Update On Heart Failure Management and Future Directions: Hong-Mi Choi, Myung-Soo Park, and Jong-Chan Youn

REVIEW
Korean J Intern Med 2019;34:11-43

https://doi.org/10.3904/kjim.2018.428
Update on heart failure management and future

directions
Hong-Mi Choi1,*, Myung-Soo Park2,*, and Jong-Chan Youn2
1
Division of Cardiology, Hallym Heart failure (HF) is an important cardiovascular disease because of its increas-
University Sacred Heart Hospital, ing prevalence, significant morbidity, high mortality, and rapidly expanding
Anyang; 2Division of Cardiology,
Hallym University Dongtan Sacred health care cost. The number of HF patients is increasing worldwide, and Korea
Heart Hospital, Hwaseong, Korea is no exception. There have been marked advances in definition, diagnostic mo-
Received : November 28, 2018 dalities, and treatment of HF over the past four decades. There is continuing ef-
Accepted : December 9, 2018 fort to improve risk stratification of HF using biomarkers, imaging and genetic
testing. Newly developed medications and devices for HF have been widely adopt-
Correspondence to
Jong-Chan Youn, M.D. ed in clinical practice. Furthermore, definitive treatment for end-stage heart fail-
Division of Cardiology, Hallym ure including left ventricular assist device and heart transplantation are rapidly
University Dongtan Sacred Heart evolving as well. This review summarizes the current state-of-the-art manage-
Hospital, 7 Keunjaebong-gil,
Hwaseong 18450, Korea
ment for HF and the emerging diagnostic and therapeutic modalities to improve
Tel: +82-31-8086-2530 the outcome of HF patients.
Fax: +82-31-8086-2559
E-mail: jong.chan.youn@gmail.com
Keywords: Heart failure; Diagnosis; Management; Prognosis
*These authors contributed
equally to this work.
This paper was contributed by

The Korean Society of Cardiology.
INTRODUCTION DEFINITION, EPIDEMIOLOGY, AND

DIAGNOSIS
Heart failure (HF) is an important cardiovascular dis-
ease due to its increasing prevalence and high mortality Definition
rate. HF is associated with a diverse range of compli- HF is a clinical syndrome characterized by distinct
cations, such as hospitalization, lethal arrhythmia, and symptoms and signs, which is caused by structural and/
death during the disease progression. In addition, HF or functional cardiac abnormalities [1-3]. Currently, the
can be the terminal condition of many cardiovascular most common terminology for describing HF is based
diseases, including myocardial infarction (MI), valvular on left ventricular ejection fraction (LVEF). HF with
heart disease, and various cardiomyopathies. Due to normal LVEF (≥ 50%) is defined as HF with preserved
these unique characteristics, various pharmacological ejection fraction (HFpEF), and HF with decreased LVEF
and non-pharmacological treatments have been devel- (< 40%) as HF with reduced ejection fraction (HFrEF).
oped, not only to improve underlying cardiac disease HF patients with LVEF in the range of 40% to 49%
but also to prevent hospitalization and death. In this re- are defined as HF with mid-range ejection fraction
view, we will address the state-of-the-art management (HFmrEF). Although HFmrEF is now categorized as
of HF and ongoing studies. a separate entity, the epidemiology, pathophysiology,
Copyright © 2019 The Korean Association of Internal Medicine pISSN 1226-3303

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The Korean Journal of Internal Medicine Vol. 34, No. 1, January 2019
North America
Canada 1.5%
Asia USA 1.5–1.9%
South Korea 1.53%
Japan 1%
China 1.3%
India 0.12–0.44%
Malaysia 6.7%
Singapore 4.5%
Europe
South America
UK 1.3%
Australia 1–2% Brazil 1%
France 2.2%
Portugal 1–2%
Spain 2.1%
Germany 1.6–1.8%
Sweden 1.8-2.2%
Italy 1.44%
Figure 1. Global epidemiology of heart failure.
treatment, and prognosis of HFmrEF remain unclear [1]. stable HF. Patients with chronic stable HF showing un-
The increasing amount of research in this area has expected deterioration are described as having decom-
gradually led to elucidation of the characteristics of pensated HF. The New York Heart Association (NYHA)
HFmrEF, although there is still a great deal of debate. functional classification has been used to describe the
HFmrEF is a heterogeneous group comprised of at severity of HF symptoms, and the Killip classification
least three subsets: HFmrEF improved group (prior is used to describe the disease severity in patients after
LVEF < 40%), HFmrEF unchanged group (prior LVEF acute MI.
40% to 49%), and HFmrEF deteriorated group (prior
LVEF ≥ 50%). The improved and deteriorated groups Epidemiology
account for 90% of the total, with the unchanged group The prevalence of HF differs according to definition
accounting for only 10% of cases. Therefore, most pa- and region, but has been estimated to be approximately
tients classified as HFmrEF have various features of 1% to 2% in developed countries (Fig. 1). The prevalence
HFrEF and HFpEF, rather than belonging to groups rate tends to increase with age, and it is > 10% among
with unique characteristics. These results indicate the people > 70 years old [5]. The epidemiological and eti-
limitations of the current HF classification system ological profiles of HFrEF and HFpEF are different.
based on LVEF and, therefore, a novel taxonomy is re- In comparison with HFrEF, patients with HFpEF are
quired [4]. older, show female predominance, and often show hy-
Several terms are often used to describe the status of pertension and atrial fibrillation (AF) with a lower rate
HF patients. Patients with low LVEF and no symptoms of MI [6].
or signs of HF can be described as having asymptom- In Korea, the prevalence of HF in 2013 was 1.53% ac-
atic left ventricular (LV) systolic dysfunction. Patients cording to the National Health Insurance Service-Na-
experiencing HF symptoms and signs are described as tional Sample Cohort [7]. The increasing prevalence of
having chronic HF, and those whose disease status does HF with age in Korea is consistent with the worldwide
not change for at least 1 month are diagnosed as having trend, and the rate was reported to be 1.0% for individ-
12 www.kjim.org https://doi.org/10.3904/kjim.2018.428
Choi HM, et al. Update on HF management
2.0 STRATEGIES TO PREVENT NEW-ONSET HEART

Men
Women FAILURE IN PATIENTS WITH RISK FACTORS
1.5 1.65 1.72
1.57
Prevalence (%)
1.34
1.0 1.11 1.18 1.15
1.22 1.29
1.19 1.25 1.12 There is considerable evidence on how to prevent the
1.07 1.10
0.96
0.76 0.76 0.79 0.82 0.80
0.87 development of overt HF. Hypertension is one of the
0.5 0.63 0.69
0.54 major risk factors of HF. Many studies have indicat-
0 ed that proper control of blood pressure can prevent
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 HF. In the Systolic Blood Pressure Intervention Trial
A Year
(SPRINT), intensive blood pressure control (systolic
14.0 13.2 blood pressure < 120 mmHg) was more beneficial for
12.0 11.1
the prevention of cardiovascular diseases than standard
Prevalence (%)
10.0 Men
8.0
Women treatment, but controversy over optimal blood pressure
5.2 5.8 persists because the study population had a high risk of
6.0
4.0 cardiovascular disease [9]. With regard to diabetes mel-
2.0 1.2 0.9
0
litus, recent studies have shown that sodium-glucose
40–59 60–79 ≥ 80 cotransporter-2 (SGLT-2) inhibitors reduced mortality
B Age (yr)
and HF hospitalization in type 2 diabetic patients. In
Figure 2. Epidemiology of heart failure in Korea according patients with ST-segment elevation MI, rapid primary
to (A) years and (B) age and sex. Adapted from Lee et al. [7]. percutaneous coronary intervention and administra-
tion of angiotensin-converting enzyme inhibitor (ACEI),
β-blocker, mineralocorticoid receptor antagonist (MRA),
uals below 60 years old, 5.5% for those aged 60 years or and statin can reduce HF hospitalization and mortality.
older, and 12.6% for those aged 80 years or older (Fig. 2) In addition, ACEI and β-blocker can decrease mortality
[7]. in patients with coronary artery disease (CAD) without
LV systolic dysfunction and reduce HF hospitalization
Diagnosis in patients with asymptomatic LV systolic dysfunction,
In the initial evaluation of HF, it is necessary to exam- regardless of the etiology [1].
ine natriuretic peptides (NPs) and to perform echocar-
diography [1]. Both B-type natriuretic peptide (BNP)
and N-terminal pro-BNP (NT-proBNP) have diagnostic EMERGING CARDIAC IMAGING AND OTHER
power and are applicable to HFrEF and HFpEF. In DIAGNOSTIC TESTS
situations when echocardiography is not immediately
available, examination of NPs allows identification of Cardiac imaging enables us to visualize and quantify
patients requiring further cardiac evaluation by deter- the structure and function of the heart. LVEF is not
mining the likelihood of HF. In patients with NP values only the most widely used indicator of systolic function
below the cut-off, HF can be excluded because the neg- but is also one of the most powerful prognostic mark-
ative predictive value of NPs is very high (0.94 to 0.98). ers in patients with HF. As LVEF is crucial for diagno-
On the other hand, the positive predictive value is rela- sis, classification, and establishment of an appropriate
tively low (0.66 to 0.67), so the use of NPs is suitable for management plan, transthoracic echocardiography
excluding HF, but not for confirming the diagnosis [8]. is the most important tool in the initial evaluation of
Echocardiography is the most useful test providing HF patients. Recently, strain measured by echocardi-
immediate information, including systolic and diastol- ography and other modalities such as cardiovascular
ic function of LV and right ventricle (RV), chamber size, magnetic resonance (CMR) and computed tomography
wall thickness, and valve abnormalities. Physicians can (CT) have attracted attention. In this section, we review
establish the precise diagnosis of HF and set up a treat- emerging imaging modalities in the field of HF.
ment plan based on echocardiographic findings.
https://doi.org/10.3904/kjim.2018.428 www.kjim.org 13
Strain imaging tion, poorer RV-GLS was an independent predictor of

all-cause mortality in acute HF patients without pulmo-
Left ventricular strain nary hypertension [21]. Limitations, such as intervendor
LVEF can divide the HF population into two groups ac- variability, the impact of age and sex, load dependency,
cording to prognosis and drug responsiveness: HFrEF and variable cutoff value, make GLS difficult to incor-
vs. HFpEF. In HF patients with LVEF ≥ 45%, mortality porate into daily practice; however, accumulating evi-
does not show a negative correlation with LVEF [10,11]. dence may result in more universal usage of GLS in the
Moreover, most drugs used for HF show a mortality future [13,16,22].
benefit only in patients with HFrEF, and not in those
with HFmrEF and HFpEF [12]. This is because LVEF CT and CMR
cannot discriminate subclinical LV dysfunction from Cardiac CT can be used to evaluate the coronary ar-
normal systolic function. In addition, substantial num- teries in HF patients with low to intermediate pretest
bers of patients with cardiomyopathy other than isch- probability of CAD or equivocal noninvasive stress test
emic cardiomyopathy have preserved systolic function. results. CMR has the unique advantage of myocardial
Therefore, there is a need for a more accurate prog- tissue characterization, which helps to determine the
nostic marker to classify HF patients, and LV global etiology of various cardiomyopathies and estimate
longitudinal strain (GLS) is expected to be useful in this myocardial viability. However, the role of imaging mo-
regard [13,14]. Park et al. [14] demonstrated the utility of dalities other than transthoracic echocardiography was
LV-GLS as a prognostic indicator in patients with acute restricted in the 2016 European Society of Cardiology
HF throughout all ranges of LVEF. They demonstrat- (ESC) guidelines to estimation of the etiology in HF pa-
ed that the rate of all-cause death was well stratified tients [1].
according to GLS, but not to LVEF [14]. With regard to With recent progress in CMR techniques, additional
the specific etiology of HF, LV-GLS worse than −14% information about myocardial tissue has become avail-
was an independent predictor of all-cause mortality able. Pre- and post-contrast T1 time and extracellular
and hospitalization for HF in acute MI with LVEF > volume (ECV) are known to be related to myocardial
40% [15]. In patients receiving potentially cardiotoxic tissue composition [23]. Mascherbauer et al. [24] re-
chemotherapy, baseline and follow-up measurement of ported a negative correlation between post-contrast T1
LV-GLS are recommended because LV-GLS can detect time and E/e' in 61 HFpEF patients with diagnoses con-
early subclinical LV dysfunction in these patients [16]. firmed by right heart catheterization. They also showed
that short post-contrast T1 time (< 388.3 ms) was an
Right ventricular strain independent predictor of HF hospitalization and car-
The RV has a complex structure that causes difficulty diovascular mortality [24]. In a prospective cohort study
in the estimation of systolic function. The pathophys- of 117 non-ischemic dilated cardiomyopathy (NIDCM)
iology of RV dysfunction is also complex, because RV patients, ECV was a better prognostic marker of cardiac
function is influenced by a wide range of factors, such events than the presence of mid-wall late gadolinium
as volume status, pulmonary vascular resistance, and enhancement (LGE) [25]. However, the difference in ad-
LV function [17]. Therefore, many studies have failed ministration, distribution, and excretion of gadolinium
to show the predictive value of RV function in patients can cause potential variability of post-contrast T1 time
with HF [18]. RV strain has recently become one of the and ECV and, therefore, native T1 has emerged as a new
most actively investigated topics in the measurement of alternative method [26]. In 637 NIDCM patients, native
RV function [19]. Iacoviello et al. [20] reported that RV- T1 was an independent predictor of all-cause and HF
GLS and RV free wall strain were independent predic- composite endpoint, while post-contrast T1 was not [27].
tors of all-cause mortality in patients with chronic sta- Furthermore, efforts are being made to use CT for
ble HF. The most recent study, including 1,824 patients tissue characterization. Prior studies have shown that
with acute HF, showed that the group with decreased CT could be used to evaluate myocardial delayed en-
biventricular strain had the poorest prognosis. In addi- hancement for non-ischemic cardiomyopathy as well
as MI, through similar contrast kinetics of iodine to markers, such as procalcitonin, mid-regional pro-atrial
gadolinium. Moreover, the recently developed dual-en- NP, and growth differentiation factor-15, are also under
ergy technique could improve the image quality of CT investigation [34,40]. Individual novel biomarkers may
for evaluation of myocardial delayed enhancement not be useful as prognostic indicators, but combina-
through monochromatic imaging. Mapping of iodine tions of these biomarkers can show better performance
distribution within the myocardium using the dual-en- in the prediction of mortality [41].
ergy technique could improve diagnostic accuracy for Nevertheless, the results of studies regarding bio-
evaluation of myocardial perfusion and ECV fraction marker-guided therapy were variable [42]. NP-guided
[28-30]. In patients with HF, myocardial scarring detect- pharmacological therapy reduced all-cause mortality
ed by CT is similar to the presence of LGE by CMR [31]. and HF hospitalization in a meta-analysis of 2,686 pa-
Despite limitations including radiation exposure and tients with chronic HF [43]. However, Guiding Evidence
a shortage of experience, CT may supersede CMR in Based Therapy Using Biomarker Intensified Treat-
the future due to its versatility, especially in the field of ment in Heart Failure (GUIDE-IT), the most recent
ischemic cardiomyopathy [32]. multi-center randomized controlled trial (RCT), yielded
disappointing results. In that study, NT-proBNP-guid-
Novel biomarkers and genetic testing ed therapy did not show significant benefits compared
with usual care in high-risk HFrEF patients [44]. There
Biomarkers were a number of possible reasons for this failure,
As there is a considerable body of evidence for NP bio- including: (1) the patients allocated to the biomark-
markers, they have already been incorporated into the er-guided group in the clinical trials already had a low
American expert consensus for HF [33]. In the European level of NP because they generally received strict guide-
guidelines, NPs are essential elements for the diagnosis line-directed medical therapy (GDMT) in advance; (2)
of HFpEF and acute HF [1]. the additional treatment in patients with high NP levels
There are increasing numbers of novel biomarkers. was limited to increases or addition of diuretics; and
The biomarkers for myocardial injury and fibrosis, (3) it was not clear how much low NP level is needed to
such as soluble suppression of tumorigenicity-2 (ST2), improve the patient outcomes. Therefore, it would be
galectin-3, and high-sensitivity cardiac troponin, can be erroneous to conclude that biomarker-guided therapy
used for additive risk stratification in HF patients [33, is useless. GDMT has not been used in real-world sit-
34]. Soluble ST2, a marker for cardiac stress and fibrosis, uations due to the gap between guidelines and clinical
showed good performance for additive risk stratifica- practice [45,46]. Thus, biomarker-guided therapy may
tion of death in acute HF in an individual patient-based still have room for improvement.
meta-analysis [35]. In addition, a smaller decrease in sol-
uble ST2 48 hours after presentation was an indepen- Genetic testing
dent predictor of 1-year mortality in patients with acute Inherited cardiomyopathies account for a small portion
HF who visited the emergency department [36]. The of HF cases. However, such cases cannot be ignored
value of soluble ST2 as a prognostic indicator was also because the diagnosis, clinical manifestations, and
demonstrated in ambulatory HF patients [37]. Notably, treatment are different from those of other types of HF.
soluble ST2 can be useful in patients with renal insuffi- For example, a patient with Anderson-Fabry disease can
ciency because it is not influenced by renal function [37, show systemic manifestations, including chronic kid-
38]. Galectin-3 is a marker of inflammation and fibrosis. ney disease with proteinuria and stroke. The diagnosis
It can also provide prognostic information in patients requires confirmation by a specific test for enzyme
with acute or chronic HF and identify patients who activity or genetic testing and should be treated with
can benefit from medical therapy [34,39]. In addition, enzyme replacement therapy [47]. Accordingly, genetic
galectin-3 can also be a potential treatment target for fi- testing provides accurate information regarding the eti-
brosis. Several galectin-3 inhibitors are being developed ology of HF, potentially followed by a specific therapy
in experimental studies [39]. In addition, other new bio- and better clinical outcome [48,49].
Recently, the Heart Failure Society of America pub- by administration of inotropic drugs to HF patients.
lished new guidelines for genetic testing in patients di- However, most clinical trials of inotropic agents were
agnosed with genetic cardiomyopathy [50]. The guide- stopped prematurely because of their poor results [90].
lines were developed according to evidence about the From the mid-1970s, vasodilators have been used to
validity and influence of genetic testing on the progno- increase cardiac efficiency by reducing afterload, and
sis of diseases. Briefly, genetic testing is recommended the first large RCT of vasodilator treatment in HF was
in patients with hypertrophic cardiomyopathy (HCM), published in 1986. In this study, vasodilator treatment
NIDCM, arrhythmogenic right ventricular cardiomyop- improved mortality, but subsequent larger studies sug-
athy, cardiomyopathy with other extracardiac manifes- gested that it was not beneficial for the long-term sur-
tations, and LV non-compaction. Careful family history vival of HF patients [54].
taking, phenotypic screening, and genetic counseling Since the 1980s, HF has been understood as a neu-
are recommended for family members of patients with rohormonal disease, and physicians attempted to
genetically confirmed inherited cardiomyopathies. improve cardiac function by blocking the renin-angio-
In addition, a new classification method of genetic tensin-aldosterone system and sympathetic activation.
cardiomyopathy was proposed. Traditionally, the type of ACEI was reported to reduce mortality and hospi-
cardiomyopathy was defined by morphology, i.e., dilated, talization in HFrEF patients [91], and β-blockers also
hypertrophic, and restricted cardiomyopathy. The Eu- improved LV function and reduced mortality and hos-
ropean and American guidelines utilized complex clas- pitalization rates [92]. Unlike ACEI, β-blockers do not
sification methods because a wide variety of mutations have a class effect, and evidence of beneficial effects in
as well as non-genetic cardiomyopathy can show similar treatment of HF have been reported only for bisoprolol,
findings [51,52]. Recent progress in testing methods, such sustained-release metoprolol, carvedilol, and nebivolol
as next-generation sequencing, revealed that several [93,94]. Subsequently, additional prognostic benefits
genetic mutations are responsible for single inherited were reported when MRA was combined with ACEI and
cardiomyopathy and that there are many subclinical β-blocker therapy [95]. Angiotensin receptor blockers
mutation carriers in the population. Therefore, a new also showed beneficial effects on prognosis in patients
classification incorporating these factors was required. with HFrEF and has been used as an alternative treat-
The MOGE(S) classification includes morphofunctional ment option when ACEI cannot be used [96]. Combi-
phenotype (M), involved organ system (O), genetic inher- nation therapy targeting the neurohormonal system
itance pattern (G), etiology (E), and functional status (S) significantly improved the prognosis of patients with
of the disease. This new classification integrates the phe- HFrEF compared to the use of vasodilator and inotro-
notype, genotype, and function of an individual patient. pic agents and is still the mainstay of pharmacological
Therefore, it has advantages regarding standardization treatment of HF [94].
and expandability of nomenclature [53]. In the 2000s, several new medications were intro-
duced for treatment of HF. Ivabradine is an inhibitor
that acts on the If channel of the sinoatrial node, which
PHARMACOLOGICAL TREATMENT reduces heart rate independently of β-blocker use. In
patients with HFrEF, ivabradine improves the clinical
Conventional pharmacological treatment outcome in cases with resting heart rate > 70 bpm de-
Pharmacological treatment of HF has been evolving spite adequate β-blocker therapy [55]. Tolvaptan is an
through increased understanding of its pathophysiology oral vasopressin-2 receptor antagonist with excellent
and the development of new drugs (Table 1 [54-89], Fig. diuresis activity and is expected to be beneficial in de-
3). Before the 1980s, treatment of HF largely depended congestion of acute heart failure (AHF) patients [97]. As
on bed rest and fluid restriction, and only digitalis and many AHF patients have renal dysfunction, resistance
diuretics were prescribed for HF patients. As decreased to diuretics, and electrolyte imbalance such as hypona-
LV contractility was thought to be the main cause of tremia, tolvaptan seemed to be more beneficial in these
HF, there were many attempts to improve contractility patients [98]. However, tolvaptan failed to show a posi-
Table 1. Landmark pharmacological and non-pharmacological studies of heart failure
Primary end- Important sec-
Topic Study Year Author Patients No. Intervention Comparator Outcome FU duration
point ondary outcome
Drug V-HeFT [54] 1986 Cohn et al. LVEF < 45%, 642 ISDN/ Prazocin or All-cause death RRR 0.34 2.3 yr (mean)
DCMP hydralazine placebo (0.04–0.54; vs.
placebo, at 2 yr)
a
CONSENSUS 1987 CONSENSUS NYHA IV 253 Enalapril Placebo All-cause death RRR 0.40 at 6 RRR for mortality 188 day
[57] Trial Study mon (p = 0.002) at 1 yr 0.31 (mean)
a
group (p = 0.001)a
SOLVD [58] 1991 SOLVD Inves- LVEF ≤ 35%, 2,569 Enalapril Placebo All-cause death RRR 0.16 RRR for all-cause 4 yr
tigators et al. NYHA II–IV (0.05–0.26)a death or HF
hospitalization:
0.26 (0.18–0.34)a
USCP [59] 1996 Packer et al. LVEF ≤ 35% 1,094 Carvedilol Placebo All-cause death RRR 0.65 RRR for CV death 12 mon
(0.39–0.80)a or hospitaliza-
tion: 0.38
(0.18–0.53)a
RALES [60] 1999 Pitt et al. LVEF ≤ 35%, 1,663 Spironolactone Placebo All-cause death RR 0.70 CV death or hos- 2 yr
NYHA III–IV (0.60–0.82)a pitalization RR:
0.68 (0.59–0.78)a
ATLAS [61] 1999 Packer et al. LVEF ≤ 30%, 3,164 High dose lisin- Low dose All-cause death HR 0.92 HR for all-cause 45.7 mon
NYHA II–IV opril lisinopril (0.82–1.03)b death or hos- (median)
pitalization for
any cause: 0.88
(0.82–0.96)a
CHARM [62] 2003 Granger et al. LVEF ≤ 40%, 2,028 Candesartan Placebo CV death, HF HR 0.70 HR for CV death: 33.7 mon
NYHA II–IV hospitalization (0.60–0.81)a 0.80 (0.66–0.96)a (median)
SHIFT [55] 2010 Swedberg et LVEF ≤ 35%, 6,558 Ivabradine Placebo HF death or HR 0.82 HR for HF hos- 22.9 mon
al. NYHA II–IV hospitalization (0.75–0.90)a pitalization: 0.74 (median)
(0.66–0.83)a
PARADIGM 2014 McMurray et LVEF ≤ 40%, 8,399 Valsartan/sacu- Enalapril CV death or HR 0.80 HR for all-cause 27 mon
-HF [56] al. NYHA II–IV bitril hospitalization (0.73–0.87)a death: 0.84 (median)
for HF (0.76–0.93)a
EMPA-REG 2015 Zinman et al. T2DM at high 7,020 Empagliflozin Placebo CV death, HR 0.89 HR for all-cause 3.1 yr
OUTCOME risk for CV nonfatal MI, (0.74–0.99)a death: 0.68 (median)
[63] events nonfatal stroke (0.57–0.82)a
LEADER 2016 Marso et al. T2DM at high 9,340 Liraglutide Placebo CV death, HR 0.87 HR for all-cause 3.8 yr
www.kjim.org
[64] risk for CV nonfatal MI, (0.78–0.97)a death: 0.85 (median)
events nonfatal stroke (0.74–0.97)
HR for CV death:
17
0.78 (0.66–0.93)a
Table 1. Continued
18
CANVAS [65] 2017 Neal et al. T2DM at high 10,142 Canagliflozin Placebo CV death, HR 0.86 HR for CV death: 188 wk
risk for CV nonfatal MI, (0.75–0.97)a 0.87 (0.72–1.06)b (mean)
events nonfatal stroke HR for amputa-
tion: 1.97
(1.41–2.75)c
www.kjim.org
CANTOS [66] 2017 Ridker et al. History of MI 10,061 Canakinumab Placebo CV death, HR 0.85 Increase fatal 3.7 yr
patients and nonfatal MI, (0.74–0.98)a infection or sep- (median)
elevated hsCRP nonfatal stroke sis (0.31 per 100
person/yr vs. 0.18
per 100 person/
yr, p = 0.02)c
DECLARE- 2018 Wiviott et al. T2DM with mul- 17,160 Dapagliflozin Placebo CV death, MI, HR 0.93 HR for CV death 4.2 yr
TIMI 58 [67] tiple risk factors ischemic stroke (0.84–1.03)a and HF hospi- (median)
for CV disease talization: 0.83
or known CV (0.73–0.95)a
disease
ATTR-ACT 2018 Maurer et al. TTR cardiac 441 Tafamidis Placebo All-cause death HR 0.70 30 mon
[68] amyloidosis with (0.51–0.96)a
HF
ICD MADIT [69] 1996 Moss et al. Prior MI (3 wk), 196 ICD Medical ther- All-cause death HR 0.46 27 mon
LVEF ≤ 35%, apy (0.26–0.82)a (mean)
NYHA I–III,
asymptomatic
NSVT or induc-
ible VT
MUSTT [70] 1999 Buxton et al. CAD, LVEF ≤ 704 Antiarrhythmic Medical ther- Cardiac arrest, HR 0.73 HR for ICD vs. no 39 mon
40%, asymp- drugs or ICD apy arrhythmic (0.53–0.99)a ICD: 0.24 (0.13– (median)
tomatic NSVT death 0.45)a
and inducible
sustained VT
MADIT II [71] 2002 Moss et al. Prior MI (≥ 1 1,232 ICD Medical ther- All-cause death HR 0.69 20 mon
mon), LVEF ≤ apy (0.51–0.93)a (mean)
30%
Table 1. Continued

DEFINITE [72] 2004 Kadish et al. NIDCM, LVEF ≤ 229 ICD Medical ther- All-cause death HR 0.65 HR for arrhyth- 29 mon
36% apy (0.40–1.06)b mic SCD: 0.20 (mean)
(0.06–0.71)a
DINAMIT 2004 Hohnloser et Recent MI (6 to 674 ICD Medical ther- All-cause death HR 1.08 HR for arrhyth- 30 mon
[73] al. 40 day), LVEF ≤ apy (0.76–1.55)b mic death: 0.42 (mean)
35%, (0.22–0.83)a
SCD-HeFT [74] 2005 Bardy et al. NYHA II–III, 2,521 Amiodarone Medical ther- All-cause death Amiodarone 46 mon
LVEF ≤ 35% ICD apy HR 1.06 (median)
(0.86–1.30)b
ICD HR 0.77
(0.62–0.96)a
DANISH [75] 2016 Kober et al. NYHA II–III, or 1,116 ICD (including Medical ther- All-cause death HR 0.87 HR for sudden 68 mon
CRT candidate CRT if indicat- apy (includ- (0.68–1.12)b death: 0.50 (median)
with IV, LVEF ≤ ed) ing CRT if (0.31–0.82)a
35%, NIDCM indicated)
VEST [76] 2018 Olgin et al. Recent MI, LVEF 2,302 Wearable ICD Medical ther- Sudden death RR 0.67
≤ 35% apy or death from (0.37–1.21)b
ventricular
tachyarrhyth-
rmia
CRT COMPANION 2004 Bristow et al. NYHA III–IV, 1,520 CRT-P Medical ther- All-cause death, CRT-P HR 0.81 HR for all-cause Medical 11.9
[77] LVEF ≤ 35%, CRT-D apy hospitalization (0.69–0.96) death: mon
QRSd ≥ 120 ms, CRT-D HR 0.80 CRT-P 0.76 CRT-P 16.2
sinus (0.68–0.95)a (0.58–1.01) mon
CRT-D 0.64 CRT-D 15.7
(0.48–0.86)a mon
CARE-HF [78] 2005 Cleland et al. NYHA III–IV, 813 CRT Medical ther- All-cause death, HR 0.63 HR for all-cause 29 mon
LVEF ≤ 35%, apy hospitalization (0.51–0.77)a death: 0.64 (mean)
QRSd ≥ 120 ms, for CV event (0.48–0.85)a
sinus, LVESD ≥
30 mm
REVERSE [79] 2008 Linde et al. NYHA I–II, LVEF 610 CRT-on CRT-off HF clinical Worsened HR for HF 12 mon
≤ 40%, QRSd ≥ composite primary end- hospitalization:
120 ms, sinus, response point: 0.47
LVEDD ≥ 55 mm (worse) 16% vs. 21% (p = 0.03)a
www.kjim.org
(p = 0.10)b
19
Table 1. Continued
20
MADIT-CRT 2009 Moss et al. NYHA I–II, LVEF 1,820 CRT-D ICD All-cause death HR 0.66 HR for all-cause 2.4 yr (mean)
[80] ≤ 30%, QRSd ≥ or HF (0.52–0.84)a death: 1.00
130 ms, sinus (0.69–1.44)b
HR for HF: 0.59
(0.47–0.74)a
www.kjim.org
RAFT [81] 2010 Tang et al. NYHA II–III, 1,798 CRT-D ICD All-cause death HR 0.75 HR for all-cause 40 mon
LVEF ≤ 30%, or HF hospital- (0.64–0.87)a death: 0.75 (mean)
QRSd ≥ 120 ms, ization (0.62–0.91)
sinus or AF HR for HF hospi-
talization: 0.68
(0.56–0.83)a
VAD REMATCH 2001 Rose et al. NYHA IV, LVEF 129 Axial pulsatile Medical All-cause death RR 0.52 RR for serious NA
[82] ≤ 25%, ineligible flow LVAD therapy (0.34–0.78)a adverse event: 2.35
for HT (HeartMate) (1.86–2.95)c
HMII-BTT [83] 2007 Miller et al. NYHA IV, 133 Axial continu- Status at 180 day Survival during Improved NYHA 126 day
awaiting HT ous flow LVAD (HT, recovery, support: 68% functional class (median)
(HeartMate II) on mechanical at 6 mon and quality of life
support) at 3 mona
HMII-DT [84] 2009 Slaughter et NYHA IIIB–IV, 200 Axial continu- Axial Disabling HR 0.38 Less infection, Continuous
al. LVEF ≤ 25%, in- ous flow LVAD pulsatile stroke or (0.27–0.54)a right HF, respira- 1.7 yr
eligible for HT (HeartMate II) flow LVAD device removal tory failure, renal Pulsatile
(HeartMate due to mal- failure, rehospi- 0.6 yr
XVE) function talizationa (median)
at 2 yr
ENDURANCE 2017 Rogers et al. NYHA IIIB–IV, 446 Centrifugal Axial Disabling Noninferior More stroke NA (2 yr)
[85] LVEF ≤ 25%, continuous flow continuous stroke or device (p = 0.01 (29.7% vs. 12.1%, p
ineligible for LVAD (Heart- flow LVAD removal due to for noninferi- < 0.001)c
HT Ware) (HeartMate malfunction at ority)b
II) 2 yr
MOMENTUM 2017 Mehra et al. Advanced HF 294 Centrifugal Axial Disabling Noninferior No pump throm- NA (6 mon)
3 [86] patients who continuous flow continuous stroke or device (p < 0.001 for bosis (0% vs.
are ineligible or LVAD (Heart- flow LVAD removal due to noninferiority) 10.1%, p < 0.001)
waiting for HT Mate 3) (HeartMate malfunction at HR 0.55 HR at 2 yr: 0.46
II) 6 mon (0.32–0.95)a (0.31–0.69)a
CABG STICH [87] 2016 Velazquez et LVEF ≤ 35%, CAD 1,212 CABG Medical All-cause death HR 0.86 HR for all-cause NA
al. amenable to therapy (0.72–1.04)b death or hospi-
CABG talization due to
CV cause: 0.74
(0.64–0.85)a
Table 1. Continued

HT SCHEDULE 2014 Andreassen et De novo HT 115 Everolimus with Standard GFR at 12 mon 79.8 mL/ Less cardiac NA (12 mon)
[88] al. recipient low dose dose min/1.73 m2 allograft vascu-
cyclosporin cyclosporin vs. 61.5 mL/ lopathy (50.0% vs.
min/1.73 m2 64.6%, p = 0.003)a
(p < 0.001)a
PROCEED II 2015 Ardehali et al. HT recipient 130 Organ Care Standard cold Patient and 94% vs. 97% NA
[89] System storage graft (p = 0.45)b
survival
at 30 day
FU, follow-up; V-HeFT, Vasodilator-Heart Failure Trial I; LVEF, left ventricular ejection fraction; DCMP, dilated cardiomyopathy; ISDN, isosorbide dinitrate; RRR, relative risk reduc-
tion; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; NYHA, New York Heart Association; SOLVD, Studies of Left Ventricular Dysfunction; HF, heart failure;
USCP, U.S. Carvedilol Program; CV, cardiovascular; RALES, Randomized Aldactone Evaluation Study; RR, relative risk; ATLAS, Assessment of Treatment with Lisinopril and Survival;
MADIT, Multicenter Automatic Defibrillator Implantation Trial; HR, hazard ratio; CHARM, Candesartan in Heart failure-Assessment of moRtality and Morbidity; SHIFT, Systolic
Heart failure treatment with the If inhibitor ivabradine Trial; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity
in Heart Failure; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus; T2DM, type 2 diabetes mellitus; MI, myocardial infarction;
LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; CANVAS, Canagliflozin Cardiovascular Assessment Study; CANTOS, Canakinum-
ab Anti-inflammatory Thrombosis Outcome Study; hsCRP, high-sensitivity C-reactive protein; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events Thrombolysis
in Myocardial Infarction 58; ATTR-ACT, Transthyretin Amyloidosis Cardiomyopathy Clinical Trial; TTR, transthyretin; ICD, implantable cardioverter-defibrillator; MADIT, Mul-
ticenter Automatic Defibrillator Implantation Trial; NSVT, nonsustained ventricular tachycardia; VT, ventricular tachycardia; MUSTT, Multicenter Unstained Tachycardia Trial;
CAD, coronary artery disease; DEFINITE, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; NIDCM, nonischemic dilated cardiomyopathy; SCD, sudden car-
diac death; DINAMIT, Defibrillator in Acute Myocardial Infarction Trial; SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial; DANISH, Danish Study to Assess the Efficacy of
ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality; CRT, cardiac resynchronization therapy; VEST, Vest Prevention of Early Sudden Death Trial; COMPANION,
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; QRSd, QRS duration; CRT-P, cardiac resynchronization therapy without defibrillator; CRT-D, cardiac
resynchronization therapy with defibrillator; CARE-HF, Cardiac Resynchronization in Heart Failure; LVESD, left ventricular end-systolic dimension; REVERSE, REsynchronization
reVErses Remodeling in Systolic left vEntricular dysfunction; LVEDD, left ventricular end-diastolic dimension; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial
with Cardiac Resynchronization Therapy; RAFT, Resynchronization–Defibrillation for Ambulatory Heart Failure Trial; AF, atrial fibrillation; HT, heart transplantation; VAD, ven-
tricular assisted device; REMATCH, Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure; LVAD, left ventricular assist device; HMII-BTT,
HeartMate II bridge to transplant; HMII-DT, HeartMate II destination therapy; ENDURANCE, The HeartWare™ Ventricular Assist System as Destination Therapy of Advanced
Heart Failure; NA, not available; MOMENTUM 3, Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3;
CABG, coronary artery bypass surgery; STICH, Surgical Treatment for Ischemic Heart Failure; SCHEDULE, Scandinavian Heart Transplant Everolimus De novo study with Early Cal-
cineurin Inhibitors Avoidance; GFR, glomerular filtration rate; PROCEED II, ex vivo perfusion of donor hearts for human heart transplantation.
a
Positive result.
b
Neutral results.
c
Serious adverse event.
www.kjim.org
21
1960–1969 1970–1979 1980–1983
Digoxin & Diuretics
1st HT 1st TAH Cyclosporin
1984 1986 1988 1990 1992 1994 1996 1998 2000
V-HeFT SOLVD USCP RALES
CONSENSUS ATLAS
MADIT MUSTT
Bicaval
Tacrolimus
1st VAD technique
& MMF
2002 2004 2006 2008 2010 2012 2014 2016 2018
CHARM SHIFT PARADIGM-HF EMPA-REG CANTOS
MADIT II DEFINITE SCD-HeFT REVERSE RAFT CANVAS ATTR-ACT

DINAMIT CARE-HF MADIT-CRT STICH LEADER DECLARE
COMPANION DANISH VEST
REMATCH mTOR HVAD BTT HMII DT SCHEDULE ENDURANCE

inhibitor
PROCEED II MOMENTUM 3
Pharmacologic treatment
ICD & CRT
VAD & HT
Figure 3. Progression of heart failure treatment: medications, devices, and transplantation. HT, heart transplantation; TAH,
total artificial heart; V-HeFT, Vasodilator-Heart Failure Trial I; CONSENSUS, Cooperative North Scandinavian Enalapril Sur-
vival Study; SOLVD, Studies of Left Ventricular Dysfunction; USCP, U.S. Carvedilol Program; RALES, Randomized Aldactone
Evaluation Study; ATLAS, Assessment of Treatment with Lisinopril and Survival; MADIT, Multicenter Automatic Defibrillator
Implantation Trial; MUSTT, Multicenter Unstained Tachycardia Trial; VAD, ventricular assisted device; MMF, mycophenolate
mofetil; CHARM, Candesartan in Heart failure-Assessment of moRtality and Morbidity; SHIFT, Systolic Heart failure treat-
ment with the If inhibitor ivabradine Trial; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Im-
pact on Global Mortality and Morbidity in HF; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Dia-
betes Mellitus; CANVAS, Canagliflozin Cardiovascular Assessment Study; LEADER, Liraglutide Effect and Action in Diabetes :
Evaluation of Cardiovascular Outcome Results; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcome Study; AT-
TR-ACT, Transthyretin Amyloidosis Cardiomyopathy Clinical Trial; DECLARE, Dapaglif lozin Effect on CardiovascuLAR
Events; DEFINITE, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation; DINAMIT, Defibrillator in Acute
Myocardial Infarction Trial; COMPANION, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure;
SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial; CARE-HF, Cardiac Resynchronization in Heart Failure; REVERSE,
REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction; MADIT-CRT, Multicenter Automatic De-
fibrillator Implantation Trial with Cardiac Resynchronization Therapy; RAFT, Resynchronization–Defibrillation for Ambula-
tory Heart Failure Trial; STICH, Surgical Treatment for Ischemic Heart Failure; DANISH, Danish Study to Assess the Efficacy
of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality; VEST, Vest Prevention of Early Sudden Death Tri-
al; REMATCH, Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure; mTOR,
mammalian target of rapamycin; HVAD BTT, HeartWare ventricular assist device bridge to transplant; HMII-DT, HeartMate
II destination therapy; SCHEDULE, Scandinavian Heart Transplant Everolimus De novo study with Early Calcineurin Inhibi-
tors Avoidance; PROCEED II, ex vivo perfusion of donor hearts for human heart transplantation; ENDURANCE, The Heart-
Ware™ Ventricular Assist System as Destination Therapy of Advanced Heart Failure; MOMENTUM 3, Multicenter Study of
MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3; ICD, implantable
cardioverter-defibrillator; CRT, cardiac resynchronization therapy.
tive result in several clinical trials in AHF, and further rate of empagliflozin was similar, but the rate of genital
studies are needed, therefore, to determine its applica- infection was higher than placebo [63]. Canagliflozin
bility in the treatment of HF [99]. also reduced the risk of cardiovascular death and hos-
The Prospective Comparison of ARNI with ACEI to pitalization due to HF in patients with type 2 diabetes
Determine Impact on Global Mortality and Morbid- and elevated risk of cardiovascular disease (Canaglifloz-
ity in HF (PARADIGM-HF) study published in 2014 in Cardiovascular Assessment Study [CANVAS] trial).
demonstrated the clinical efficacy of angiotensin recep- However, administration of canagliflozin increased the
tor-neprilysin inhibitor (ARNI) in HFrEF [56]. ARNI is a incidence of volume depletion, fracture, and amputa-
combination of valsartan and the neprilysin inhibitor, tion compared with placebo [65]. In addition, dapagli-
sacubitril. Neprilysin is an endopeptidase that degrades flozin also reduced the rates of cardiovascular death
several endogenous vasoactive peptides, including NPs, and hospitalization for HF in a recent RCT (Dapagli-
bradykinin, and adrenomedullin. Sacubitril increas- flozin Effect on Cardiovascular Events-Thrombolysis in
es the concentrations of these peptides by inhibiting Myocardial Infarction 58 [DECLARE-TIMI 58]) [67].
neprilysin, and peptides antagonize the opposite action SGLT-2 inhibitors induce glycosuria and diuresis,
of neurohormonal overactivation [100]. Experimental which can be expected to reduce blood pressure, im-
studies have suggested that simultaneous inhibition prove glycemic control, result in weight loss, and im-
of the renin-angiotensin system and neprilysin can prove insulin sensitivity [102]. In addition, it has been
more effectively decrease neurohormonal activation, reported that SGLT-2 inhibitors have cardioprotective
which aggravates HF. As the combination of ACEI and effects by improving cardiac metabolism. A study in
sacubitril increased serious angioedema, valsartan and a murine model showed that empagliflozin increases
sacubitril constituted ARNI. In a large double-blind cardiac adenosine triphosphate (ATP) production by ac-
RCT, ARNI was superior to ACEI alone in reducing the tivating cardiac oxidation of glucose and fatty acids [103],
risk of death and hospitalization for HFrEF patients although the precise underlying mechanism is not fully
[56]. ARNI is already being used for HFrEF patients as understood yet.
a standard practice, and clinical trials are underway re- Large-scale cardiovascular outcome studies using
garding the role of ARNI in HFpEF patients and post- other SGLT-2 inhibitors are underway [104], and a mul-
MI patients. tinational observational study, including South Korea,
While there have been steady developments regard- is currently in progress [105,106]. Moreover, the benefit
ing pharmacological treatment for use in patients with of SGLT-2 inhibitors may persist regardless of the pres-
HFrEF, no drugs have shown clear mortality benefits in ence of diabetes. Empagliflozin significantly reduced
patients with HFpEF. At present, drug therapy in HF- the rate of cardiac deterioration in HF without diabetes
pEF is focused on controlling symptoms and treating in a murine model [107]. Human clinical studies on the
risk factors and comorbidities [12]. effects of SGLT-2 inhibitors in HF without diabetes are
also underway; DAPA-HF (NCT03036124) for dapagli-
Emerging pharmacological treatment flozin, EMPEROR-Reduced (NCT03057977) and EMPER-
OR-Preserved (NCT03057951) for empagliflozin [108].
SGLT-2 inhibitor and glucagon-like peptide 1 agonist Liraglutide, a glucagon-like peptide 1 analog, showed
The SGLT-2 inhibitors represent a novel class of anti- decreased all-cause mortality and cardiovascular death
hyperglycemic agents that increase urinary excretion compared with placebo in a large-scale RCT [64]. As the
of glucose in the renal tubules [101]. Empagliflozin U.S. Food and Drug Administration requires cardiovas-
showed good outcomes in large RCT (Empagliflozin cular safety data for any new antidiabetic medications
Cardiovascular Outcome Event Trial in Type 2 Diabetes before approval, novel antidiabetic medications with
Mellitus Patients [EMPA-REG OUTCOME]). Empagli- additional cardiovascular benefits are likely to be devel-
flozin reduced HF hospitalization and cardiovascular oped in the future as well.
death in patients with type 2 diabetes, with a consistent
benefit in patients with HF. The serious adverse event
New drugs in specific cardiomyopathy fields Anti-inflammatory therapy

New drugs that act on cardiac myosin have been de- Various cytokines have been shown to play important
veloped and tested for efficacy in specific diseases. roles in determining cardiac function under patho-
Mavacamten, which acts as an inhibitor of cardiac my- physiological conditions. Several cytokines, including
osin ATPase and reduces cardiac contractility, is under tumor necrosis factor α, transforming growth factor β,
investigation in patients with obstructive HCM [109]. and interleukins (ILs), such as IL-1, IL-4, IL-6, IL-8, and
PIONEER-HCM (NCT02842242) is a phase 2 trial of ma- IL-18, are involved in the development of various in-
vacamten. In a pilot study performed in 11 patients with flammatory cardiac pathologies. There have been many
symptomatic obstructive HCM, significant decreases clinical trials to improve cardiac pathology by blocking
in both post-exercise peak and resting LV outflow tract these cytokines, but most have failed to demonstrate
gradient were observed in patients with mavacamten clinical efficacy [114].
treatment [110]. With these positive results, a phase Anti-inflammatory therapy using canakinumab, a
3 study of EXPLORER-HCM is currently underway monoclonal antibody targeting IL-1β, led to a signifi-
(NCT03470545). cantly lower rate of recurrent cardiovascular events in
In contrast to mavacamten, omecamtiv mecarbil (OM) patients with previous MI compared to placebo. Howev-
is a selective cardiac myosin activator that increases er, because canakinumab caused serious infectious com-
myocardial systolic function. When administered to plications, the all-cause mortality rate was not different
patients with AHF, the clinical effect of OM in relieving from the placebo group (Canakinumab Anti-inflamma-
dyspnea was not clear (Acute Treatment With Omecam- tory Thrombosis Outcome Study [CANTOS] trial) [66].
tiv Mecarbil to Increase Contractility in Acute Heart The IL-1 receptor antagonist, anakinra, is another po-
Failure [ATOMIC-AHF]) [111]. However, patients with tential candidate for anti-inflammatory therapy. Admin-
chronic HF showed positive results after OM treatment istration of anakinra showed improvement of peak VO2
with increased cardiac function, decreased ventricular in recently decompensated systolic HF patients (Recently
dimension, and decreased serum NT-proBNP level Decompensated Heart Failure Anakinra Response Trial
(Chronic Oral Study of Myosin Activation to Increase [REDHART]) [115], but did not lead to changes in HF-
Contractility in Heart Failure [COSMIC-HF]) [112]. pEF patients (Decompensated Heart Failure Anakinra
The Global Approach to Lowering Adverse Cardiac Response Trial 2 [DHART2]) [116]. It is unclear whether
Outcomes Through Improving Contractility in Heart anakinra is effective in preventing cardiac remodeling
Failure (GALACTIC-HF; NCT02929329) trial is current- after acute MI, but a multicenter, double-blind place-
ly underway to determine the clinical role of OM in bo-controlled clinical trial is currently underway (Vir-
comparison with placebo when added to current HF ginia Commonwealth University-Anakinra Remodeling
standard medication in patients with chronic HF [113]. Trial 3 [VCU-ART3] trial; NCT01950299) [117].
The Transthyretin Amyloidosis Cardiomyopathy
Clinical Trial (ATTR-ACT) showed remarkable results Gene therapy
in transthyretin amyloid cardiomyopathy. Fibrillogene- Cardiac gene therapy, involving the production of
sis in amyloid cardiomyopathy occurs when the tetram- proteins with curative efficacy by transferring specific
eric structure of the transthyretin protein dissociates exogenous genes, was proposed as an important alter-
into intermediates, which misassemble into amyloid native therapeutic approach [118]. The major targets of
fibrils. Tafamidis binds to the thyroxine-binding sites gene therapy are the β-adrenergic system, angiogenesis,
of transthyretin with high affinity and selectivity, and cytoprotection, and stem cell homing, among which re-
inhibits dissociation of tetramers into monomers. In search on Ca2+ cycling protein is a representative proj-
this multicenter, double-blind RCT, tafamidis showed ect. The sarcoplasmic/endoplasmic reticulum Ca2+-AT-
reductions in all-cause mortality and cardiovascular-re- Pase (SERCA2a) regulates the contraction and relaxation
lated hospitalization rates and reduced the decline in of myocardial cells by transporting calcium into the
functional capacity compared with placebo [68]. sarcoplasmic reticulum from the cytosol. Regardless of
the etiology, it has been demonstrated that SERCA2a is
deficient in experimental models of HF, and correction neering technology to improve the therapeutic effects
of SERCA2a deficiency can improve calcium influx and of hPSC-derived cardiomyocytes have improved over
cardiac function. However, a recent study showed that the past several decades. However, cellular heterogene-
administration of SERCA2a does not improve the clin- ity, immaturity, arrhythmogenicity, and tumorigenicity
ical course of HFrEF patients [119]. Despite disappoint- are problems that remain to be resolved [123].
ing results, gene therapy still has potential and further
studies are required. One of the major obstacles to gene
therapy is the delivery method of the therapeutic mate- DEVICES AND NON-SURGICAL
rials into the target cells. As intravenous injection did INTERVENTIONS
not show sufficient effect to transduce the myocardi-
um, intracoronary injection, myocardial injection, and Implantable cardioverter-defibrillator & cardiac
pericardial injection have been suggested according to resynchronization therapy
the condition of the patient, the type of vector, and the Many pioneering landmark trials from the 1990s have
target gene. Further advances in vectors and delivery confirmed the efficacy of implantable cardioverter-de-
methods will be essential for the clinical application of fibrillator (ICD) and cardiac resynchronization therapy
gene therapy [120]. (CRT) for improving cardiovascular outcome in HF pa-
tients (Table 1, Fig. 3). Current ESC guidelines generally
Stem cell therapy suggest ICD for primary prevention in symptomatic
As there is no alternative way to regenerate or replace HF patients with LVEF ≤ 35%, despite > 3 months of op-
damaged cardiomyocytes, there has been a great deal of timal medical therapy [1]. The detailed indications are
interest in the development of stem cell therapy [121]. slightly different according to the specific cardiomyop-
Numerous studies yielded optimistic results using athy in patients (Table 2) [1,124,125]. For example, HCM
stem cells to improve myocardial function and ventric- with a high risk of sudden cardiac death, dilated cardio-
ular remodeling, but the results were inconsistent [122]. myopathy due to lamin A/C (LMNA) mutation, cardiac
Human pluripotent stem cells (hPSCs) have emerged to sarcoidosis with unexplained syncope, or myocardial
replace embryonic stem cells, which maintain the sim- scarring seen on CMR, are indications for ICD regard-
ilarity to embryonic stem cells but without the ethical less of LVEF [126]. However, the Danish Study to Assess
issues or risks of rejection [123]. The efficiency of differ- the Efficacy of ICDs in Patients with Non-ischemic Sys-
entiation from hPSCs to cardiomyocytes and bioengi- tolic Heart Failure on Mortality (DANISH) trial, which
Table 2. Current class I indications of cardiac implantable electronic devices in patients with heart failure
ICD for secondary
ICD for primary prevention CRT
prevention
ACC/AHA (2013) NIDCM or ICM at least 40 days post-MI on Sinus rhythm with LVEF ≤ 35% on
[125] chronic GDMT with (1) LVEF ≤ 35% and GDMT and LBBB with QRSd ≥ 150
NYHA class II or III symptom (I-A) or (2) ms and NYHA class III (I-A) or am-
LVEF ≤ 30% and NYHA class I symptom (I-B) bulatory IV (I-A) or II (I-B)
ESC (2016) [1] Recovery from ven- Symptomatic HF (NYHA II–III) with LVEF ≤ Symptomatic HF with sinus rhythm
tricular arrhythmia 35% despite ≥ 3 months of OMT in ICM (IA) or and LVEF ≤ 35% despite OMT with
with hemodynamic NIDCM (IB) LBBB with QRSd ≥ 150 ms (I-A) or
instability (IA) 130–149 ms (I-B)
ICD, implantable cardioverter-defibrillator; CRT, cardiac resynchronization therapy; ACC/AHA, American College of
Cardiology/American Heart Association; NIDCM, nonischemic dilated cardiomyopathy; ICM, ischemic cardiomyopathy; MI,
myocardial infarction; GDMT, goal-directed medical therapy; LVEF, left ventricular ejection fraction; NYHA, New York Heart
Association; LBBB, left bundle branch block; QRSd, QRS duration; ESC, European Society of Cardiology; HF, heart failure;
OMT, optimal medical therapy.
1,500 Lead Placement to Guide Cardiac Resynchronization

ICD CRT-P + CRT-D Therapy (TARGET) study, 220 patients were randomly
assigned to two groups with or without targeted LV
1,000 lead deployment using speckle-tracking 2-dimensional
Annual number
radial strain measured by transthoracic echocardiog-

raphy. The targeted LV lead placement group showed
500 a higher portion of CRT responders and lower rate of
combined endpoint compared with the control group
[129]. The combination of multimodality imaging, in-
0
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 cluding nuclear imaging and radial strain, demonstrat-
Year ed a higher response rate compared with the control
group, but the clinical outcomes were similar between
Figure 4. Temporal trends of cardiac implantable electronic
device implantation in Korea. ICD, implantable cardiovert- the two groups [130].
er-defibrillator; CRT-P, cardiac resynchronization therapy
without def ibrillator; CRT-D, cardiac resynchronization Role of AF ablation in HF
therapy with defibrillator.
AF is the most common type of arrhythmia in HF
populations, and it can cause deterioration of LV func-
tion as well as symptoms of HF [131]. Rate control and
included 1,116 nonischemic cardiomyopathy patients, anticoagulation are the mainstays of AF treatment.
showed no mortality benefit with prophylactic ICD im- The 2016 ESC guidelines specify that a rhythm con-
plantation [75], which reflects the different risk of sud- trol strategy using amiodarone or AF ablation may be
den cardiac death in nonischemic cardiomyopathy and considered in chronic AF patients with HFrEF who are
ischemic cardiomyopathy. However, as more than half symptomatic despite optimal medical therapy (Class
of the patients received optimal medical therapy and IIb) [1]. However, a recently published RCT showed a
CRT in both groups, this may have influenced the lack beneficial effect of AF ablation in HFrEF patients com-
of significant results associated with prophylactic ICD. pared with pharmacological control (Catheter Ablation
Therefore, the role of prophylactic ICD implantation to for Atrial Fibrillation with Heart Failure [CASTLE-AF]
reduce mortality in HF patients may be reestablished trial). In this RCT, patients who received AF ablation
with the further development of HF therapy. The ap- therapy showed lower rates of all-cause mortality, wors-
plication of wearable ICD in patients with recent MI ening or hospitalization for HF, and cardiovascular
and LVEF ≤ 35% did not show significant differences death after about 3 years [132]. Another RCT (Ablation
compared with GDMT, with regard to rates of sudden versus Amiodarone for Treatment of Atrial Fibrilla-
death or death from ventricular tachyarrhythmia at 90 tion in Patients With Congestive Heart Failure and an
days [76]. Implanted ICD/CRTD [AATAC] trial) showed that AF
The generally accepted class I indications for CRT are ablation was superior to amiodarone treatment with
restricted to symptomatic patients with LVEF ≤ 35%, regard to maintenance of sinus rhythm, unplanned
despite optimal medical therapy, who have left bundle hospitalization, and mortality [133]. However, the CAS-
branch block and QRS duration ≥ 130 ms [127]. In Ko- TLE-AF trial included a highly selected population (398
rea, there has been a rapid increase in the implantation of 3,013 screened patients), and a beneficial effect of AF
of cardiac implantable electronic devices (Fig. 4). ablation was observed in patients with young age (< 65
Recent studies have focused on determining ways years), NYHA functional class II, LVEF ≥ 25%, and with-
to achieve a high response rate in patients with CRT out diabetes [132]. The results of the Catheter Ablation
implants. Based on LGE detected by CMR, which can Versus Anti-arrhythmic Drug Therapy for Atrial Fibril-
directly visualize myocardial scarring, patients receiv- lation (CABANA) trial (NCT00911508), which enrolled
ing LV lead placement away from LGE showed better 2,204 patients ≥ 65 years or with more than one risk
clinical outcome [128]. In the Targeted Left Ventricular factor for stroke, did not show a beneficial effect of AF
ablation in patients with high risk of stroke. The com- lower rate of clinical composite endpoint was observed
posite primary endpoints consisting of death, disabling in the telemonitoring group at 1 year [138]. Remote
stroke, serious bleeding, or cardiac arrest at 5 years were monitoring also decreased the time to clinical decision
similar between ablation and drug therapy groups (haz- and the length of hospital stay for cardiovascular hospi-
ard ratio, 0.86; 95% confidence interval, 0.65 to 1.15 for talization in the Clinical Evaluation of Remote Notifica-
intention-to-treat analysis) [134]. If a patient has HF and tion to Reduce Time to Clinical Decision (CONNECT)
symptomatic AF but is not a candidate for AF ablation trial [139]. However, a meta-analysis including nine
or has failed to respond to this treatment, atrioventric- RCTs of remote monitoring showed no additional ben-
ular junction ablation followed by CRT may be a useful efit with regard to survival or patient safety [140].
treatment option. Despite the small size of the study The diagnostics included in implantable devices
population, the Ablate and Pace in Atrial Fibrillation show good predictive capability for impending HF
plus Cardiac Resynchronization Therapy (APAF-CRT) decompensation using device-specific algorithms,
trial showed a decreased rate of hospitalization for HF such as OptiVol (Medtronic, Minneapolis, MN, USA)
and improved quality of life in patients undergoing [141]. However, the OptiLink HF study did not show a
atrioventricular junction ablation and CRT [135]. significant difference in mortality according to alerts
regarding changes in intrathoracic impedance reflect-
Remote monitoring ing patients’ fluid status [142]. The Multisensor Chronic
Remote monitoring has become one of the most active Evaluation in Ambulatory Heart Failure Patients (Mul-
fields in the management of HF. Due to the importance tiSENSE) study showed that HeartLogic multisensory
of volume status in HF patients, there have been efforts index and alert algorithm (Boston Scientific, Marlbor-
to estimate and use hemodynamics as a guide for treat- ough, MA, USA) can be a good predictor of HF decom-
ment. The CardioMEMS (St. Jude Medical, St. Paul, MN, pensation [143]. Based on these findings, the Multiple
USA) Heart Sensor Allows Monitoring of Pressure to Cardiac Sensors for Management of Heart Failure
Improve Outcomes in NYHA Class III Heart Failure Pa- (MANAGE-HF) trial in which patients were randomized
tients (CHAMPION) trial, a prospective RCT enrolling according to whether HeartLogic alerts were turned
550 symptomatic patients with chronic HF regardless on or off is currently ongoing (NCT03237858). As meth-
of LVEF, showed that hemodynamic monitoring with a odologies for remote monitoring using implantable
wireless implantable pulmonary artery pressure moni- devices can be extended, we expect better results in the
toring system (CardioMEMS) could significantly reduce near future.
HF hospitalization rate [136]. In the subgroup of 445
HFrEF patients on GDMT in the CHAMPION study, Percutaneous correction of functional mitral
pulmonary artery pressure-guided management also re- regurgitation
duced HF hospitalization and mortality rates [137]. Based Functional or secondary mitral regurgitation (MR),
on the previous results, CardioMEMS was approved by frequently accompanied by HFrEF, is a meaningful
the U.S. Food and Drug Administration in 2014 and was predictor of mortality after adjusting for clinical, echo-
included in the 2016 European guideline (Class IIb) [1]. cardiographic, or laboratory variables [144]. However,
Large amounts of information are available from pa- surgical treatment of moderate ischemic MR in addi-
tients with a preexisting cardiac implantable electronic tion to coronary artery bypass surgery failed to show LV
device, including heart rate, lead profile, battery status reverse remodeling and mortality improvement [145].
and arrhythmic events. In the INfluence of home mon- As the benefit of surgery for functional MR is question-
iToring on mortality and morbidity in heart failure able, the American guidelines for valvular heart disease
patients with IMpaired lEft ventricular function (IN- published in 2014 recommended mitral valve surgery
TIME) trial, without the need for additional invasive for secondary MR only in patients with symptomatic
procedures, 664 patients with LVEF ≤ 35% implanted severe MR or moderate MR undergoing other cardiac
with ICD or CRT were randomized into two groups surgery [146]. Percutaneous approaches to correct sec-
with or without telemonitoring, and a significantly ondary MR in HF patients are actively studied because
the devices for percutaneous treatment of MR have nificantly reduced post-exercise pulmonary capillary
been advanced throughout repair, annuloplasty, and re- wedge pressure at 1 month [153] and showed similar
placement of the mitral valve [147], and the surgical risk safety outcome at 1 year [154]. As autonomic imbalance
of HFrEF combined with MR is high. A recent RCT for is important in the pathophysiology of HF, vagus nerve
severe secondary MR comparing percutaneous mitral stimulation is thought to be a potential treatment tar-
valve repair using MitraClip with medical therapy ver- get [155]. Recent phase II (NEural Cardiac TherApy foR
sus medical therapy alone (Percutaneous Repair with Heart Failure [NECTAR-HF]) [156,157] and phase III
the MitraClip Device for Severe Functional/Secondary RCTs (Increase of Vagal Tone in Heart Failure (INO-
Mitral Regurgitation [MITRA-FR]) showed similar mor- VATE-HF) [158] for symptomatic HF with LV dysfunc-
tality and HF hospitalization rates [148]. On the other tion reported results of vagus nerve stimulation but
hand, in the Cardiovascular Outcomes Assessment of failed to show significant decreases in LV end-systolic
the MitraClip Percutaneous Therapy for Heart Failure diameter or improvement of clinical outcomes.
Patients with Functional Mitral Regurgitation (COAPT) Although renal denervation has been suggested as an
trial performed in 614 symptomatic patients with HF alternative treatment option for resistant hypertension,
and moderate-to-severe secondary MR despite maximal the results of RCTs were disappointing [159,160]. How-
medical therapy, the addition of percutaneous mitral ever, another RCT indicated the possibility of revival.
repair with MitraClip to medical therapy was associat- In the Renal Denervation With the Symplicity Spyral™
ed with lower rates of HF hospitalization and all-cause Multi-electrode Renal Denervation System in Patients
mortality than medical therapy alone within 2 years of With Uncontrolled Hypertension in the Absence of An-
follow-up [149]. tihypertensive Medications (SPYRAL HTN-OFF MED)
Other percutaneous approaches to improve the out- trial, the renal denervation group showed a decrease of
comes of functional MR are also under investigation. about 5 mmHg in systolic and diastolic blood pressure
The outcomes with the Cardioband system, a device with 24-hour ambulatory blood pressure monitoring
for percutaneous mitral annuloplasty, were reported after 3 months, while the sham group showed no signif-
recently. Most patients showed moderate or less re- icant changes in blood pressure [161]. Two new RCTs for
sidual MR and improved symptoms at 1 year [150]. The renal denervation have recently begun: endovascular ul-
Annular ReduCtion for Transcatheter Treatment of trasound renal denervation to treat hypertension (RADI-
Insufficient Mitral ValvE (ACTIVE) randomized trial is ANCE-HTN SOLO; NCT02649426) and SPYRAL HTN-
recruiting patients to evaluate the efficacy of the Car- ON MED (NCT02439775). As hypertension is one of the
dioband system along with optimal medical therapy most important etiologies of HF, renal denervation may
(NCT03016975). Various devices for percutaneous mitral be a promising technology if these trials succeed.
valve replacement are also under investigation but are
still at the level of early feasibility studies at present
[151,152]. Moreover, Neochord, which was developed for MECHANICAL CIRCULATORY SUPPORT AND
transapical repair of MR with artificial chordae, is also HEART TRANSPLANTATION
the subject of an RCT in comparison with surgical mi-
tral valve repair in degenerative MR (NCT02803957). Mechanical circulatory support
Left ventricular assist devices (LVAD) are rapidly being
Other interventions: inter-atrial shunting, vagus adopted for advanced HF treatment. These devices were
nerve stimulation, and others initially used as a bridge to transplantation, but are now
Several forward-looking device therapies are under de- also commonly used as destination therapy. Advances
velopment. The Reduce Elevated Left Atrial Pressure in in mechanical technology and surgical techniques have
Patients With Heart Failure (REDUCE LAP-HF) I study greatly increased the success rate and duration of ven-
is a phase II RCT of an interatrial shunt in symptomat- tricular assist devices. The HeartWare ventricular assist
ic HF patients with LVEF ≥ 40% and elevated exercise device (HVAD), which is a commercial LVAD using a
pulmonary capillary wedge pressure. The device sig- centrifugal heart pump, showed a non-inferior outcome
control play important roles in reducing the incidence

Bleeding
15%
Drive-line
20% of stroke [163]. There have also been improvements in
infection
Adverse events of HVAD at 2 years
(surgical)
minimally invasive techniques to reduce surgical com-
GI
plications (Fig. 5) [164].
35% Sepsis 24%
bleeding Heartmate II, another LVAD, also showed acceptable
clinical outcomes and safety for destination therapy
Right heart Renal [84] as well as use as a bridge to transplantation [83].
39% 15%
failure failure
The newly developed Heartmate 3 is equipped with a
Pump fully magnetically levitated centrifugal flow pump, and
Stroke 30% 6.4%
thrombosis
showed a survival rate of 77.9% without serious compli-
cations at 2 years after device implantation (Multicenter
Bleeding
12%
Drive-line
24%
Study of MagLev Technology in Patients Undergoing
Adverse events of HM 3 at 2 years
(surgical) infection
Mechanical Circulatory Support Therapy with Heart-
Mate 3 [MOMENTUM 3]) [165]. This is an improvement
GI
27% Sepsis 14%
bleeding compared with 56.4% for the previous version, Heart-
mate II. Although the survival rate is improving, many
Right heart 32%
Renal
13% patients with Heartmate 3 implants still experience a
failure failure
range of complications, including bleeding, infection,
Pump stroke, right HF, and arrhythmias (Fig. 5) [86,165].
Stroke 10% thrombosis 1.1%
SynCardia, a sole total artificial heart (TAH) approved
by the U.S. Food and Drug Administration, provides
Figure 5. Adverse events of left ventricular assist devices. the most definitive treatment options for patients with
The data of HeartWare ventricular assist device (HVAD) and biventricular failure who are not candidates for isolated
Heartmate 3 (HM 3) were quoted from different clinical tri-
als, so direct comparison of adverse event rates is inappro- LVAD placement [166]. The SynCardia system has re-
priate. GI, gastrointestinal. cently developed a smaller 50 cc TAH that was designed
to accommodate patients with low body surface area.
This technical improvement should allow the device to
in comparison with Heartmate II (The HeartWare™ be implanted in women and children, and it might be
Ventricular Assist System as Destination Therapy of particularly useful in growing adolescents with palliat-
Advanced Heart Failure [ENDURANCE]) [85]. This de- ed congenital heart disease [167].
vice is highly miniaturized to facilitate minimally in-
vasive surgery and reduce surgical complications [162]. Heart transplantation
HVAD showed good clinical outcome and safety in Heart transplantation (HT) has become the standard
the real-world registry data. Follow-up of 254 patients treatment for selected patients with end-stage HF.
in a multicenter prospective registry study of patients Improvements in immunosuppressants, donor pro-
transplanted with HVAD revealed a mean duration of curement, surgical techniques, and post-HT care have
support of 363 ± 280 days and success rates of 87% at 6 resulted in a substantial decrease in the incidence of
months, 85% at 1 year, and 73% at 3 years (post-market acute allograft rejection, which had previously sig-
Registry to Evaluate the HeartWare Left Ventricular nificantly limited survival of HT recipients. However,
Assist System [ReVOLVE] study). During the follow-up there are limitations to long-term allograft survival,
period, 17% of the patients died, and the most common including rejection, infection, coronary allograft vas-
adverse event was bleeding (28%). In particular, the rel- culopathy, and malignancy (Fig. 6). Careful balance of
atively high incidence of cerebrovascular accidents after immunosuppressive therapy and vigilant surveillance
HVAD implantation in previous studies was reduced for complications can further improve long-term out-
to acceptable levels in the ReVOLVE study. Vigorous comes of HT recipients. Most transplant recipients
anticoagulation therapy and adequate blood pressure have been treated with a combination of a calcineurin
dd-cfDNA could increase up to 5-fold from the baseline

Adverse events of HT < 1 year
Acute
Infection 30% rejection 5% value in the blood [171]. The dd-cfDNA is a potential
candidate as a noninvasive tool for diagnosis of graft
Graft
20% CAV 2% rejection, as the degree of dd-cfDNA elevation has been
failure
shown to be correlated with acute cellular rejection
events, as determined by endomyocardial biopsy in ear-
MOF 20% Renal 2%
failure ly studies [172].
Expanding the donor pool

Adverse events of HT > 5 years
Cancer 25% CAV 10% As the number of the donors is very small compared
to patients requiring HT, there have been continuing
Graft efforts to expand the donor pool. To maximize the
failure 20% MOF 10%
number of patients receiving HT, some transplantation
centers now use extended criteria donor (ECD) hearts
Renal
Infection 15% failure 10% in high-risk recipients, and the outcomes seem to be
acceptable. The general characteristics of ECD hearts
are as follows: age > 50 years, female donor, heart from
Figure 6. Adverse events of heart transplantation: within 1 patients with cardiovascular death, hypertension, diabe-
year and after 5 years. HT, heart transplantation; MOF,
multi-organ failure; CAV, cardiac allograft vasculopathy. tes, elevation of cardiac troponin, LV systolic dysfunc-
tion (LVEF < 50%), and regional wall motion abnormal-
ities. Moreover, the criteria for high-risk recipients are
inhibitor, mycophenolate mofetil, and steroids [168]. as follows: age > 65 years, renal insufficiency, peripheral
To monitor the effects of immunosuppressive drugs artery disease, or poorly controlled diabetes. The ECD
and adjust the dose, physicians check the serum con- program has had little impact on the outcome of trans-
centration of immunosuppressant. However, the serum planted patients and seems to accomplish the purpose
concentration does not accurately reflect the degree of expanding the donor pool [173].
of immunosuppression in a specific patient. Immune The concept of donation after circulatory death (DCD)
monitoring assay (Immuknow, Cylex, Columbia, MD, was introduced as part of the efforts to expand the do-
USA), a peripheral blood test, helps physicians to deter- nor pool. To minimize the damage due to ischemic
mine the degree of immunosuppression in patients by time in DCD organs, trials to utilize ex vivo perfusion
measuring the amount of ATP released from activated systems were performed. The ex vivo heart perfusion
lymphocytes [169]. In a study to determine the efficacy system maintains the heart in a beating and metabol-
of immune monitoring assay, patients with infectious ically active state by supplying warm, oxygenated, and
complications had a low immune monitoring score, nutrient-enriched donor blood. Recently, ex vivo per-
and some patients with rejection had a high score [170]. fusion systems have been reported to show non-inferi-
Further large-scale studies with more sophisticated ority with regard to outcome compared with standard
measurements of immune monitoring methods are cold storage methods, and further trials are currently
needed to achieve personalized immunosuppression. underway [89].
Rejection diagnostic methods

Donor-derived cell-free DNA (dd-cfDNA) is an emerg- ACUTE HEART FAILURE
ing noninvasive tool for diagnosis of rejection. The
dd-cfDNA is detectable in both blood and urine of AHF refers to rapid onset or worsening of symptoms
transplant recipients. After transplantation, dd-cfDNA and/or signs of HF. It is a life-threatening medical
rises to > 5% of total cfDNA and decreases sequentially condition requiring urgent evaluation and treatment,
to < 0.5% within 1 week. When a rejection event occurs, typically leading to urgent hospital admission [1]. The
Table 3. Clinical characteristics and outcomes of acute heart failure registry
AHEAD Main
Characteristic KorAHF [46] KorHF [175] ATTEND [176] ADHERE [177] OPTIMIZE-HF [178] EHFS II [179]
[180,181]
Region Korea Korea Japan USA USA Europe Czech
Recruitment period Mar 2011– Jun 2004– Apr 2007– Sep 2001– Mar 2003– Oct 2004– Sep 2006–
Feb 2014 2009 Apr Dec 2011 Jan 2004 Dec 2004 Aug 2005 Oct 2009
No. of patients 5,625 3,200 4,842 159,168 48,612 3,580 4,153
Follow-up 5 years 5 years 180 day NA 60, 90 day 3, 12 months 20 months (median)
(median 2.2 years)
Demographics
Age, yr, mean ± SD 69 ± 15 68 ± 14 73 ± 14 72 ± 14 73 ± 14 70 ± 13 72 ± 12
Male sex, % 53 50 58 48 48 61 60
Co-morbidities, %
Hypertension 62 47 69 74 71 63 73
Diabetes 40 31 34 44 42 33 43
Atrial fibrillation 29 NA 36 31 31 39 27
Chronic lung disease 11 4 10 31 28 19 NA
Etiology, %
Ischemic 38 52 31 58 46 54 56
Hypertensive 4 NA 18 NA 23 11c 4
Clinical status on
admission
De novo HF, % 52 70 64 24 12 37 58
Lung congestion, % 79 (edema) NA 71 (rale) 75 (edema) 64 (rale) NA 18 (edema)
Pulse rate, /min, 93 ± 26 92 ± 26 99 ± 29 NA 87 ± 22 95 (median) 90 (median)
mean ± SD
SBP, mmHg, mean ± SD 131 ± 30 131 ± 30 146 ± 37 144 ± 33 143 ± 33 135 (median) 135 (median)
LVEF < 40%, % 55 74 (EF < 50%) 53 51 49 66 (EF < 45%) 38 (EF < 30%)
Creatinine, mg/dL, mean 1.5 ± 1.5 1.5 ± 1.2 1.4 ± 1.6 1.8 ± 1.6 1.8 ± 1.6 NA 1.2 (median)
± SD
Pharmachologic treatment
IV diuretics 75 68 76 87 NA 84 84
www.kjim.org
IV inotropes 31 22 19 8 7 < 29.8 NA
IV vasodilators 41 36 78 9 14 31 19
31
not available; SD, standard deviation; HF, heart failure; SBP, systolic blood pressure; LVEF, left ventricular ejection fraction; EF, ejection fraction; IV, intravenous; ACEI,
KorAHF, Korean Acute Heart Failure; KorHF, Korean Heart Failure; ATTEND, Acute Decompensated Heart Failure Syndromes registry; ADHERE, Acute Heart Failure
Database; OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure; EHFS II, EuroHeart Failure Survey II; NA,
outcome of hospitalized HF patients in Korea has
shown a modest improving trend over time, although
AHEAD Main
[180,181]
treatment of AHF has not changed for several decades
20.3
12.7
35.5
69
77
57
7
[3]. Clinical characteristics and outcomes of AHF reg-
istry according to different countries are summarized
in Table 3 [46,174-181]. Many novel drugs have shown
no clinical improvement [1]. This is because AHF syn-
drome is an event in the context of underlying HF, and
EHFS II [179]
NA
not a disease entity per se [182]. Notably, the mid- or
NA
6.7
80
48
61
long-term outcome of AHF may not depend on treat-

ment at the acute stage, but on the underlying disease
status causing decompensation [46,183]. In addition, the
classification of AHF is not clear [184-187]. Inadequate
ATTEND [176] ADHERE [177] OPTIMIZE-HF [178]
phenotyping is also responsible for the failure of treat-

ments to improve outcomes in AHF. In this section, we
NA
NA
NA
NA
NA
3.8
4
focus on new treatment strategies and the attempt to

reduce readmission to hospital (Table 4).
angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AA, aldosterone antagonist.
Diuretics are the mainstay of pharmacological treat-

ment in AHF to improve symptoms [188]. Recently, the
time-to-diuretics concept was proposed for AHF. A
NA
NA
3.8
4.3
80
83
33
large prospective observational study showed a lower

rate of in-hospital mortality in patients with door-to-di-
uretics time < 1 hour [189]. In contrast, another obser-
vational study failed to show any associations between
clinical outcomes and short door-to-diuretics time
NA
NA
NA
6.4
67
21
77
[190]. Newly developed intravenous vasodilators failed

to improve outcomes in AHF. Nesiritide, recombinant
BNP with a vasodilating effect, did not show improve-
ment in dyspnea and in death or rehospitalization but
KorHF [175]
showed a significantly higher rate of hypotension in the

NA
6.4
26
59
54
53
15
Acute Study of Clinical Effectiveness of Nesiritide in

Decompensated Heart Failure (ASCEND HF) RCT [191].
Serelaxin, i.e., recombinant human relaxin-2, improved
dyspnea and 180-day mortality rate in the RELAXin in
KorAHF [46]
acute heart failure (RELAX-AHF) randomized trial [192],

18.2
34.7
4.8
66
50
45
but did not show consistent results in the subsequent

RELAX-AHF-2 study (NCT01870778) [193]. Ularitide did
not improve clinical outcomes in the Trial of Ularitide
Efficacy and Safety in Acute Heart Failure (TRUE-AHF)
In-hospital mortality, %
trial [194]. The inodilator, levosimendan, was associated

with reduction of short- and long-term mortality rates
Length of stay, day
Table 3. Continued
3-yr mortality, %
1-yr mortality, %
compared with placebo in LV dysfunction patients with

Characteristic
ACEIs/ARBs
acute MI [195]. However, there was no mortality benefit

β-Blockers
(median)
of levosimendan in comparison with dobutamine [196].

Outcomes
Recently, the PIONEER-HF study showed encourag-

AAs
ing results in HFrEF patients who were hospitalized
Table 4. Recent evidence regarding mortality in treatment of acute heart failure

Topic Study Year Author No. Intervention Comparator Finding
Diuretics REALITY- 2017 Matsue 1,291 Door to NA Early treatment with IV loop
AHF et al. [189] diuretics time (prospective diuretics (< 60 min) was
cohort) associated with lower in-
hospital mortality.
KorAHF 2018 Park et al. 5,625 Door to NA Door to diuretics time was
[190] diuretics time (prospective not associated with clinical
cohort) outcome.
EVEREST 2017 Konstam 4,133 Tolvaptan Placebo Tolvaptan did not show benefit
et al. [99] in long-term mortality and
composite of cardiovascular
death and HF hospitalization.
Vasodilators ASCEND-HF 2011 O'Connor 7,141 Nesiritide Placebo Nesiritide was not associated
et al. [191] with change of HF
rehospitalization and death
within 30 days.
RELAX-AHF 2013 Teerlink 1,161 Serelaxin Placebo Serelaxin was associated with
et al. [192] dyspnea relief and decrease in
180-day mortality.
RELAX-AHF-2 2017 Abstract 6,545 Serelaxin Placebo Serelaxin did not showed
[193] significant difference in
180-day all-cause and
cardiovascular mortality.
TRUE-AHF 2017 Packer 2,157 Ulraritide Placebo Ularitide did not showed
et al. [194] significant difference in
cardiovascular death at
a median follow-up of 15
months.
Inodilator RUSSLAN 2002 Moiseyev 504 Levosimendan Placebo Levosimendan was associated
et al. [195] with reduction in 14- and 180-
day mortality in patients with
LV dysfunction due to AMI.
SURVIVE 2007 Mebazaa 1,327 Levosimendan Dobutamine Levosimendan did not
et al. [196] significantly reduce all-cause
mortality at 180 days.
REALITY-AHF, Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure;
NA, not available; IV, intravenous; KorAHF, Korean Acute Heart Failure; EVEREST, Efficacy of Vasopressin Antagonism
in Heart Failure Outcome Study With Tolvaptan; HF, heart failure; ASCEND-HF, Acute Study of Clinical Effectiveness of
Nesiritide in Decompensated Heart Failure; RELAX-AHF, Trial of RELAXin in Acute Heart Failure; TRUE-AHF, Ularitide
Efficacy and Safety in Acute Heart Failure; RUSSLAN, Randomised stUdy on Safety and effectivenesS of Levosimendan in
patients with left ventricular failure due to an Acute myocardial iNfarct; LV, left ventricle; AMI, acute myocardial infarction;
SURVIVE, Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support.
for acute decompensated HF. The initiation of sacu- lemia, and angioedema [197]. However, the role of ARNI
bitril-valsartan therapy led to a greater reduction of in AHF should be verified in larger prospective study.
NT-proBNP concentration than enalapril therapy, with As outlined above, the treatment strategy for AHF
no significant difference in rate of adverse events, such has not changed markedly over the last several years.
as deteriorating renal function, hypotension, hyperka- However, the rate of readmission after an AHF episode
is consistently high, reaching 20% and 50% at 1 and 6 been studied to improve clinical outcome in terms of
months after discharge, respectively [198]. To reduce mortality and quality of life in HF patients. Although
the healthcare costs associated with AHF, the hospital few studies showed encouraging results, researchers are
readmission reduction program was introduced in the attempting to find subgroups in whom certain medica-
USA, which awarded a penalty to hospitals with high tions or devices could be most effective, new methods
30-day readmission rates. However, the results have for better diagnosis and prediction of prognosis in HF
been disappointing. The 30-day and 1-year readmission patients, and new tools for treating HF.
rates decreased, while the mortality rate tended to in-
crease [199]. In addition, the quality of care and clinical Conflict of interest
outcome were similar between hospitals with high and No potential conflict of interest relevant to this article
low risk-adjusted 30-day HF readmission rates [200], was reported.
and the mortality rate was lower in the higher hospi-
tal-level 30-day episode payment [201]. It is possible that Acknowledgments
some hospitals attempted to improve the index rather This study was supported by Basic Science Research
than the true outcome by adopting methods, such as Program through the National Research Foundation of
increased admission period, delaying readmission af- Korea (NRF) funded by the Ministry of Science, ICT &
ter 30 days, etc., resulting in an unintended increase in Future Planning (NRF-2018R1C1B6005448). The funders
mortality rate [202]. Remote monitoring mentioned in had no role in study design, data collection and anal-
the previous section can be utilized for the early detec- ysis, decision to publish, or preparation of the manu-
tion of deterioration and the prevention of readmission script.
in AHF patients. The authors express sincere gratitude to all mem-
bers of Korean Society of Heart Failure, which is the
Korea’s leading academic organization dedicated to the
DIGITAL HEALTHCARE IN HEART FAILURE study of heart failure since 2003. For critical sugges-
tions, discussion and manuscript review, we thank Sang
Digital healthcare has received much attention recently. Eun Lee, Sung-Ho Jung, Jae-Joong Kim (Asan Medical
As the amounts of information from diverse sources, Center), Sang-Hyun Ihm (Bucheon St. Mary's Hospi-
such as electronic medical records, wearable devices, tal), Jae Yeong Cho, Kye Hun Kim (Chonnam National
and genomic data, are increasing rapidly, artificial in- University Hospital), Ju-Hee Lee, Kyung-Kuk Hwang,
telligence and machine learning are essential to collect, Myeong-Chan Cho (Chungbuk National University
manage, and apply these data appropriately [203]. Ah- Hospital), Jae-Hyeong Park, Jin-Ok Jeong (Chungnam
mad et al. [204] reported that machine learning could National University Hospital), Kyung-Jin Kim (Ewha
improve prognostic prediction and phenotyping with Womans University Medical Center), Wook-Jin Chung,
different treatment responses in a large cohort of HF Mi-Seung Shin (Gachon University Gil Medical Cen-
patients. The use of artificial intelligence and clinical ter), Mi-Hyang Jung (Hallym University Chuncheon
decision support systems is not suitable for clinical Sacred Heart Hospital), Sun Ki Lee, Suk-Won Choi,
application. However, it may help physicians to make Seongwoo Han, Kyu-Hyung Ryu (Hallym University
decisions by organizing large amounts of data and Dongtan Sacred Heart Hospital), Sang-Ho Jo (Hallym
building delicate prognostic models in the near future. University Hallym Sacred Heart Hospital), Jae Hyuk
Choi (Hallym University Hangang Sacred Heart Hos-
pital), Dae-Gyun Park (Hallym University Kangdong
CONCLUSIONS Sacred Heart Hospital), Seonghoon Choi (Hallym Uni-
versity Kangnam Sacred Heart Hospital), In-Cheol Kim
HF is becoming an increasingly important disease (Keimyung University Dongsan Medical Center), Mi‐Na
entity with the aging of society. According to its in- Kim, Jaemin Shim, Seong-Mi Park (Korea University
creasing prevalence, many new drugs and devices have Anam Hospital), Eung Ju Kim (Korea University Guro
Hospital), Se Yong Jang, Dong Heon Yang, Shung Chull 8. Roberts E, Ludman AJ, Dworzynski K, et al. The diagnos-
Chae (Kyungpook National University Hospital), Hy- tic accuracy of the natriuretic peptides in heart failure:
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Hyun Choi (Pusan National University Hospital), Darae acute care setting. BMJ 2015;350:h910.
Kim, Yang Hyun Cho, Sung-Ji Park, Jin-Oh Choi, Eun- 9. SPRINT Research Group, Wright JT Jr, Williamson JD, et
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Korean J Intern Med 2019;34:11-43

Update on heart failure management and future

This paper was contributed by

INTRODUCTION DEFINITION, EPIDEMIOLOGY, AND

Copyright © 2019 The Korean Association of Internal Medicine pISSN 1226-3303

Figure 1. Global epidemiology of heart failure.

2.0 STRATEGIES TO PREVENT NEW-ONSET HEART

Strain imaging tion, poorer RV-GLS was an independent predictor of

Primary end- Important sec-

Primary end- Important sec-

1960–1969 1970–1979 1980–1983

Digoxin & Diuretics

1st HT 1st TAH Cyclosporin

1984 1986 1988 1990 1992 1994 1996 1998 2000

V-HeFT SOLVD USCP RALES

2002 2004 2006 2008 2010 2012 2014 2016 2018

CHARM SHIFT PARADIGM-HF EMPA-REG CANTOS

MADIT II DEFINITE SCD-HeFT REVERSE RAFT CANVAS ATTR-ACT

REMATCH mTOR HVAD BTT HMII DT SCHEDULE ENDURANCE

New drugs in specific cardiomyopathy fields Anti-inflammatory therapy

1,500 Lead Placement to Guide Cardiac Resynchronization

radial strain measured by transthoracic echocardiog-

control play important roles in reducing the incidence

dd-cfDNA could increase up to 5-fold from the baseline

Expanding the donor pool

Rejection diagnostic methods

treatment of AHF has not changed for several decades

long-term outcome of AHF may not depend on treat-

phenotyping is also responsible for the failure of treat-

focus on new treatment strategies and the attempt to

Diuretics are the mainstay of pharmacological treat-

large prospective observational study showed a lower

[190]. Newly developed intravenous vasodilators failed

showed a significantly higher rate of hypotension in the

Acute Study of Clinical Effectiveness of Nesiritide in

acute heart failure (RELAX-AHF) randomized trial [192],

but did not show consistent results in the subsequent

trial [194]. The inodilator, levosimendan, was associated

compared with placebo in LV dysfunction patients with

acute MI [195]. However, there was no mortality benefit

of levosimendan in comparison with dobutamine [196].

Recently, the PIONEER-HF study showed encourag-

ing results in HFrEF patients who were hospitalized

Table 4. Recent evidence regarding mortality in treatment of acute heart failure

One 2013;8:e58287. failure. Results of a Veterans Administration Cooperative

inra Response Trial 2 (D-HART2). Clin Cardiol 2017;40: 2018;6:308-316.

Decision) trial: the value of wireless remote monitoring ehy424.

2005;26:384-416. with left ventricular failure due to an acute myocardial

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