J OU R NA LOFTHE AM ERIC AN COLLEGEOFCARDIOL OG Y VOL. 6 9, NO.

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PUBLISHEDBYELSEVIER http: / / dx. doi. org / 1 0. 1 0 1 6 / j. JACC. 2 0 1 7. 0 1. 0 6 4

THE PRESENT DAN MASA DEPAN

NEGARA-OF-THE-ART REVIEW

The Penuaan Kardiovaskular Sistem

Memahami Ini di Seluler dan Tingkat Klinis

Francesco Paneni, MD, P H D, Sebuah . b Candela Diaz Canestro, MS C, Sebuah Peter Libby, MD, P H D, c Thomas F. Luscher, MD, Sebuah . b

Giovanni G. Camici, P H D Sebuah . b

ABSTRAK

Penyakit kardiovaskular (CVD) menyajikan beban besar untuk pasien usia lanjut, pengasuh mereka, dan sistem kesehatan. perubahan struktural dan fungsional

pembuluh menumpuk sepanjang hidup, yang berpuncak pada peningkatan risiko CVD. Meningkatnya populasi lanjut usia di seluruh dunia menyoroti kebutuhan

untuk memahami bagaimana penuaan mempromosikan CVD untuk mengembangkan strategi baru untuk menghadapi tantangan ini. Ulasan ini memberikan

contoh-contoh beberapa masalah klinis yang belum terselesaikan utama yang dihadapi dalam praktek kardiovaskular sehari-hari seperti yang kita merawat pasien

usia lanjut. Berikutnya, penulis merangkum pemahaman saat ini mekanisme terlibat dalam penuaan kardiovaskular, dan potensi untuk menargetkan jalur baru

terlibat dalam disfungsi endotel, stres oksidatif mitokondria, renovasi kromatin, dan ketidakstabilan genomik. Akhirnya, penulis mempertimbangkan aspek-aspek

penting dari perbaikan pembuluh darah, termasuk transplantasi autologous sel induk berasal sumsum tulang pada pasien usia lanjut. (J Am Coll Cardiol 2017; 69:

1952 - 67) © 2017 oleh American College of Cardiology Foundation.

SEBUAH
meningkat secara dramatis, terutama di negara-negara berpenghasilan rendah dan

Penyakit (CVD) (1,2) . Memang, munculnya perawatan kontemporer menengah (misalnya, Chili, Cina, Iran, dan Rusia).

untuk akut sindrom koroner dan stroke telah membantu untuk

ge mendominasi memperpanjang
faktor risiko kardiovaskular

harapan hidup (3) . Meskipun sukses besar dari perspektif individu, resultan Meskipun penuaan hadiah array gangguan (5) .

demografi pergeseran hadiah salah satu tantangan terbesar bagi sistem sosial CVD membawa beban terbesar untuk populasi yang lebih tua, pemberi perawatan

dan perawatan kesehatan di seluruh dunia (4) . Populasi lebih dari 65 tahun akan mereka, dan sistem kesehatan (6) . Penyakit jantung koroner (PJK) asosiasi kuat

berlipat ganda dari 12% pada tahun 2010 menjadi 22% di 2040 (2) . Memang, pada dengan usia, dan merupakan penyebab utama kematian di Eropa dan Amerika

tahun 2020, jumlah orang 60 tahun dan lebih tua akan melampaui jumlah anak di Serikat (7 - 9) . Prevalensi meningkat CVD pada orang> 65 tahun, terutama pada

bawah usia 5 tahun. Laju penuaan populasi di seluruh dunia adalah mereka

> 80 tahun, dan akan meningkat w 10% selama 20 tahun ke depan (2) . Dari

2010-2030, tambahan 27 juta orang akan memiliki hipertensi, 8 juta

Dari Sebuah Pusat Molekuler Kardiologi, Universitas Zurich, Zurich, Swiss; b Universitas Heart Center, Kardiologi, Universitas Rumah Sakit Zurich, Zurich, Swiss; dan c Brigham dan Women ' s Hospital, Divisi

Kedokteran Kardiovaskular, Boston, Massachusetts. Karya ini didukung oleh Swiss National Science Foundation (Drs. Luscher dan Camici) dan Alfred dan Annemarie von Hibah Sakit untuk Translational

dan Clinical Research Kardiologi dan Onkologi (Dr. Camici), penelitian hibah tak terbatas oleh P fi zer, Inc (Dr. Luscher), Yayasan Penelitian Kardiovaskular - Zurich Heart House dan

Dengarkan naskah ini ' s audio yang

Ringkasan oleh US National Institutes of Health (RO1 HL080472), dan dari RRM Dana Amal (Dr. Libby). Drs. Paneni dan Camici adalah penerima dari Sheikh Khalifa ' Yayasan Asisten profesor di Fakultas Kedokteran
JACC Editor-in-Chief Dr Valentin Universitas Zurich. Dr Libby telah menjadi konsultan dibayar untuk Amgen, AstraZeneca, Esperion Therapeutics, Ionis Farmasi, Kowa Farmasi, Merck & Co, Novartis, P fi zer, Sano fi Regeneron, Takeda
Fuster. Farmasi, dan XBiotech; menjabat sebagai ilmiah yang fi c anggota dewan penasehat untuk Amgen, Athera Biotechnologies, Corvidia Therapeutics, DalCor Farmasi, Interleukin Genetika, Kowa Farmasi,

MedImmune, dan Novartis; dan telah menerima dana lab dari Novartis. Semua penulis lain telah melaporkan bahwa mereka tidak memiliki hubungan yang relevan dengan isi tulisan ini untuk

mengungkapkan.

Naskah diterima 12 Juli 2016; direvisi naskah diterima 23 Januari 2017, diterima 24 Januari 2017.
JACCVOL. 6 9, NO. 1 5, 2 0 1 7 Paneni et al. 1953

1 Apr 8, 2 0 1 7: 1 9 5 2 - 6 7 The Penuaan Kardiovaskular Sistem

akan memiliki PJK, 4 juta akan memiliki stroke, dan 3 juta akan memiliki gagal penentu dari kebutuhan oksigen miokard. paparan kronis meningkat SINGKATAN DAN AKRONIM

jantung akibat akumulasi cepat tua (2) . mengarah tekanan sistolik hipertrofi LV, menyebabkan kenaikan lebih

lanjut dalam permintaan oksigen miokard. Mediator, seperti TGF- b, angiotensin

BM = sumsum tulang
Peningkatan prevalensi CVD juga interplays dengan kelemahan, kondisi II, dan aldosteron mineralokortikoid,
CAC = beredar sel angiogenik
meningkatnya kerentanan terhadap stres. Sebuah meta-analisis yang termasuk

54.250 pasien usia lanjut terkait CVD dengan rasio odds (OR) dari 2,7-4,1 untuk
PJK = penyakit jantung koroner
kelemahan umum dan OR 1,5 untuk insiden kelemahan pada mereka tanpa berkontribusi secara mekanis untuk
CI = menipu fi Interval dence
kelemahan pada awal hipertrofi dan fi fibrosis di LV pressureoverloaded. Dengan demikian,
PENGEMUDI = siklooksigenase
hipertensi sistolik dan penurunan tekanan diastolik dikaitkan dengan
CV = kardiovaskular
(10) . proyeksi saat ini memprediksi peningkatan pengeluaran untuk PJK dan gagal penuaan hasil sebuah “ badai yang sempurna ” dari penurunan suplai
CVD = penyakit kardiovaskular
jantung dari w 200% selama 20 tahun ke depan, stroke diharapkan dapat oksigen dalam menghadapi kebutuhan oksigen augmented. Sebagai

memberikan kontribusi peningkatan relatif terbesar dalam biaya kesehatan tahunan aterosklerosis koroner juga kemajuan dengan usia, pembatasan eNOS = endotel oksida nitrat sintase

dari 238% (2) . Pertimbangan-pertimbangan ini menyoroti pentingnya memahami tambahan ini untuk suplai oksigen sering senyawa kebutuhan oksigen
EPC = sel progenitor endotel
mengapa usia kontribusi krusial untuk pengembangan CVD untuk memungkinkan yang meningkat biasanya ditemui dalam sistem CV penuaan ( Gambar

kita untuk mengatasi penuaan penduduk. Ulasan ini memberikan bukti klinis dan 1 ). Selain fungsi arteri besar berubah, hipertensi kronis
HFpEF = gagal jantung dengan fraksi
eksperimental untuk mendukung link didirikan antara penuaan dan CVD. mempromosikan renovasi dari mikrovaskulatur miokard. Penebalan
ejeksi diawetkan

tunika media dari arteriol miokard bisa lebih menghamhat LV perfusi

LTL = leukosit panjang telomer
dan merusak vasomotion. Konsekuensi ini dari peningkatan sistolik

dan penurunan tekanan diastolik yang biasanya menyertai penuaan LV = ventrikel kiri

bersekongkol untuk menyebabkan iskemia miokard. Regulasi renovasi

MI = infark miokard
ASPEK KLINIS CVD pada pasien usia lanjut
arteriol di miokardium mengalami peningkatan sistolik dan penurunan
MMP = matriks
tekanan diastolik kemungkinan melibatkan jalur yang sama terlibat metaloproteinase

dalam generasi kekakuan aorta. Kami kekurangan suf fi pemahaman NF k B = faktor nuklir kappa-B
Sejumlah kondisi yang berkaitan dengan usia menyajikan tantangan khusus untuk
efisien pemicu terkait usia utama untuk patofisiologi ini
ATAU = rasio odds
perawatan klinis kardiovaskular (CV) pasien kami. Akumulasi orang lanjut usia
PBMC = sel mononuklear darah
dalam populasi kami menggarisbawahi semakin pentingnya CV penuaan untuk
perifer
praktisi.
Raas = renin-angiotensinaldosterone

sistem

Hipertensi sistolik dan memperlebar PULSA TEKANAN. Dengan penuaan, menegang aorta ROS = spesies oksigen reaktif

karena peningkatan kolagen dan elastin menurun ( Gambar 1 ). RR = risiko relatif

TGF = transforming growth factor

Augmented faktor pertumbuhan transformasi (TGF) - b

Kegiatan nikmat akumulasi kolagen pada dinding aorta. Aktivitas berbagai TNF = tumor necrosis factor

elastases, termasuk matriks metalloproteinase (MMPs), seperti MMP-9 dan proses bahwa menyumbang VSMC = sel otot polos pembuluh

MMP-12, serta berlebih dari cathepsins proteinase sistein S, K, dan L, dan elastase besar terhadap komplikasi CV dalam populasi yang menua. darah

serin proteinase neutrofil, diuraikan oleh di fl Sel-sel inflamasi, semua bisa wtTTR = -Tipe liar

transthyretin
berkontribusi untuk penipisan elastin (11) . Perubahan ini di aorta ' s matriks Untung, beberapa intervensi dapat

ekstraselular kontribusi penting kerugiannya dari distensibility. Ini meningkat meningkatkan hasil pada pasien dengan hipertensi sistolik terisolasi. The SHEP

kenaikan gaji kekakuan ulang fl gelombang ected dan meningkatkan tekanan (sistolik Hipertensi pada Usia Lanjut), Syst-Eur (Systolic Hypertension di Eropa),

sistolik. Namun tekanan diastolik cenderung menurun dengan usia. Sebagai aorta Syst-China (sistolik Hipertensi di Cina), dan penelitian lain menawarkan af

pulsa gelombang kecepatan meningkat, tekanan nadi meningkat (12) . Memang, database yang kaya fi rming kemampuan pengobatan farmakologis individu dalam

tekanan nadi merupakan faktor risiko independen untuk acara CV (13) . Terisolasi 60-an atau 70-an mereka untuk mengurangi secara substansial stroke dan

hipertensi sistolik menyumbang mayoritas hipertensi yang tidak terkontrol di kematian total, dengan bene lebih rendah fi t untuk acara jantung iskemik (16) .

Amerika lebih dari 50 tahun (14,15) . Penurunan tekanan diastolik menurun drive Menghindari asupan natrium yang berlebihan dapat memberikan tambahan,

untuk perfusi koroner yang terjadi terutama selama diastole, mendukung intervensi nonfarmakologi untuk mengontrol hipertensi pada orang tua (17,18) .

pengembangan iskemia miokard. peningkatan tekanan sistolik dengan peningkatan Beberapa telah menyuarakan keprihatinan tentang keamanan agresif menurunkan

usia ventrikel kiri (LV) afterload, utama tekanan darah pada pasien usia lanjut, terutama mereka dengan penyakit arteri

koroner bersamaan (19) . Memang, kurva J-berbentuk berkaitan hasil CV tekanan

darah mungkin berkaitan dengan ini

1954 Paneni et al. JACCVOL. 6 9, NO. 1 5, 2 0 1 7

The Penuaan Kardiovaskular Sistem 1 Apr 8, 2 0 1 7: 1 9 5 2 - 6 7

GAMBAR 1 Patofisiologi aorta-LV Dynamics di CV Sistem Penuaan

Ang II ¼ angiotensin II; BP ¼ tekanan darah; CV ¼ kardiovaskular; HFpEF ¼ gagal jantung dengan fraksi ejeksi diawetkan; HFrEF ¼ gagal jantung dengan fraksi ejeksi berkurang; LV ¼ ventrikel kiri; MMP ¼ matriks

metaloproteinase; MV O2 ¼ konsumsi oksigen miokard; TGF ¼ mengubah faktor pertumbuhan.

populasi (20 - 22) . Namun HYVET (Hipertensi di Pengadilan Sangat Lansia) dan atau menipiskan risiko CVD pada orang tua.

SPRINT (Sistolik Tekanan Darah Intervensi Trial) studi con fi rmed relatif aman dan

ef fi keampuhan pengobatan antihipertensi pada populasi yang lebih tua, meskipun Beberapa (pra) studi klinis baru-baru ini telah membentuk modi vaskular kunci fi kation

data terakhir menunjukkan mempertahankan tekanan diastolik di atas 70 mm Hg terjadi dengan penuaan (31,32) , Mengidentifikasi 2 fitur utama: umum disfungsi

pada mereka dengan penyakit arteri koroner didirikan (21 - 25) . Dokter harus endotel dan kekakuan arteri pusat. Berkenaan dengan mantan, pembuluh darah

menyesuaikan agresivitas pengobatan antihipertensi pasien geriatri secara alter penuaan fungsi endotel, sel-sel yang melapisi lumen pembuluh darah.

individual, tergantung pada status arteri koroner, kelemahan, integritas fungsi disfungsi endotel termasuk mengurangi vasodilatasi dan sifat antitrombotik, dengan

otonom, dan variabel lainnya (26) . Selain mengurangi stroke, hambatan utama peningkatan stres oksidatif dan di fl sitokin inflamasi (33 - 35) mendukung

untuk hidup mandiri dan fungsi pada pasien yang lebih tua, terapi antihipertensi aterosklerosis dan trombosis, dan predisposisi untuk CVD

dapat membatasi perkembangan penyakit demensia, seperti yang ditunjukkan

dalam sidang Syst-Eur (27) . Penurunan demensia dan kognitif penurunan akru

dengan durasi yang lebih lama pengobatan antihipertensi (28) . Kerugian asimetris

untuk menindaklanjuti individu dengan gangguan kognisi mungkin bias hasilnya

demensia dalam studi SHEP ke nol (29) . (36) . Manusia dan studi eksperimental setuju bahwa bioavailabilitas berkurang dari

oksida nitrat (NO), mediator kunci dari vasorelaxation dan proses antiatherogenic,

mendasari disfungsi endotel usia tergantung (37,38) . Mengurangi bioavailabilitas

NO dapat terjadi karena sintesis menurun atau meningkat degradasi NO. Dalam

kondisi normal, endotel nitrat oksida sintase (eNOS) menghasilkan NO dari

L- arginin di hadapan tetrahydrobiopterin kofaktor (BH4) (39) . Meskipun studi

berbeda mengenai eNOS ekspresi protein dengan usia (34,40,41) , Data terakhir

VASCULAR PENUAAN: DEFINISI, PATOFISIOLOGI, DAN DAMPAK. Perubahan dalam menunjukkan suatu perubahan yang berkaitan dengan usia dalam fungsi eNOS,

struktur dan fungsi arteri menemani penuaan, dan berkontribusi terhadap disebut sebagai eNOS uncoupling ( 42) . Efek ini atau diperoleh, setidaknya

peningkatan risiko pengembangan CVD (9,30) . Dengan demikian, memahami sebagian, dari penurunan ketersediaan BH4, sehingga gangguan NO rilis dan

mekanisme yang usia mempengaruhi pembuluh darah harus memposisikan kita peningkatan produksi yang sangat pro-oksidan

untuk mencegah
JACCVOL. 6 9, NO. 1 5, 2 0 1 7 Paneni et al. 1955

1 Apr 8, 2 0 1 7: 1 9 5 2 - 6 7 The Penuaan Kardiovaskular Sistem

anion superoksida (O 2 ) ( 33) . Selain itu, ketersediaan substrat eNOS, L- arginin, juga fungsi yang mengacukan arteri homeostasis, mendukung aktivasi kronis

dapat membatasi produksi NO. Dalam hal ini, aktivitas arginase, enzim yang pro-oksidan dan proin-

bersaing dengan eNOS untuk fl jalur inflamasi, dan pergeseran ke arah pro vasokonstriktor fi le, predisposisi untuk

CVD dan efek samping (51) .

L- arginin, meningkat dengan usia, menyediakan mekanisme yang masuk akal untuk

penurunan sintesis NO (43) . Namun demikian, sebagian besar bukti mekanistik ini Peningkatan kekakuan arteri pusat, khususnya dari aorta toraks, juga

telah muncul dari studi hewan, menyoroti kebutuhan untuk penelitian lebih mencirikan penuaan pembuluh darah manusia (52) ( Gambar 1 ). Manusia dan

manusiawi mengenai batasan usia tergantung dari NO sintesis. hewan studi menunjukkan bahwa mengurangi distensibility besar hasil arteri elastis

terutama dari hilangnya elastis fi bers, serta peningkatan kolagen (53) . Mekanis,

peningkatan terkait usia degradasi elastin mungkin dihasilkan dari kegiatan

Selain itu, penuaan dapat meningkatkan NO degradasi augmented protease dengan aktivitas elastinolytic, termasuk MMPs tertentu dan

(34) karena konsentrasi tinggi dari spesies oksigen reaktif (ROS), dimediasi, cathepsins cysteinyl, enzim yang, pada gilirannya, diatur oleh di fl mediator inflamasi

sebagian, dengan di kronis fl inflamasi, yang merupakan lingkaran setan yang

menghabiskannya NO (35) . Misalnya, usia tergantung kenaikan tumor necrosis

factor pembuluh darah dan darah-ditanggung (TNF) - Sebuah, asosiasi dengan

peningkatan ekspresi nikotinamida adenin dinukleotida fosfat (NADPH) oksidase ( Gambar

2 ). Augmented NADPH aktivitas oksidase hasil kelebihan O 2 . yang, pada gilirannya, (54,55) . Kolagen katabolisme jatuh di arteri penuaan. Akumulasi modi kolagen fi ed

bereaksi dengan NO bentuk peroxynitrite (ONOO ), Oksidan kuat terlibat dalam oleh canggih akhir glikasi-produk (AGEs)

nitrosylation enzim antioksidan dan eNOS (34) . Selain di fl sitokin inflamasi, sistem (Kondensat dari

renin-angiotensin-aldosteron (RAAS) dapat berkontribusi pada peningkatan terkait glukosa yang dihasilkan oleh reaksi nonenzimatik yang membentuk cross-link

usia di NO inaktivasi. Dengan penuaan, aktivitas Raas dan konsentrasi angiotensin antara molekul kolagen) dapat menyebabkan peningkatan terkait usia ini dalam

II, suatu RAAS efektor utama, kenaikan, meningkatkan produksi ROS dengan kolagen arteri. AGE-dimediasi cross-link dapat memberikan resistensi terhadap

mengaktifkan NADPH oksidase (44) . Pada gilirannya, agerelated peningkatan degradasi enzimatik, dan dengan demikian mengganggu collagenolysis (56) . Selain

produksi ROS dapat mempromosikan vaskular itu, peningkatan aktivitas TGF b dengan penuaan merangsang sintesis kolagen

interstitial oleh sel-sel otot polos pembuluh darah (VSMC), dan dengan demikian

menambah kekakuan arteri (57) . Juga,

peningkatan aktivitas Raas mungkin

Augment kolagen sintesis dan meningkatkan elastolysis

di fl inflamasi (45) . Memang, hidrogen (58) .

peroksida (H 2 HAI 2) mengaktivasi faktor nuklir kappa-B (NF k B), yang menambah disfungsi endotel dan kekakuan arteri erat berhubungan mediator disfungsi

transkripsi proin- vaskular usia tergantung (59) . The kaku arteri, semakin besar pemaparan dari

fl gen inflamasi, yang mengarah ke peningkatan ekspresi TNF Sebuah, interleukin 6, endothelium untuk hemodinamik

kemokin, dan molekul adhesi terlibat dalam aterogenesis ( Gambar 2 ).

beban, mempromosikan endotel pengaktifan,

Peningkatan tonus vasokonstriktor mungkin senyawa gangguan agedependent di fl inflamasi, dan kerusakan (60) . pengurangan berhubungan dengan usia pada NO

di vasodilatasi endotel-dependen. Manusia penuaan rekan dengan peningkatan bioavailabilitas dijelaskan sebelumnya dapat berkontribusi untuk gangguan

sirkulasi dan tingkat dinding arteri endotelin (ET) -1, vasokonstriktor kuat terlibat distensibility arteri melalui perubahan tonus otot polos (61) . terapi baru yang

dalam gangguan dilatasi endotelium-dependent bertujuan untuk menghaluskan CVD terkait usia dapat menargetkan fitur ini

penuaan pembuluh darah, dengan penekanan khusus pada disfungsi endotel dan

perubahan dalam matriks ekstraselular arteri yang menyebabkan arteri pusat

(40,46) . Selain itu, bukti dari sel endotel tikus menunjukkan bahwa konsentrasi kekakuan.

siklooksigenase (COX) eikosanoid -derived juga berubah drastis dengan usia.

Dengan usia, eikosanoid COX-diturunkan berhubungan dengan vasokonstriksi dan

peningkatan trombosis (yaitu, prostaglandin H 2 [ PGH2], tromboksan A 2

GAGAL JANTUNG DENGAN dilestarikan dan BERKURANG fraksi ejeksi. Terkait etiologi

untuk kedua akuisisi kekakuan aorta dan renovasi dari miokardium, matriks

[TXA 2]. dan prostaglandin F 2 Sebuah [ PGF 2 Sebuah]), sedangkan prostaglandin ekstraseluler, serta mikrovaskulatur nya, gagal jantung dengan fraksi ejeksi

Saya 2 ( PGI 2, prostasiklin) jatuh (47,48) . Selain itu, gangguan respon endotel diawetkan (HFpEF) tulah pasien usia lanjut, terutama perempuan. Risiko

tergantung ke prostaglandin menyertai penuaan pada manusia dan hewan (49,50) . mengembangkan skyrockets HFpEF dengan usia (62,63) . Memang, hipertrofi

Dengan demikian, asosiasi dengan terpadu penurunan endotel penuaan

1956 Paneni et al. JACCVOL.69,NO.15,2017

The Aging Cardiovascular System APRIL18,2017:1952–67

GAMBAR 2 Representasi skematik Persiapan Molekuler Terlibat dalam arteri Aging

sel endotel berusia down-mengatur Jund dan SIRT1expression, yang mengarah ke pro-oksidan dan proin fl ekspresi gen inflamasi. Peningkatan ROS dan di fl sitokin inflamasi mengurangi ketersediaan NO. Secara paralel,

yang berkaitan dengan usia up-regulasi angiotensin II dan COX-diturunkan eikosanoid hasil mediator vasokonstriktor augmented, seperti ET-1, TXA2, dan PGF 2 Sebuah. Ketidakseimbangan antara dilator dan konstriktor

faktor petunjuknya gangguan fungsi pembuluh darah. Selanjutnya, peningkatan MMP ekspresi perubahan VSMC menginduksi dalam komponen struktural dinding arteri (misalnya, penurunan elastin / kolagen rasio),

memberikan kontribusi untuk kekakuan arteri. A A ¼ asam arakidonat; ALDH-2 ¼ aldehida dehidrogenase; AMPK ¼ 5 0 adenosine kinase protein monofosfat-diaktifkan; Arg II ¼ arginase II; AT-1 ¼ angiotensin II tipe reseptor

1; BH4 ¼ tetrahydrobiopterin; ca 2 þ ¼ ion kalsium; cGMP ¼ siklik guanosin monofosfat; PENGEMUDI ¼ cyclooxygense; DP ¼

prostaglandin reseptor D2; ecSOD ¼ ekstraseluler superoxide dismutase; EPI-4 ¼ prostaglandin E2 reseptor 1-4; ETA ¼ endotelin reseptor A; FP ¼ prostaglandin reseptor F; GC ¼ guanylate adenilat; GTP ¼ guanosin

trifosfat; ICAM ¼ molekul adhesi antar; AKU P ¼ reseptor prostasiklin; MCP ¼

monocyte chemotactic protein; MnSOD ¼ manganese superoxide dismutase; NF- k B ¼ nuclear factor k B; NO ¼ nitric oxide; PGD 2 ¼ prostaglandin D 2; PGF 2 a ¼

prostaglandin F 2 a; PGI 2 ¼ prostacyclin; PKG ¼ protein kinase G; ROS ¼ reactive oxygen species; TNF- a ¼ tumor necrosis factor alpha; TP ¼ thromboxane receptor; TxA 2 ¼ thromboxane A 2; VCAM ¼ vascular cell

adhesion protein; VSMC ¼ vascular smooth muscle cell; other abbreviations as in Figure 1 .
JACCVOL.69,NO.15,2017 Paneni et al. 1957

APRIL18,2017:1952–67 The Aging Cardiovascular System

and fi brosis of the aged LV can impair lusitropy. Practitioners generally people over 80 years of age have wtTTR amyloid deposits in their hearts at

acknowledge the increasing prevalence of HFpEF, its accentuation in elderly autopsy. Although the clinical signi fi cance of this fi nding remains uncertain, it is

patients, and its adverse outcomes in our aging patient population, with regard, not highly likely that with the aging of the population and the advent of novel diagnostic

only to morbidity, but also to reduced quality of life and increased resource modalities, wtTTR amyloidosis will become better recognized as a contributor to

utilization (64) . Unfortunately, we possess few (if any) evidence-based interventions heart failure in the older population. Amyloidosis due to wtTTR requires

to stem the development or consequences of HFpEF. Studies in progress of differentiation from amyloid light-chain amyloidosis, because the prognosis and

neurohumoral blockade may help to fi ll this important gap in our therapeutic treatment diverge substantially. Although we currently lack effective therapy for

approach to HFpEF in our elderly patients (65) . However, myocardial treating amyloidosis, promising imaging technologies should provide evolving tools

to evaluate novel therapies currently in development or under investigation (72) .

ischemia, due to either myocardial

infarction (MI) (ischemic cardiomyopathy) or subendocardial ischemia in the

hypertrophied LV, can predispose to heart failure with reduced ejection fraction.

Thus, aging can promote the development of both major forms of heart failure that
FRAILTY AND SARCOPENIA IN THE AGING POPULATION. Frailty and loss of muscle
constitute a key challenge to quality of life of aging individuals, as well as an
mass and function (sarcopenia) present a major challenge to maintenance of
enormous drain on health care resources ( Figure 1 ).
independence, mobility, quality of life, and the ability of our CV patients to undergo

surgery and other interventions (such as transcatheter valve procedures)

successfully. Moreover, the ability to tolerate CV therapies may decline with frailty

and sarcopenia, as discussed earlier for pharmacological treatment of

hypertension. We lack definite criteria for de fi ning sarcopenia and frailty

VALVULAR AND CARDIAC SKELETON CALCIFICATION. With age, calcium in the axial

skeleton particularly tends to decline, while accumulating in CV structures.

Appreciation has increased that conditions such as calci fi c aortic stenosis actually

re fl ect a systemic process (66) . Evidence points to in fl ammation as a potential

physiological contributor to CV calci fi cation. Strong human genetic data also

(73,74) , which associate with both osteoporosis and obesity (75) . Potential
implicate lipoprotein(a) in the pathogenesis of aortic valve calci fi cation (67) . Despite
pathophysiological pathways that link these apparently disparate conditions include
initial enthusiasm, clinical trials have not substantiated that statin therapy can limit
proin fl ammatory cytokines. Further clarity in diagnosis and pathophysiological
progression of aortic valvular calci fi cation. Indeed, statins tend to accelerate
mechanisms would be highly desirable, given the increase in the elderly population
coronary arterial calci fi cation (68,69) . Given the pressing clinical importance of calci fi
affected by CV disease, and the limitations these conditions present to patients and
c aortic stenosis in geriatric patients, we urgently need a greater understanding of
their management. Increased physical activity could provide a nonpharmacological
its pathophysiology and preventive measures to mitigate its genesis, as once CV
preventive approach to augmenting patient quality of life and function, and could
structures have calci fi ed, therapeutic reversal of this process may prove elusive.
conceivably improve the ability to tolerate pharmacological and interventional

treatment of CV conditions, hence improving CV outcomes.

MOLECULAR FEATURES OF AGE-RELATED

AMYLOIDOSIS AND THE AGING CV SYSTEM. Certain forms of amyloidosis also CVD

particularly affect the older population (70) . The incidence of amyloid light-chain

amyloidosis rises in older patients, related to the increase in multiple myeloma with TELOMERES AND CELLULAR SENESCENCE. Accumulation of senescent cells within

age. Cardiac amyloidosis associated with wild-type transthyretin (wtTTR) the vascular wall and heart can contribute to structural and functional decline of the

particularly affects the older population, especially men. Although many have CV system with age (58) . Considerable evidence implicates telomere shortening in

regarded cardiac amyloidosis as a rare condition, current data using novel imaging cellular senescence. Telomeres consist of repetitive nucleotide sequences

modalities show that some 13% of cases of HFpEF in individuals $60 years of age (TTAGGG) at the ends of mammalian chromosomes, that preserve chromosome

associate with wtTTR amyloidosis (71) . At least 20% of stability and integrity by preventing deterioration or fusion with neighboring

chromosomes (76) ( Central Illustration ).

1958 Paneni et al. JACCVOL.69,NO.15,2017

The Aging Cardiovascular System APRIL18,2017:1952–67

CENTRAL ILLUSTRATION Molecular Hallmarks of CV Aging (Cellular Senescence, Genomic Instability, Chromatin Remodeling, and Mitochondrial Oxidative Stress)

Paneni, F. et al. J Am Coll Cardiol. 2017;69(15):1952 – 67.

These molecular events are strongly interconnected and contribute to vascular and cardiac dysfunction in elderly patients. A thorough understanding of these complex processes may offer pharmaceutical targets to

improve human health during aging. CV ¼ cardiovascular; CVD ¼ cardiovascular disease; eNOS ¼ endothelial nitric oxide synthase; NADPH ¼ nicotinamide adenine dinucleotide phosphate; SIRT1 ¼ sirtuin 1; VSMC ¼ vascular

smooth muscle cell.

Each cell division shortens telomeric DNA until, at a critical length, the cells lose setting of CVD. Leukocyte telomere length (LTL) associates signi fi cantly with

capping function at the chromosomal ends, activating DNA damage checkpoints, vascular cell senescence, aortic valve stenosis, CV risk factors (i.e., hypertension,

cell senescence, and eventually apoptosis. Telomere shortening has particular type 2 diabetes, obesity, and smoking), and risk of atherothrombotic events.

relevance in the However, the causality of

JACCVOL.69,NO.15,2017 Paneni et al. 1959

APRIL18,2017:1952–67 The Aging Cardiovascular System

these associations remains uncertain (77) . Patients with clinical and subclinical sarcoplasmic reticulum calcium, as well as calcium release-induced I Ca calcium

features of atherosclerosis display reduced LTL compared with healthy controls, channel inactivation (84) . These changes dampen mechanical ef fi ciency and

even after adjustment for relevant confounders, such as age, sex, and race (78) . In electrophysiological properties, and increase the risk of arrhythmias (i.e., atrial fi brillation)

a recent case-control study, individuals with shorter LTL had a higher presence of in the older population.

ischemic (OR: 1.37; 95% con-

fi dence interval [CI]: 1.06 to 1.77) and hemorrhagic stroke (OR: 1.48; 95%CI: 1.08 MITOCHONDRIAL OXIDATIVE STRESS. Mitochondrial overproduction of ROS likely

to 2.02) as comparedwith the highest tertile of telomere length (79) . Moreover, contributes to cellular senescence (9) . This process ultimately leads to formation of

patients with reduced LTL had a signi fi cantly increased risk for both incident plaque the highly reactive products O 2 or H 2 O 2,

(hazard ratio:

whose accumulation and diffusion fosters senescence, DNA mutations, in fl ammation,

1.49; 95% CI: 1.09 to 2.03) and plaque progression (hazard ratio: 1.61; 95% CI: and multiple cell death pathways ( Central Illustration ) ( 82) . The mitochondrial

1.26 to 2.07) (80) . A recent meta-analysis, including prospective and retrospective

studies on the association between LTL and CHD (43,725 participants of whom adaptor p66 Shc gained

8,400 had CVD), revealed that patients with the shortest LTL had a higher relative increasing attention due to its pivotal role in ROS generation and cellular apoptosis

risk (RR) for CHD (RR: 1.54; 95%CI: 1.30 to 1.83) and cerebrovascular disease ( Central Illustration )

(RR: 1.42; 95% CI: 1.11 to 1.81) (81) . (83) . Cells lacking the p66 Shc gene have reduced intracellular free radicals, and
mice lacking p66 Shc

exposed to high oxidative stress have diminished systemic and intracellular ROS (83)

. Additionally, genetic deletion of p66 Shc in the mouse extended lifespan by 30% (84)

Critical aspects associated with cellular senescence include age-dependent . Age-dependent alteration of

defects of adrenergic

signaling and calcium handling. Plasma levels of norepinephrine signi fi cantly p66 Shc signaling profoundly affects CV homeostasis. Indeed, deletion of p66 Shc in

increase with age, as the result of reduced plasma clearance and increased mice protects from systemic and cerebral age-dependent endothelial dysfunction by

spillover from the tissues (81) . A reduction of the catecholamine reuptake virtue of decreased ROS production and conserved NO bioavailability (83,85,86) .

transporter localized in sympathetic nerve terminals also contributes to elevated Our own recent work also underscored the relevance of this gene in the

catecholamine concentrations with aging. Together, these alterations progressively pathogenesis of stroke.

impair adrenergic responsiveness, resulting in b- adrenergic desensitization. This

phenomenon ultimately reduces the number, af fi nity, and internalization of In fact,

p66 Shc- de fi cient mice display decreased ROS production in the brain, and have

reduced stroke size following ischemia-reperfusion brain injury (87) . We further

demonstrated that even post-ischemic in vivo silencing of p66 Shc prevents

ischemia-reperfusion brain injury in mice, mainly through preservation of

b- adrenergic receptors (namely the b 1-adrenergic receptor subtype), coupled with blood-brain barrier integrity (88) . The observation that p66 Shc expression increases

abnormalities in membrane adenylate cyclase activity or cellular production of cyclic signi fi cantly in stroke patients and correlates with neurological deficits supports the

adenosine monophosphate (82) . Such defects of autonomic modulation favor clinical relevance of these experimental fi ndings (88) . Expression of p66 Shc also

chronotropic incompetence and reduced inotropic reserve of the LV, thus affecting increases in peripheral blood mononuclear cells (PBMCs) of patients with acute

exercise tolerance. coronary syndrome and type 2 diabetes (89,90) . The activation of this protein by

several CV risk factors, such as hyperglycemia, oxidized low-density lipoprotein,

smoking, and hypertension, further supports its contribution to clinical CVD (9,83) .

Reduction of calcium reuptake by the myocardial sarcoplasmic reticulum Taken together, experimental and clinical data strongly indicate p66 Shc as a

calcium adenosine triphosphatase (SERCA2a) is another key feature of potential therapeutic target in the setting of age-related CVD ( Figure 2 ).

cardiomyocyte aging, yielding impaired early diastolic LV fi lling and a compensatory

increase in atrial contraction (83) . Calcium transient amplitude decreases gradually

with age, being 3.2-fold smaller in myocytes from patients $75 years of age than in

those younger than 55 years of age (84) . An age-related delay in propagation of the

calcium transient from the sarcolemma to the cell center may also occur (84) .

Moreover, aged myocytes have reduced SERCA2 expression,

The Activated Protein-1 (AP-1) transcription factor JunD has emerged as a

mediator of oxidative stress in aging ( Figure 2 ). Dimeric complexes from 3 main

limiting the amount of releasable

1960 Paneni et al. JACCVOL.69,NO.15,2017

The Aging Cardiovascular System APRIL18,2017:1952–67

families of DNA-binding proteins (Jun, Fos, and ATF/CREB) assemble to form AP-1 regulator of p66 Shc transcription, controlling acetylation of histone H3 bound to the p66

transcription factors with activities that depend critically on their speci fi c Shc promoter (102) . Impaired SIRT1 activity also favors acetylation of NF- k B p65,

components and the cellular microenvironment (91) . JunD regulates cell growth and leading to its nuclear translocation and transcription of in fl ammatory genes, as

survival, and protects cells against oxidative stress by modulating genes involved in described earlier (103) . Moreover, SIRT1 represses detrimental pathways of arterial

antioxidant defense and ROS production (92) . We recently reported that JunD falls aging, such as Forkhead box O (FOXO) 1, 3, and 4, thus preventing DNA damage,

during aging both in the mouse aorta and in PBMCs from old as compared with cell cycle arrest, and oxidative stress (104) . SIRT1 deacetylates LKB1, leading to

young, healthy humans activation of the fi nal effector enzyme 5 0 adenosine monophosphate-activated

protein kinase, a central energy regulator involved in glucose homeostasis,

maintenance of cellular adenosine triphosphate levels, and endothelial integrity via

regulation of eNOS activity and autophagy ( Figure 2 ) ( 105) .

(93) . Young mice lacking JunD display premature endothelial dysfunction and

vascular senescence similar to aged wild-type mice (93) . Aortas from

JunD / mice have augmentation of the aging markers p53 and p16 INK4a, reduced

telomerase activity, and mitochondrial DNA damage. By contrast, in vivo

overexpression of JunD rescues vascular aging features in old mice (93) .

Mechanistic experiments revealed that age-associated reductions in JunD cause an Klotho has also emerged as an important antiaging gene (106) . Klotho protein

imbalance between oxidant (NADPH oxidase) and scavenger enzymes (namely, functions as a circulating hormone that binds to a cell-surface receptor, and

manganese superoxide dismutase and aldehyde dehydrogenase represses intracellular signals of insulin and insulinlike growth factor 1, key

molecules preserving longevity (107) . Genetic deletion of Klotho in mice associates

with premature aging features, including vascular calci fi cation, altered

calcium/phosphate metabolism, and reduced lifespan (108) . By contrast,

2), leading to early redox changes, mitochondrial dysfunction, and vascular

senescence (93) . In accord with our fi ndings, lack of JunD promotes pressure

overload-induced apoptosis of myocytes, hypertrophic growth, and angiogenesis in

the heart (94) . Ongoing screening of chemical libraries aim to identify compounds Klotho overexpression prolongs lifespan in mice and protects against age-related

capable of restoring JunD activity in the vasculature and the heart. CV and renal impairment

(109) . Of clinical relevance, higher plasma Klotho levels associate independently

with a lower likelihood of CVD in humans, whereas low serum Klotho

concentrations independently predict coronary artery disease and arterial stiffness (106)

The family of nicotinamide adenine dinucleotidedependent proteins termed . Validation of Klotho as a clinically useful biomarker and a therapeutic target to

sirtuins have an established role in human aging ( Figure 2 ) ( 9) . A recent study found counteract age-related CVD requires further study.

that endogenous SIRT1 expression in VSMCs correlated inversely with donor age (95)

. Age-related loss of SIRT1 correlated with functional de fi cits, diminished stress

response, reduced capacity for migration/proliferation, and increased senescence

GENOMIC INSTABILITY. Accumulation of genetic damage through the course of life

likely contributes importantly to aging ( Central Illustration ). Genome alterations fall

(95) . Moreover, activation of SIRT1 may promote preservation of endothelial cell into 3 main categories: 1) chemical damage to genomic DNA; 2) mutations (e.g.,

function during aging. Hypercholesterolemic mice with endothelial-speci fi c SIRT1 addition, deletion, or substitution of bits of genetic code); and

overexpression or those exposed chronically to a SIRT1 activator exhibit attenuated

atherogenesis, whereas reduced SIRT1 activity results in greater foam cell

formation and atherosclerosis (96 – 98) . The observation that immunosuppressant 3) epigenetic alterations, which modify gene activity without affecting DNA

drugs (i.e., sirolimus and everolimus) cause endothelial senescence via SIRT1 sequence. To cope with genetic lesions, organisms have evolved highly pro fi-

inhibition supports these results (99) . SIRT1 blockade also impairs eNOS

functionality, whereas its activation improves endothelial NO availability (100) . cient DNA repair systems that can, in most cases, restore the correct base pair

Moreover, microRNA-217, an endogenous SIRT1 inhibitor, triggers endothelial sequence (110) . Defects in DNA repair nonetheless occur, and can contribute to

senescence by suppressing SIRT1-dependent eNOS functionality cellular senescence and organ dysfunction (111) . Genomic instability particularly

affects the CV system

(112) . Hutchinson – Gilford progeria syndrome, characterized by massive nuclear

DNA damage, associates with premature atherosclerosis and CVD, which lead to

fatal MI or stroke by an average age of 13 years

(101) . Recent work identi fi ed SIRT1 as a master

JACCVOL.69,NO.15,2017 Paneni et al. 1961

APRIL18,2017:1952–67 The Aging Cardiovascular System

(113) . Similarly, mice with genomic instability resulting from defective nucleotide epigenetic modi fi cations caused by environmental stimuli can be inherited, thus

excision repair genes contributing to early senescent traits and CVD in young adults (121) . Chromatin

ERCC1 and XPD recapitulate aging features, such as endothelial cell senescence, modi fi cations include DNA methylation and post-translational histone modi fi cations

vascular stiffness, and hypertension, at a very young age (114) . CV aging in this ( Central Illustration ). DNA methylation, which involves the addition of a methyl group

setting results mostly from eNOS and sirtuin deregulation, as well as augmented to DNA nucleotides, represses gene transcription by affecting chromatin

NADPH oxidase accessibility to the transcriptional machinery. DNA methylation progressively

decreases with age in mice and humans, whereas the rate of demethylation

(114) . associates inversely with age (122,123) . Large-scale analysis revealed

Beyond genetic diseases, a growing body of evidence indicates that sporadic unmethylated or partially methylated CpG islands in atherosclerotic plaques and

genomic mutations accumulated across the lifetime represent a major underpinning leukocytes from both patients and atherosclerosis-prone mice (124) . Changes in

of CVD (115) . Several studies have shown the presence of DNA damage in both DNA methylation localize at the promoters of several genes, including NOS,

circulating cells of patients with atherosclerosis and in the plaques themselves (116) estrogen receptors, collagen type XV alpha 1 (COL15A1), and the vascular

. PBMCs from patients with CHD have chromosomal damage and mitochondrial endothelial growth factor receptor (VEGFR). Hence, aberrant DNA methylation

DNA deletions that correlate with disease severity (117) . Similarly, data from the during the lifetime results in altered transcription of critical regulatory genes for the

AortaGen Consortium showed that genetic variation in the nucleotide excision induction of proatherogenic and senescent cellular functions (125) . Together with

repair components (namely, a single-nucleotide polymorphism [rs2029298] in the DNA-related changes,

promoter region of the DNA damage-binding protein 2 [ DDB2] gene) associated

strongly with carotid-femoral pulse wave velocity

(114) . Genomic instability in senescent VSMCs increases phosphodiesterase type post-

1 (PDE1) expression, with subsequent impairment of NO/cyclic guanosine translational histone modi fi cations, among them methylation, acetylation,

monophosphate signaling and endothelial dysfunction. Human genetic studies ubiquitination, and phosphorylation, may cluster in different patterns to regulate

consistently reveal signi fi cant associations of PDE1A single-nucleotide chromatin architecture. Histone methylation may result in different chromatin states,

polymorphisms with diastolic blood pressure and carotid intima-media thickness (118) depending on the methylated residue and the number of methyl groups added (120) .

. Overall, extensive evidence shows that genomic damage accompanies CV aging. Methylation marks on histone H3 regulate lifespan, as well as vascular homeostasis

With age, humans can accumulate somatic mutations that give rise to

hematopoietic clones associated not only with myelodysplastic syndromes and

hematologic malignancies, but surprisingly, even more strongly with CV risk (119) .

Future research in this area should unveil new interventions aimed at preserving (126,127) . For example, histone methylation by the mammalian methyltransferase

genome stability to alleviate age-related CVD. Set7 regulates endothelial NF- k B signaling, a pivotal modulator of in fl ammation and

longevity (128,129) . In addition, methylation by Set7 fundamentally regulates key

lifespan determinants heavily involved in the modulation of CV homeostasis,

namely SIRT1, FoxO3, and p53 (130) . Set7 expression increases in PBMCs of

patients with type 2 diabetes, and signi fi cantly correlates with NF- k B – mediated in fl ammation,

oxidative stress, and endothelial dysfunction, supporting the clinical relevance of

these observations (131) . Histone deacetylation by SIRT1 may also in fl uence

age-related CV disease. Transgenic overexpression of SIRT1 improves metabolic

CHROMATIN MODIFICATIONS. Although many studies have focused on the genes that ef fi ciency and endothelial function in aged mice (103) . SIRT6 can prevent

in fl uence aging, nongenomic regulation of aging has gained increasing attention. endothelial dysfunction and atherosclerosis by epigenetic modulation of multiple

Growing evidence suggests that epigenetic modi fi cations can derail transcriptional atherosclerosis-related genes, including the proatherogenic gene, tumor necrosis

programs implicated in oxidative stress, in fl ammation, angiogenesis, and cellular factor superfamily member 4 ( TNFSF4) ( 132) . These results shed light on how

chromatin modi fi cations may regulate aging-related features, and identify

metabolism, thus fostering maladaptive pathways and features of vascular aging ( Central

Illustration ) ( 120) . Epigenetic modi fi cations acquired during life appear durable and

relatively stable, thus providing a molecular framework through which the

environment interacts with the genome to alter gene expression.

Indeed,
1962 Paneni et al.
The Aging Cardiovascular System
reversal of epigenetic modi fi cations as an attractive therapeutic target.
AGE-ASSOCIATED DEFECTS IN VASCULAR REPAIR
IMPAIRMENT OF ANGIOGENESIS. Elderly individuals not only have increased
incidence of stroke, peripheral artery disease, and MI, but also display worsened
outcomes than younger patients. Aged patients with acute limb ischemia have
higher mortality and an increased rate of limb amputation (133) . Moreover, about
35% to 40% of elderly patients experience inadequate myocardial reperfusion
post-MI, eventually leading to adverse LV remodeling, heart failure, and CV death (134) of antioxidant enzymes also produces senescent cell changes. Early endothelial
. Available evidence strongly indicates an association of aging with several defects
in angiogenesis. Elderly men display reduced capillary density, which is associated
with microvascular disease, defective eNOS functionality, and impaired insulin
sensitivity (135) . Furthermore, senescent endothelial cells have lower proliferative
capacity, decreased telomerase activity, and reduced production of angiogenic
growth factors, such as VEGF-A. Endothelial migration is also impaired, leading to
reduced tube formation (133) . Reduced hypoxiainducible factor 1 a ( HIF1 a) activity,
mainly due to increased degradation and reduced nuclear translocation by importin a,
signi fi cantly contributes to age-related impairment of
angiogenesis after
ischemia. Interestingly, adenoviral delivery of a constitutively active form of HIF1 a improved
neovascularization and rest pain in patients with critical limb ischemia, whereas it
failed to improve walking performance in patients with intermittent claudication (136,137)
. The activity of PGC-1 a, an emerging transcriptional coactivator that plays an
essential role in hypoxia-driven angiogenesis, also declines with age (133) .
Dysregulation of angiogenic pathways is associated with an age-dependent
reduction in the number and functionality of stem and progenitor cells (i.e.,
circulating angiogenic cells [CACs] and bone marrow [BM]-derived cells) (133) .
Understanding how aging deteriorates stem cell functionality is of paramount
importance to develop new therapeutic approaches in this area.
MECHANISMS OF STEM CELL AGING. Recent data obtained in hematopoietic stem
cells (HSCs) indicate that, by the age of 70 years, clonal diversity collapses,
resulting in the dominance of 1 HSC clone (138) . Such collapse of highly polyclonal
into quasi-monotypic hematopoiesis may in fl uence stem cell competency during
ischemia or infarction. In addition, several
JACCVOL.69,NO.15,2017
APRIL18,2017:1952–67
studies have documented a reduced number of BMderived cells and CACs in aged
patients, as well as in subjects exposed to modi fi able CV risk factors
(139) . Features of senescence, such as telomere shortening, genomic instability,
and subsequent cell cycle arrest, accompany this reduced cell number
(140) ( Figure 3 ). Kushner et al. (141) showed an approximately 60% decline in
telomerase activity in CACs of older men (56 to 67 years of age). Overexpression of
human telomerase reverse transcriptase in CACs preserved telomerase activity,
delayed cell senescence, and improved age-related CAC dysfunction in mice with
ischemic hind limbs (142) . Increased production of ROS and decreased expression
progenitor cells (EPCs) from elderly subjects show reduced activity of the
antioxidant enzyme glutathione peroxidase-1 in association with enhanced cell
apoptosis (143) . Increased angiotensin II may also stimulate ROS production and
cellular senescence in early EPCs
(144) . The mobilization of progenitor cells from the BM, and their homing and
engraftment depend upon a number of angiogenic factors, SDF1/CXCR4
interaction, and VEGF (145) . We recently showed profound dysregulation of the
aging and longevity genes p66 Shc
and JunD in old (as compared with young) EPCs, promoting mitochondrial oxidative
stress and impairing SDF-1 secretion (146) . This study indicates that altered gene
expression trajectories during life strongly affect stem and progenitor cell functions.
ROLE OF EPIGENETICS. Time-dependent accumulation of adverse epigenetic modi fi cations
has emerged as a potential underpinning of stem cell dysfunction in aging ( Figure 3 ).
Transfer of epigenetic information (i.e., noncoding RNAs [ncRNAs]), which may
occur either by direct cell-to-cell contact or from the bloodstream into the cell, may
strongly in fl uence phenotype and cell fate decisions (139) . More recent studies
showed that extracellular vesicles, including microparticles, exosomes, and
apoptotic bodies, can mediate intercellular communication of BM-derived cells with
other cell types, with modi fi cation of the transcriptional pro fi le mediated by ncRNAs (147)
. MicroRNA pro fi ling in BM cells from young and aged mice revealed that miR-10A*
and miR-21, and their common target gene Hmga2, can drive EPC senescence (148)
. Suppression of those microRNAs in aged EPCs increased Hmga2 expression and
blunted expression of the senescence genes p16 INK4a/ p19 ARF,
thus ameliorating angiogenic properties. In another study, miR-34a induced EPC
senescence by suppressing SIRT1 (149) . These novel data illustrate how
JACCVOL.69,NO.15,2017 Paneni et al. 1963

APRIL18,2017:1952–67 The Aging Cardiovascular System

FIGURE 3 Features of Age-Related Stem Cell Dysfunction and Approaches to Boost Their Therapeutic Potential in Elderly Patients With CVD

elderly patient with

CVD (MI, HF)
epigenetic changes
“ Dysfunctional
BM-derived cells ” genomic instability

clonal diversity

telomere shortening

oxidative stress
“aged” bone marrow
inflammation

ex-vivo reprogramming in situ reprogramming

(epigenetic signals, gene therapy) (cardiomyocyte dedifferentiation, stimulation
of endogenous CSC)

intracoronary stem cell reinfusion

Future strategies to ameliorate the ef fi ciency of autologous transplantation may include ex vivo reprogramming of maladaptive pathways, in situ reprogramming by stimulating

cardiomyocyte dedifferentiation, or in situ stimulation of endogenous cardiac stem cells. BM ¼ bone marrow; CSC ¼ cardiac stem cell; CVD ¼ cardiovascular disease; HF ¼ heart failure;

MI ¼ myocardial infarction.

editing the epigenetic landscape of aged EPCs can furnish a novel the SWISS AMI trial (Swiss Multicenter Intracoronary Stem Cells Study in Acute

mechanism-based approach to promoting vascular repair in elderly patients with Myocardial Infarction), which recruited a similar number of patients, treatment with

CVD. BM-derived mononuclear cells for either 5 to 7 days or 3 to 4 weeks after acute MI

failed to improve LV function (assessed by cardiac magnetic resonance imaging) at

STEM CELL – BASED THERAPIES. Available evidence on the CV effects of stem 12 months (152) . Furthermore, a very recent meta-analysis in patients with

cell-based therapies is overall very dif fi cult to interpret due to heterogeneous refractory angina showed that cell-based therapy improves anginal episodes,

populations, and different technical

approaches. The ACCRUE study (meta-Analysis of Cell-based CaRdiac stUdiEs),

which included randomized trials in patients with a recent acute MI, revealed that reduces the use of

intracoronary cell therapy provided no bene fi t, in terms of clinical events or changes antianginal medications, ameliorates exercise tolerance and myocardial perfusion,

in LV function (150) . However, the PreSERVE-AMI trial (A Prospective Randomized and reduces the risk of major adverse cardiac events and arrhythmias compared

Double Blind Placebo Controlled Phase II Trial of Intra-coronary Infusion of with maximal medical therapy (153) . The explanation behind these con fl icting and

AMR-001, a Bone Marrow Derived Autologous CD34 þ highly debated results lies in the fact that, in most cases,

“ aged ” BM cells, which have already traveled down the aforementioned senescence

Selected Cell Product, in Patients With Acute pathways, are reinfused. Moreover, the older recipient organ presents a diseased

Myocardial Infarction), the largest study of cell-based therapy for ST-segment milieu whereby activation of several pathophysiological pathways may hamper the

elevation MI completed in the United States, showed that intracoronary infusion of healing potential of stem cells. In this regard, new-generation approaches should

autologous CD34 þ cells in patients with ischemic LV dysfunction may exert include identi fi cation of competent cells from the BM aspirate, as well as ex vivo

favorable, albeit small, cell dose-dependent effect on LV ejection fraction, infarct reprogramming of maladaptive pathways and

size, and survival after discharge (151) . By contrast, in

1964 Paneni et al. JACCVOL.69,NO.15,2017

The Aging Cardiovascular System APRIL18,2017:1952–67

epigenetic signals. Of clinical relevance, the growing understanding of chromatin JunD, and SIRT1, have gained increasing attention due to their involvement in

architecture and metabolism has led to the design of speci fi c compounds (some essential pathways regulating ROS production and/or scavenging and proin fl ammatory

already approved by the Food and Drug Administration and tested in clinical trials) cytokines. Indeed, the SIRT1 activator SRT2104 has already undergone clinical

that can modulate epigenetic modi fi cations, and thereby restore gene expression. study

(157) . These more targeted and selective interventions merit attention, given the

disappointments encountered with the application of blunt approaches to limit

oxidative stress in humans. Recent clinical trials have shown that therapeutic
CONCLUSIONS AND FUTURE PERSPECTIVES
targeting of oxidative stress using ROS scavengers not only lacks ef fi cacy, but can

even prove harmful (82) . Ultimately, from a lifestyle perspective, regimens such as
More than 2 decades of dedicated research have
caloric restriction or regular endurance exercise may attenuate signs of vascular
fi rmly established the concept that increased oxidative stress and in fl ammation
aging by increasing SIRT1 levels, PGC-1 a – dependent mitochondrial biogenesis,
promote CV aging. However, generalized antioxidant supplementation, including
eNOS functionality, and antioxidant response via enhanced activity of the
vitamin E and b- carotene, failed to reduce CV events in asymptomatic individuals,
transcription factor Nfr-2 (41,158) . Translation of the basic and clinical science
as well as in patients at high CV risk (154,155) . Anti-in fl ammatory interventions,
reviewed here should prepare us better to confront the burden of CVD in our
such as anti-TNF a treatments, did not demonstrate bene fi cial effects on morbidity
growing older population.
and mortality in patients with chronic heart failure

(156) . Despite these disappointing results, emerging innovative strategies that

target ROS, either by inhibiting speci fi c pro-oxidant enzymes or by augmenting

endogenous antioxidants, have yielded some promising preclinical results. Other

efforts seek to develop selective anti-in fl ammatory agents that might reduce CVD

without disturbing metabolic homeostasis. New molecular targets, such as p66 Shc, ADDRESS FOR CORRESPONDENCE: Prof. Giovanni G. Camici, Center for Molecular

Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Zurich,

Switzerland. E-mail: giovanni.camici@uzh.ch .

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KEY WORDS arterial stiffness, endothelium, epigenetics,
and secretion from circulating CD34 þ and CD14 þ PBMCs: role for
stem cells