AJH 2003; 16:18S – 22S

Dari Hipertensi ke Gagal Jantung: Update tentang

Pengelolaan sistolik dan diastolik Disfungsi

John B. Kostis

Penuaan penduduk Amerika Serikat (AS) akan membawa dengan itu jumlah
yang lebih dari pasien dengan penyakit jantung koroner dan gagal jantung
(HF). Karena HF sudah membebankan beban ekonomi dan kesehatan yang
parah pada sistem perawatan kesehatan kita, sangat penting untuk
mengoptimalkan pencegahan primer dan sekunder penyakit kardiovaskular
(CV).
In most cases, HF develops as a result of either longstanding
hypertension or a myocardial infarction (MI). Other than cardiac death,
HF represents the last stage in the progression of CV disease, which
is poor, the 5-year survival rate being approximately 25%. Heart failure
may be due to either LV systolic or diastolic dysfunction, the latter having
a normal ejection fraction.
Because CV disease is progressive, interventions are possible
at all stages along the CV continuum. -Blockers ( B) are
recommended agents at several stages of CV disease. Large-scale
trials have shown that B significantly reduce risks for morbidity and
mortality in patients with HF. Ongoing studies should help to clarify
further the optimal cardioprotective therapies in patients with HF.

begins with CV risk factors such as hypertension, dyslipidemia, obesity,

Am J Hypertens 2003;16:18S–22S © 2003 American Journal of
Hypertension, Ltd.
and smoking. These risk factors lead to the development of left
ventricular (LV) hypertrophy or an MI (or both), which lead to LV
dysfunction and, finally, to HF. The prognosis of HF Key Words: Hypertension, heart failure, - blockers,
cardiovascular disease.

A
earlier stages of CV disease. 3 Heart failure may develop from either
the number of patients with coronary heart disease (CHD) long-standing hypertension or an acute MI. Cardiovascular disease is
and heart failure
s the (HF) will
population agescontinue
in theto impose
United substantial
States (US), medical and a continuous and progressive disease, usually starting with the classic
economic burdens on our health care system. A study that we risk factors such as hypertension, obesity, diabetes, smoking, and
conducted in the state of New Jersey, for example, showed that dyslipidemia 4 ( Fig. 1). In this early stage, left ventricle (LV) structure
although CHD fatalities declined between 1986 and 1996, the rate of and function will typically be normal. Over time, however, the
nonfatal events increased, particularly in individuals 75 years old. 1 Furthermore,
pathologic effects of one or more CV risk factors may cause LV
although the median age at which subjects experienced a first
hypertrophy (LVH) to develop or an MI to occur. Through LV
myocardial infarction (MI) was 68 years in 1986, it increased to 70
remodeling, systolic or diastolic dysfunction may develop, which can
years in 1996. 1
lead to symptomatic HF.

These data suggest that a rising life expectancy could bring with it a higher
number of patients with cardiovascular (CV) events. The consequences of
Systolic HF and diastolic HF (better named HF with preserved
an aging population are already apparent: hospital discharges for HF in the
ejection fraction [EF]) have many similar cardiac characteristics,
US more than quintupled in women and quadrupled in men between 1970
including high LV mass, reduced contractility, interstitial fibrosis, and
and 2000. 2 The total economic expenditure for HF in the US is now
depleted preload reserve 5
estimated to be $22.2 billion annually. 2
(Table 1). The most important difference between them is that systolic
HF is characterized by low EF with large ventricular volumes, whereas
diastolic HF is associated with normal EF and small ventricular
volumes. 5 Heart failure with preserved systolic function and normal EF
The Continuum of Cardiovascular
is more likely to occur among elderly patients, women, and those with
Disease
systolic hypertension (Table 2).
Findings from the Systolic Hypertension in the Elderly Program
(SHEP) study show that HF is the end result of The Cardiovascular Health Study in 5888 subjects 65

Received June 10, 2003. First decision June 10, 2003. Accepted June 10, 2003. Professor of Medicine and Pharmacology, Chairman, Department of Medicine, Robert
From the Department of Medicine, Robert Wood Johnson Medical School, New Wood Johnson Medical School, One Robert Wood Johnson Place, Room MEB-491,
Brunswick, New Jersey. New Brunswick, NJ 08903; e-mail: kostis@umdnj.edu
Address correspondence and reprint requests to Dr. John B. Kostis,

0895-7061/03/$30.00 © 2003 by the American Journal of Hypertension, Ltd.

doi:10.1016/S0895-7061(03)00966-X Published by Elsevier Inc.
AJH – September 2003 – VOL. 16, NO. 9, PART 2 PENGELOLAAN sistolik dan diastolik DISFUNGSI 19S

Table 2. Characteristics of patients with heart failure and normal

ejection fraction Older age and female sex Systolic hypertension
Exacerbated hypertensive response Cardiac artery disease
Diabetes Abrupt pulmonary edema Ventricular stiffening Arterial
stiffening Diastolic dysfunction Impedance mismatch

ARA. 1. Perkembangan dari hipertensi gagal jantung. 4 CHF gagal jantung kongestif; CV kardiovaskular;
HF gagal jantung; LV
ventrikel kiri; LVH hipertrofi ventrikel kiri; MI urat
infark cardial. (Dicetak ulang dengan izin dari Vasan RS et al: Peran hipertensi dalam endpoint, indicating the potential usefulness of antihypertensive or
patogenesis gagal jantung Bagan mekanistik klinis Arch Intern Med 1996; 156:.. 1789 - cardioprotective therapy.
pencegahan primer dan sekunder penyakit CV tidak dapat dicapai
1796.)
melalui terapi antihipertensi saja, bagaimanapun, tetapi juga harus
mencakup pengobatan faktor risiko CV umum lainnya. Satu studi di 2489
pria dan 2856 wanita menemukan, misalnya, bahwa sekitar 28% dari
years of age, for example, found that LV function was normal in 63%
kejadian PJK pada pria dan 29% pada wanita yang disebabkan tingkat
of the 269 participants with HF. 6 Although the mortality risk was lower
tekanan darah 130/85 mm Hg setelah penyesuaian untuk faktor-faktor lain. 8
among the HF patients with normal LV systolic function, there was a
Analisis ini juga menunjukkan bahwa 27% dari kejadian PJK pada pria dan
higher number of absolute deaths among them because of the higher
34% pada wanita yang disebabkan setelah penyesuaian ke kadar
prevalence, compared to subjects with HF and impaired LV systolic
kolesterol total tinggi (yaitu, 200 mg / dL).
function. 6

Implications for Treatment

Mengevaluasi Gagal Jantung
Left ventricular remodeling is a key mechanism in the progression of
Dalam praktek klinis, status fungsional pasien dengan HF yang paling sering
systolic and diastolic dysfunction. 7 Reversal of LV remodeling, with a
dinilai dengan menggunakan New York Heart Association (NYHA)
return to more normal ventricular dimensions, has been seen as a
klasifikasi, 9 berdasarkan tingkat aktivitas fisik yang diperlukan untuk
result of therapy with angiotensin-converting enzyme (ACE)
memperoleh gejala HF:
inhibitors,
- blockers ( B), and cardiac resynchronization. 7 The ability to reverse ● Kelas I: Tidak ada pembatasan aktivitas fisik. Aktivitas fisik biasa tidak
LVH in HF patients is an important surrogate menyebabkan kelelahan yang tidak semestinya, palpitasi, atau dyspnea.

● Kelas II: pembatasan Sedikit aktivitas fisik. Nyaman saat

Tabel 1. Karakteristik gagal jantung sistolik dan diastolik 5 istirahat, tapi biasa hasil aktivitas fisik kelelahan, palpitasi,
atau dyspnea.
● Kelas III: Ditandai pembatasan aktivitas fisik. Nyaman saat
sistolik Jantung diastolik Jantung
Kegagalan Kegagalan
istirahat, tetapi kurang dari hasil kegiatan biasa dalam kelelahan,
palpitasi, atau dyspnea.
EF rendah yang normal EF
massa LV Tinggi High LV mass ● Kelas IV: Tidak dapat melakukan aktivitas fisik tanpa
Myocyte hypertrophy Myocyte hypertrophy Interstitial fibrosis ketidaknyamanan. Gejala saat istirahat. Jika aktivitas fisik
Interstitial fibrosis dilakukan, ketidaknyamanan meningkat. Sebuah klasifikasi baru
Abnormal calcium Abnormal calcium handling
HF dikembangkan untuk menekankan perkembangan penyakit
handling
Reduced contractility Reduced contractility Slowed relaxation dan peran aktivasi neurohormonal dalam patogenesis LV
Slowed relaxation remodeling 10
Depleted preload Depleted preload reserve
(Tabel 3). Berkurang arteri atau perfusi perifer di HF memicu aktivasi
reserve
Large volumes Small volumes sistem saraf simpatik (SNS) dan renin-angiotensin-aldosteron
system (RAAS). 11 aktivasi kronis dari respons-respons
EF ejection fraction; LV left ventricular.
neurohormonal kompensasi dari waktu ke waktu memberikan
(Reprinted with permission from Konstam MA: “ Systolic and Diastolic Dysfunction ” in heart
failure? Time for a new paradigm. J Card Fail 2003;9:1 – 3.)
kontribusi pada perkembangan HF.
- Blocker, yang menekan aktivasi SNS,
20S MANAGEMENT OF SYSTOLIC AND DIASTOLIC DYSFUNCTION
Table 3. Stages of heart failure (American College of
Cardiology/American Heart Association) 10
Stage A At high risk for developing heart failure
No identified structural or functional abnormality; no
signs/symptoms
Stage B Developed structural heart disease that
is strongly associated with the development of
heart failure, but without signs/symptoms
Stage C Symptomatic heart failure associated
with underlying structural heart disease
Stage D Advanced structural heart disease and
marked symptoms of heart failure at rest despite
maximal medical therapy
dan ACE inhibitor, yang menghambat aktivitas RAAS, sangat manfaat resmi
pada setiap tahap HF 10 ( Gambar. 2).
- Blocker di Gagal Jantung
Tujuan utama terapi HF adalah untuk meningkatkan gejala dan memperpanjang hidup
dengan memperlambat perkembangan penyakit. 12
penggunaan kronis B pada pasien dengan HF telah ditunjukkan dalam beberapa
penelitian skala besar untuk meningkatkan tanda-tanda dan gejala HF dan untuk
mengurangi angka kematian. Bukti pertama dari manfaat efek resmi dari
- blokade pada kelangsungan hidup pada pasien
dengan HF berasal dari analisis dikumpulkan dari empat uji coba terkontrol
plasebo terpisah yang melibatkan total 1.094 subyek dengan ringan, sedang,
atau berat HF ​(EF 35%). Dalam analisis dikumpulkan ini, B carvedilol
menunjukkan penurunan yang signifikan dalam risiko semua penyebab
kematian dan rawat inap CV dibandingkan dengan plasebo. 13
Untuk menyelidiki lebih lanjut dampak dari B pada kelangsungan
hidup pada pasien dengan HF, Jantung insufisiensi Bisoprolol Study II
(CIBIS-II) dilakukan pada 2647 pasien dengan NYHA kelas III atau IV
HF (LV EF 35%) yang menerima terapi standar dengan diuretik dan
ACE inhibitor. 14 Subyek secara acak ditugaskan untuk B bisoprolol 1,25
mg ( n
1327) atau plasebo ( n 1320) sekali
sehari-hari, dengan terapi obat semakin meningkat ke
FIG. 2. Recommendations for management of heart failure by stage include the use of -blockers
at all stages. ACE angiotensinconverting enzyme. 10
AJH – September 2003 – VOL. 16, NO. 9, PART 2
FIG. 3. In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study,
treatment with carvedilol reduced the relative risk of death by 35% ( P . 0014), and the combined
risk of death or hospitalization by 24% ( P . 001), compared with placebo, in 2289 patients with
severe heart failure who were clinically euvolemic. RRR relative risk reduction. 15 ( Reprinted with
permission from Packer M, et al: Effect of carvedilol on survival in severe chronic heart failure.
N Engl J Med 2001;344:1651 – 1658. Copyright © 2001. Massachusetts Medical Society. All
rights reserved.)
maksimum 10 mg / hari. Berarti tindak lanjut adalah 1,3 tahun, dan akhir
primer adalah semua penyebab kematian. Titik akhir sekunder termasuk
semua penyebab rawat inap, CV kematian atau CV rawat inap, dan
penarikan dini dari pengobatan. Setelah rata-rata tindak lanjut dari 1,3
tahun, bisoprolol B dikaitkan dengan penurunan risiko 34% untuk semua
penyebab kematian dibandingkan dengan plasebo ( P
. 0001).
Calon Acak Kumulatif Kelangsungan Hidup (Copernicus) studi
Carvedilol mengevaluasi efek dari B pada kelangsungan hidup pada 2287
pasien gagal jantung parah yang secara klinis euvolemic, memiliki EF dari
25% dan menerima terapi HF standar dengan diuretik dan ACE inhibitor. 15
Dalam percobaan double-blind ini, subjek secara acak untuk carvedilol
3,125 mg dua kali sehari (dititrasi sampai 25 mg dua kali sehari, n 1156)
atau plasebo ( n 1133), dengan maksud tindak lanjut dari 10,4 minggu. B
carvedilol mengurangi risiko kematian sebesar 35% ( P
. 0014)
(Gambar. 3), dan risiko gabungan dari kematian atau rawat inap sebesar 24% ( P
. 001) dibandingkan dengan plasebo.
The Metoprolol CR / XL Percobaan Acak Intervensi di Congestive
Heart Failure (MERIT-HF) dilakukan untuk mengetahui apakah B
extended-release (ER) metoprolol suksinat akan meningkatkan
kelangsungan hidup pada pasien dengan HF. 16 The MERIT-HF enrolled
3991 patients with NYHA Class II to Class IV HF, who had an EF of 40%
and were receiving standard therapy with diuretics and ACE inhibitors. In
this double-blind study, subjects were randomized to either ER
metoprolol succinate 12.5 mg (titrated up to 200 mg once daily, n 1990),
or to placebo ( n 2001). The co-primary endpoints were all-cause
mortality, and death or hospitalization for any reason. The study was
stopped early because of a significant reduction in mortality. Therapy
with ER metoprolol succinate achieved a 34% reduction in all-cause
mortality as compared with placebo ( P
. 0006) (Fig. 4).
A post hoc analysis investigating results by mode of
AJH – September 2003 – VOL. 16, NO. 9, PART 2 MANAGEMENT OF SYSTOLIC AND DIASTOLIC DYSFUNCTION
FIG. 4. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
(MERIT-HF) found that ER metoprolol succinate achieved an RRR of 34% for all-cause
mortality, compared with placebo ( P
. 0062), in 3991 patients with NYHA Class II to
Class IV HF and an EF of 40%, who were receiving standard therapy with diuretics and
angiotensin-converting enzyme inhibitors. EF
ejection fraction; ER extended release; HF heart
failure; NYHA New York Heart Association; RRR relative risk
reduction. 16 ( Reprinted with permission from MERIT-HF Study Group: Effect of metoprolol
CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive
Heart Failure (MERIT-HF). Lancet 1999;353:2001 – 2007.)
death found that the leading cause of mortality was sudden death, and
that treatment with ER metoprolol succinate reduced the risk of sudden
death by 41% ( P . 0002). 16
Additional subgroup analyses of MERIT-HF found that ER metoprolol
succinate therapy achieved similar risk reductions in all-cause mortality
and all-cause hospitalization in diabetic and nondiabetic patients, 17,18 in
the 65year-old and kelompok usia 65 tahun, 19 dan baik pada pria dan
wanita. 20 Selanjutnya, dalam subkelompok pasien
FIG. 5. A substudy was conducted in patients enrolled in the Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure (MERIT-HF) with severe HF (NYHA Class III/IV)
and an EF of 25% (n 795). This trial found that treatment with ER metoprolol succinate
achieved a significant relative risk reduction of 39% in total mortality ( P . 009). EF ejection
fraction; ER extended release; HF heart failure; NYHA New York Heart Association; RRR
relative risk reduction. 21 ( Reprinted with permission from Goldstein S, et al: Metoprolol
controlled release/extended release in patients with severe heart failure: analysis of the
experience in the MERIT-HF Study. J Am Coll Cardiol 2001;38:932 – 938. Copyright ©
2001. The American College of Cardiology Foundation. All rights reserved.)
21S
dengan HF berat (NYHA kelas III / IV) dan EF dari 25% ( n
795), pengobatan dengan ER metoprolol suksinat sig-
ni fi kan mengurangi semua endpoint kematian, termasuk pengurangan risiko 39% pada
total angka kematian ( P . 009) 21 ( Gambar. 5).
Gagal Jantung Dengan Diawetkan Fungsi
sistolik
Meskipun manajemen HF pada pasien dengan fungsi sistolik yang buruk
telah dipelajari dengan baik, strategi terapi yang optimal untuk HF
diastolik dikenal kurang baik. perawatan teoritis, berdasarkan
pengetahuan kita tentang patofisiologi kompleks kondisi ini, termasuk
kelebihan volume yang relieving dengan diuretik, mengurangi denyut
jantung dengan B, and general control of hypertension. The ongoing
Candesartan in Heart Failure–Assessment of Reduction in Mortality and
Morbidity (CHARM) program is being conducted to evaluate the effects
of the angiotensin II receptor blocker candesartan as compared with
placebo, in a broad spectrum of HF patients, including those with a
normal EF. 22 Results are expected later this year.
Conclusions
Gagal jantung merupakan masalah kesehatan masyarakat yang utama. Ini
dapat berkembang baik sebagai akibat hipertensi lama atau kerusakan
jantung akibat MI akut. faktor risiko untuk mengembangkan HF harus
diidentifikasi dan diobati bahkan sebelum pasien menunjukkan bukti penyakit
jantung struktural. fungsi ventrikel kiri harus dievaluasi pada semua pasien
dengan HF untuk mendeteksi orang-orang dengan disfungsi sistolik. Pasien
dengan bukti retensi fluida harus menerima terapi diuretik sampai euvolemia
dicapai. inhibitor enzim Angiotensinconverting dan B direkomendasikan pada
semua tahap HF untuk mengurangi risiko morbiditas dan mortalitas. studi
yang sedang berlangsung lebih lanjut akan menerangi terapi potensial pada
pasien HF dengan fungsi sistolik diawetkan.
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