybera®; UniQure, Netherlands) became the first gene therapy product to be approved for any indication in the Western world.5
Many developments since 1994 have revol ved around the biology, pathol-ogy, and therapeutic lowering of LDL-cholesterol levels. Only after a number of international consortia performed large Mendelian randomization studies was the link made between CAD and apo(a), tri-glyceride-rich lipoproteins, and rem nant cholesterol.6,7 These observations are
semi-nal for our understanding of athero genesis and initiated an international effort to iden-tify novel strategies to decrease circulat-ing levels of these lipoproteins. More over, the results of these Mendelian randomi-zation studies, such as those performed by Nordestgaard6 and Kathiresan,7 have
questioned the relationship between HDL cholesterol and CAD, which might explain the disappointing results of strategies that raise HDL-cholesterol levels. By contrast, Mendelian randomization and interven-tion studies have both validated the role of lowering LDL-cholesterol levels to treat dys-lipidaemia. Consequently, the dis coveries by investigators that CETP, t riglyceride-rich lipoproteins, and apo(a) are indeed involved in atherogenesis have led to a search for compounds to safely lower the levels of these proteins, as well as those of apoC-III and, of course, PCSK9. Mendelian randomization studies are now an integral approach in the development of drugs to treat dyslipidaemia.
Of all the developments over the past decade, a paper by Stein and colleagues in 2012 deserves the title of ‘game changer’. In this study, a monoclonal antibody against PCSK9 (alirocumab), reduced the relative LDL-cholesterol level by >60% in both volun teers with normal lipid levels and patients with familial hypercholesterol-aemia.8 The excellent safety profile of this
drug class has been a relief for clinicians,
especially given the previous toxicity-related failures of other compounds. Simi-lar results were obtained in studies with bococizumab and evolocumab, and all three monoclonal antibodies targeted against PCSK9 are already in advanced, phase III out come trials. Only 9 years have passed between Boileau and colleagues’ initial PCSK9 discovery and Stein and co- workers’ 2012 paper. This rapid development has been made possible by recombinant DNA and antibody technology. Compared with the >25 years between cloning of the lipo-protein lipase (LPL) gene and the LPL gene therapy trial by our own group, the devel-opment of PCSK9-based technologies has been a remarkable achievement.
However, for which patients is the dis-covery of PCSK9 monoclonal antibodies most beneficial in the short term? To have personally witnessed the ever-decreasing LDL-cholesterol levels that different thera-pies have achieved in patients with familial hypercholesterolaemia has been immensely gratifying. Between the first simva statin trial in 1986 and the RUTHERFORD study of evolocumab just last year, a steady
Figure 1 | LDL-cholesterol levels achieved by
lipid-lowering therapies developed during the past 3 decades in patients with familial hypercholesterolaemia. Dosing frequencies are per day unless otherwise stated. Abbreviations: Atorva, atorvastatixn; Evo, evolocumab; Eze, ezetimibe; LDL-C, LDL-cholesterol; Simva, simvastatin; Torcet, torcetrapib.
Simva 40 mg Evo 420 mg + statin Simva 80 mg+ Eze 10 mg Torcet 60 mg + statin No therap y Therapy LDL-C le vels (mg/dl) 0 250 200 150 100 50 300 RADIANCE RUTHERFORD 450 400 350 First Synvinolin study Simva 40 mg ASAP 1986 2013 Simva 80 mg ENHANCE Ator va 80 mg
decrease in LDL-cholesterol levels from 9.6 mmol/l (371 mg/dl) to ~1.7 mmol/l (65 mg/dl) has been achieved (Figure 1). The discovery that monoclonal antibodies against PCSK9 can lower LDL-cholesterol levels to such an extent has essentially cured familial hypercholesterolaemia; in fact, the LDL-cholesterol levels achieved in these patients are now lower than in the general population. Who would have had the temerity to predict that in 2003?
The final discovery that I would like to highlight was reported in two papers in which triglyceride-rich lipoprotein and remnant cholesterol levels were causally linked to apoC-III and CAD.9,10 ApoC-
III was first hypothesized to reduce tri gly-ceride levels and contribute to the risk of CAD, and on that basis a mRNA inhibitor of apoC-III was developed. These two papers strengthen the association between apoC-III, triglyceride metabolism, and CAD risk.9,10
The fact that the apoC-III inhibitor is already in clinical development is, therefore, timely and fortuitous. With all of these results comes the hope that novel small- molecule compounds, monoclonal antibodies, and RNA technology will transform dyslipid-aemia treatment in the coming decade, for a second time since 1994. We might finally be able to eliminate dys lipidaemia and sub-sequent atherosclerotic vascular disease for our patients in the very near future.
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
Competing interests
J.J.P.K. declares that he has acted as a consultant and received honouraria from the following companies: Aegerion, Amgen, AstraZeneca, Atheronova, Boehringer Ingelheim, Catabasis, Cerenis, CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion, Genzyme, Isis, Merck, Novartis, Omthera, Pronova, Regeneron, Sanofi, The Medicines Company, UniQure, and Vascular Biogenics. 1. Cannon, C. P. et al. Intensive versus moderate
lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504 (2004).
2. LaRosa, J. C. et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425–1435 (2005).
3. Ridker, P. M. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008).
4. Kastelein, J. J. P. et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B.
Circulation 114, 1729–1735 (2006).
5. Stroes, E. S. et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler. Thromb. Vasc. Biol. 28, 2303–2304 (2008).
6. Kamstrup, P. R., Tybjærg-Hansen, A., Steffensen, R. & Nordestgaard, B. G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
JAMA 301, 2331–2339 (2009).
7. Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).
8. Stein, E. A. et al. Effect of a monoclonal antibodies to PCSK9 on LDL cholesterol.
N. Engl. J. Med. 366, 1108–1118 (2012).
9. Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjærg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).
10. The TG and HDL Group of the Exome Sequencing Project, National, Heart, Lung, and Blood Institute. Loss-of-function mutations in
APOC3, triglycerides, and coronary heart
disease. N. Engl. J. Med. 371, 22–31 (2014).
DECADE IN REVIEW—HEART FAILURE
10 Years of progress in HF
research—what have we learned?
Henry Krum
In this Decade in Review article, I highlight the top 10 advances in heart
failure (HF) over the past decade, including new pharmacological therapies
and expanded indications for devices in HF with reduced ejection fraction.
The poor progress in acute HF and HF with preserved ejection fraction is
emphasised. Biomarkers and devices that help prevent, detect, and guide
treatment represent the future of HF management.
Krum, H. Nat. Rev. Cardiol. 11, 631–633 (2014); published online 2 September 2014; doi:10.1038/nrcardio.2014.127
One of the great advances in cardio vascular therapy during the past 20 years has been the use of cardiac resynchro nization therapy (CRT) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several studies have indicated major out-come benefits in patients with HFrEF and advanced NYHA class III–IV symptoms. Investigators in MADIT-CRT1 tested the
hypothesis that mildly symptomatic patients with HFrEF would also benefit from CRT. In a cohort of >1,000 patients, the primary end point (HF events or death) was reduced to 17.2% with CRT versus 25.3% without CRT, driven primarily by a reduction in HF events.1 These findings were supported by
a subsequent trial, in which HF events and mortality were reduced by CRT. CRT is now guideline-recommended for all patients with HFrEF and a prolonged QRS duration (>150 ms).
Major drug therapy trials directed towards novel targets have also been conducted in the past decade (Figure 1). Pharmacological inhibition of neprilysin can augment the physiological effects of endogenous natri-uretic peptides, which have beneficial vasodilatory, anti-fibrotic, and natriuretic actions. Dual therapy with angiotensin-converting enzyme (ACE) inhibitors was
shown to be unsuccessful because of study design flaws and off-target effects; however, combination with an angiotensin-receptor blocker (ARB) seems to overcome this risk and might offer clinical benefits beyond ARB monotherapy. The researchers in the PARADIGM-HF study2 aimed to
deter-mine whether the ARB–neprilysin inhibitor LCZ696 would be superior to the gold-standard ACE-inhibitor enalapril in patients with HFrEF. Patients received either the ARB–neprilysi n inhibitor LCZ696 (200 mg twice daily) or e nalapril (10 mg twice daily), with the primary end point of cardio vascular death or HF hospitalization (n = 8,442). Although the final results have not yet been presented, the study was terminated pre-maturely for overwhelming efficacy benefit. Given the positive outcome, and assuming that the drug has an acceptable safety profile, LCZ696 should supplant ACE inhibitors as standard therapy for these patients.
The clinical benefit of β-blockers for HF might be partly attributable to their capac-ity to lower heart rate. If channel-blocking
agents, which are direct sinus node inhibi-tors, were used to investigate this heart-rate-lowering hypothesis in the SHIfT study3
(n = 6,558; 89% receiving backgroun d β-blocker therapy), in which the If channel
blocker iva bradine was compared with placebo. The primary end point (cardio-vascular death or HF hospitalization) was reached by 24% of patients receiving ivabra-dine compared with 29% of patients taking placebo, driven primarily by reduced hos-pitalization for HF. The benefits of adding ivabradine were diminished with increasing dose of background β-blockers, possibly because the additive effect of ivabradine on lowering the heart-rate was abrogated by full-dose β-blocker therapy. Ivabradine is now approved as an adjunct to background ACE inhibitor, β-blocker, and mineralo-corticoid-receptor antagonists (MRAs) in symptomatic patients with HFrEF and a sinus rhythm heart rate >70 bpm.
MRAs increase survival in patients with advanced HFrEF and in those who have experienced a myocardial infarction and have HF. However, until the EMPHASIS-HF trial,4 patients with mild symptoms of HFrEF
had not been formally studied. Researchers in EMPHASIS-HF4 evaluated the efficacy of
eplerenone compared with placebo in 2,737 patients in NYHA class II. The trial was ter-minated prematurely (median follow-up 21 months) because only 18.3% of patients receiving eplerenone reached the primary end point (cardiovascular death or hospitali-zation for HF) compared with 25.9% in the placebo group.4 Importantly, these benefits
were additional to background ACE inhibi-tor and β-blocker therapy. MRAs have, there-fore, become mandated therapy for patients with mild HFrEF.
In contrast to HFrEF, pharmaco logical therapy has so far failed to reduce major adverse events in patients with HF and pre-served ejection fraction (HFpEF). Given the established benefit of MRAs in patients with HFrEF, researchers in the TOPCAT study5
evaluated the efficacy of spirono lactone (15–45 mg per day) versus placebo in 3,445 patients with an ejection fraction >45% in addition to one other HF indicator, in an attempt to recruit a more homogenous pop-ulation with ‘true’ HFpEF. The occurrence of the primary end point (cardiovascular death, cardiac arrest, or HF hospitalization) was not significantly different between the two groups. Patients who entered the study because of an elevated plasma B-type natri-uretic peptide (BNP) concentration exhibited a stand-alone benefit on the primary end point with spirono lactone. This result sug-gests that patients who fulfilled the criteria of ‘HF hospitalization’ rather than elevated BNP might not have had true HFpEF, and in turn did not benefit from MRA therapy. Further
efforts to recruit a more homogenous patient population and establish the existence of true HFpEF before study entry are required to evaluate the role of MRAs definitively in this setting.
Improving HF outcomes by treat-ing comorbidities has become a concept of great therapeutic interest. Two inter-related strategies involve the correction of HF-related anaemia and iron deficiency. Erythropoietin-stimulating agents (ESAs) are frequently used to treat anaemia, but have not reduced major cardiovascular events in HF patients. By contrast, correction of iron deficiency has produced more encouraging results. Investigators in the FAIR-HF study6
enrolled 459 patients with HFrEF and iron deficiency, based on either serum ferritin or transferrin saturation levels. Patients were randomly allocated to either intravenous ferric carboxymaltose or saline. Fifty percent of the patients who received ferric carboxy-maltose showed improvement according to the Patient Global Assessment, compared with only 28% of those receiving placebo. However, an adequately-sized trial to assess the effect of intravenous iron on morbidity and mortality has not yet been performed in patients with HFrEF who are iron-deficient.
Treatment of acute HF has not changed for ≥40 years. Numerous proposed agents have demonstrated favourable effects on natri-uresis and dinatri-uresis, but at the expense of wors-ened renal function and lack of benefit on prognosis. Relaxin is an endogenous peptide with diuretic, natriuretic, vasodilatory, and anti-fibrotic properties. Investigators in the RELAX-AHF study7 evaluated 1,061
patients with acute HF randomly allocated to serelaxin (a recombinant form of relaxin) or placebo. Serelaxin improved one of two dysp-noea end points, but had no effect on cardio-vascular/renal death or hospital readmission at 60 days in patients with acute HF. However, fewer deaths occurred at 180 days with sere-laxin, and evidence existed of reduced in-hospital worsening of HF. On the basis of
these mixed findings, regulatory authorities did not approve the agent; however, the find-ings were sufficiently compelling to warrant a definitive mortality trial, RELAX-II, which is currently ongoing.
Gene-based approaches for HF manage-ment are beginning to emerge, after much promise. Insertion of the sarcoplasmic reticu-lum Ca2+-ATPase (SERCA2a) gene into the
failing heart has been considered a potential therapeutic strategy on the basis of its pivotal role in myocardial contractile function. The CUPID study8 involved 39 patients with HF
who received intracoronary adeno-associat ed virus type 1/SERCA2a or placebo. Initial findings suggested that gene transfer might improve relevant surrogate end points and reduce cardiovascular events. The CUPID 2 trial, with an increased cohort of patients, is currently ongoing.
The discovery of biomarkers that indi-cate the likelihood of risk factors trans-itioning to left ventricular (LV) dysfunction might change the future of HF diagnosis. Investigators in the STOP-HF study9 trialled
a BNP screening programme in which high-risk asymptomatic patients (n = 1374) were randomly assigned to receive care based on knowledge of the plasma BNP level, or usual care. Using this approach, 5.3% of the BNP group developed LV dysfunction (with or without HF) compared with 8.7% receiving usual care, over a 4.2-year period. Additional biomarkers, including some specific to the LV dysfunction transition phase (such as ST2, galectin-3), have been proposed and are currently under assessment.
Tracking of patient clinical status has under gone substantial technological advance in the past decade. In an individual patient meta-analysis of over 2,000 individu-als with HFpEF or HFrEF, BNP-guided HF treatment was shown to significantly reduce all-cause mortality and HF hospitali zation in those <70 years of age.10 Newly
avail-able tools for tracking patient clinical status remotely, such as pulmonary pressure
Advances in HF
Plasma biomarker and implantable device-based tracking of patient clinic status
HF preventive strategies Gene-based therapies Expanding indications for HF therapeutic devices Improved understanding
of pathophysiology
Novel drug therapies
