Blok Jantung KELOMPOK 2 A

MAKALAH GANGGUAN BLOK JANTUNG
Disusun untuk memenuhi tugas mata kuliah

KEPERAWATAN GAWAT DARAURAT
Yang dibina oleh Ns. Cipto Susilo, S.Pd., S.Kep., M.Kep.
Oleh :
1. Nike Chandra Bella 1711011013

2. Satriyo Handoko 1711011015
3. Larasati Cahya V 1711011018
4. Trisetya Mustikawati 1711011019
5. Dwi Indri Aini 1711011022
6. Ajeng Ratu Pramestim 1711011027
7. Ilma Sakinah 1711011038
8. Sherly Silviani A.P 1711011041
9. Lubbul Fuad Al-Fathoni 1611011028
KELAS 6-A
UNIVERSITAS MUHAMMADIYAH JEMBER
FAKULTAS ILMU KESEHATAN
PROGRAM STUDI S1 ILMU KEPERAWATAN
2020
KATA PENGANTAR
Puji dan syukur kehadirat Tuhan Yang Maha Esa atas limpahan rahmat
dan karunia-Nya sehingga kami dapat menyelesaikan makalah yang berjudul
“Gangguan Blok Jantung”. Keberhasilan dalam pembuatan makalah ini juga tidak
lepas dari bantuan dan bimbingan dari berbagai pihak, untuk itu kami ucapkan
terimakasih.
Kami berharap semoga dengan adanya makalah ini dapat berguna bagi
orang yang membacanya. Kami sadar bahwa dalam pembuatan makalah ini belum
sempurna, untuk itu penulis mengharapkan saran dan kritik yang bersifat
membangun. Serta semoga makalah ini tercatat menjadi motivator bagi penulis
untuk penulisan makalah yang lebih baik dan bermanfaat.
Jember, 28 Maret 2020
Penulis
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DAFTAR ISI
COVER .................................................................................................. 1
KATA PENGANTAR ........................................................................... 2
DAFTAR ISI .......................................................................................... 3
BAB I PENDAHULUAN ..................................................................... 5
A Latar Belakang ............................................................................. 5
B Rumusan Masalah ........................................................................ 5

C Tujuan .......................................................................................... 6
BAB II TINJAUAN PUSTAKA .......................................................... 7
A. Anatomi ....................................................................................... 7
B. Difinisi ........................................................................................ 10
C. Etiologi ....................................................................................... 11
D. Manifestasi klinis ........................................................................ 12
E. Patofisiologis .............................................................................. 13
F. Pathway ...................................................................................... 14
G. Pemeriksaan Penunjang .............................................................. 15
H. Penatalaksanaan ......................................................................... 16
BAB III ASUHAN KEPERAWATAN .............................................. 19
A Pengkajian ...................................................................................... 19
B Analisa Data.................................................................................... 23
C Diagnosis Keperawatan .................................................................. 25
D Intervensi Keperawatan ................................................................. 26
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BAB IV PENUTUP .............................................................................. 29
A Kesimpulan .................................................................................. 29
DAFTAR PUSTAKA ........................................................................... 30
LAMPIRAN........................................................................................... 31
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BAB I
PENDAHULUAN
A. Latar belakang
Gangguan konduksi jantung adalah gangguan yang terjadi pada sistem
konduksi jantung sehingga aliran listrik jantung tidak berjalan lancar atau
berhenti di tengah jalan. Sistem konduksi jantung terdiri atas SA node, AV
node, berkas His, Bundle Branch, dan serabut purkinje. AV block
merupakan salah satu kondisi gangguan konduksi jantung yang terjadi jika
jalur SA node ke AV node terhambat. Waktu yang dibutuhkan impuls
listrik untuk menjalar dari atrium sampai ventrikel akan terekam di EKG
sebagai interval PR. Jika aliran ini terhambat, maka interval PR menjadi
lebih panjang. Interval PR yang normal berkisar antara 0,12-0,20 detik.
Berdasarkan pemeriksaan EKG, AV block dibedakan menjadi 3 yaitu AV
block tingkat 1, AV Block tingkat 2, dan AV Block tingkat 3 (total AV
block).
AV Block derajat 1 memiliki interval PR memanjang lebih dari 0,2
detik. Pada AV block derajat 2, terjadi kegagalan impuls dari atrium untuk
mencapai ventrikel secara intermitten sehingga denyut ventrikel
berkurang, sedangkan total AV block merupakan keadaan darurat jantung
yang membutuhkan penanganan segera. Block ini biasanya merupakan
perkembangan dari block 1 atau 2, namun bisa juga terjadi tanpa block
parsial sebelumnya. Pada keadaan ini, terjadi blok total di nodus AV
sehingga impuls dari atrium sama sekali tidak dapat sampai ke ventrikel.
Ventrikel akan berdenyut sendiri dari impuls yang berasal dari dirinya
sendiri.
B. Rumusan masalah
1. Apa anatomi dari Jantung ?
2. Apa difinisi dari gangguan blok jantung ?
3. Bagaimana etiologic dari gangguan blok jantung?
4. Bagaimana manifestasi klinis dari gangguan blok jantung?
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5. Bagaimana patofisiologi dari gangguan blok jantung?
6. Bagaimana Pathway dari gangguan blok jantung?
7. Bagaimana pemeriksaan dari gangguan blok jantung?
8. Bagaimana penatalaksanaan dari gangguan blok jantung?
9. Bagaimana asuhan keperawatan dari gangguan blok jantung?
C. Tujuan
1. Untuk mengetahui anatomi jantung.
2. Untuk mengetahui difinisi dari gangguan blok jantung.
3. Untuk mengetahui etiologic dari gangguan blok jantung.
4. Untuk mengetahui manifestasi klinis dari gangguan blok jantung.
5. Untuk mengetahui patofisiologi dari gangguan blok jantung.
6. Untuk mengetahui Pathway dari gangguan blok jantung.
7. Untuk mengetahui pemeriksaan penunjang dari gangguan blok
jantung.
8. Untuk mengetahui penatalaksanaan dari gangguan blok jantung.
9. Untuk mengetahui komplikasi dari gangguan blok jantung.
10. Untuk mengetahui asuhan keperawatan dari gangguan blok jantung.
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BAB II
TINJAUAN PUSTAKA
A. Anatomi Fisiologi Jantung
Jantung terdiri dari 4 ruang yaitu 2 ruang yang berdinding tipis disebut
atrium ( serambi ) dan 2 ruang yang berdinding tebal disebut ventrikel (bilik).
4 katup yaitu 2 katup antrioventrikuler ( triskupidalis dan biskupidalis ), 2
katup seminular ( pulmonal dan aorta ). 3 lapis yaitu epikardium,
miokardium, dan endocardium,
1. Selaput jantung
Jantung dilapisi oleh selaput yang disebut pericardium, yang terbagi

menjadi 2 lapisan yaitu :
a. Parikardium parietalis yaitu lapisan luar yang melekat pada tulang

dada dan selaput paru.
b. Pericardium viseralis, yaitu lapisan permukaan dari jantung itu sendiri,

dan disebut sebagai pericardium.
Diantara kedua lapisan selaput tersebut terdapat sedikit cairan pelumas

yang disebut cairan pericardium, dan berfungsi mengurangi gesekan yang
timbul akibat gerakan jantung saat memompa.
2. Dinding jantung
Dinding jantung terdiri dari 3 lapis yaitu :
a. Epikardium ataupericardium, merupakan lapisan yang paling luar dari

dinding jantung
b. Miokardium, merupakan lapisan tengah yang berotot yang paling tebal.
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c. Endocardium, merupakan lapisan yang paling dalam yang langsung
berhubungan dengan ruang-ruang jantung
3. Ruang-ruang jantung
Jantung terdiri atas 4 ruang yaitu :
a. Antrium
1) Anterium kanan berfungsi sebagai penampung darah yang

rendah oksigen dari seluruh tubuh.
2) Atrium kiri berfungsi menerima darah yang kaya oksigen dari

kedua paru. Kedua katup atrium dipisahkan oleh sekat yang
disebut septum atrium.
b. Ventrikel
1) Ventrikel kanan, menerima darah dari atrium kanan dan

dipompakan ke paru-paru melalui arteri pulmonalis.
2) Ventrikel kiri, menerima darah dari atrium kiri dan dipompakan

keseluruh tubuh melalui aorta.
4. Katup-katup jantung
a. Katup atrioventrikuler, terletak antara antrium dan ventrikel, yaitu :
1) Katup tricuspid, mempunyai 3 buah daun katup yang terletak

antara atrium kanan dan ventrikel kanan
2) Katup bicuspid atau katup mitral, mempunyai 2 buah daun

katup yang terletak antara antrium kiri dan ventrikel kiri.
b. Katup semilunar
1) Katup pulmonal, terletak pada arteri pulmonalis
2) Katup aorta, terletak pada antara ventrikel kiri dan aorta
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5. System konduksi atau hantaran
Didalam otot jantung terdapat jaringan khusus yang bias

menghantarkan aliran listrik. Jaringan tersebut mempunyai sifat-sifat
khusus yaitu :
a. Otomatisasi : kemampuan untuk menimbulkan implus secara

spontan.
b. Irama : kemampuan untuk membentuk implus yang teratur
c. Konduksi : kemampuan untuk menyalurkan implus
d. Rangsangan : kemampuan untuk bereaksi terhadap rangsangan.

System konduksi jantung terdiri dari :
1) SA Node ( Nodus Sino-Atrial )
Terletak diantara batas vena cava superiordan atrium kanan,

dan disebut sebagai pemacu alami karena secara teratur
mengeluarkan aliran listrik/implus yang kemudin
menggerakkan jantung secara otomatis. Pada keadaan
normal SA Node dapat mengeluarkan implus 60-100
kali/menit.
2) Traktur Internodal
Berfungsi menghantarkan implus dari nodur SA ke nodus

AV, traktus intermodal terdiri dari : Anterior tract, middle
tract, posterior tract.
3) Brachman Bundle
Menghantarkan implus dari nodus SA ke atrium kiri
4) AV Node ( Nodus Atrio-Ventrikuler )
Terletak didalam dinding septum atrium sebelah kanan,

tepat diatas katup tricuspid dekat muara sinus koronarius.
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Av Node berfungsi untuk menahan implus jantung selama
0,08-0,12 detik untuk memungkinkan pengisian ventrikel
selama atrium berkontraksi, selain AV node dapat
mengeluarkan implus 40-60 kali/menit
5) Bundle of HIS
Berfungsi menghantarkan implus dari AV ke system Branch

Bundle.
6) System bundle branch
Merupakan lanjutan dari “bundle of HIS” yang bercabang

menjadi 2 yaitu :
a) Right Bundle branch ( RBB/cabang kanan ) : mengirim

implus ke otot jantung ventrikel kanan.
b) Left bundle brach ( LBB/cabang kiri ) yang terbagi

menjadi 2 yaitu deviasi ke belakang ( left posterior
Vesicle ) menghantarkan implus ke endokard ventrikel
kiri bagian posterior dan inferior. Deviasi kedepan ( left
anterior vesicle ) menghantarkan implus ke endokard
ventrikel kiri bagian anterior dan superior.
(Reference terbaru)
B. Difinisi
Blok jantung adalah suatu kondisi medis berupa tersumbatnya aliran listrik
yang menyuplai jantung. Normalnya, aliran listrik jantung berasal dari ruang
jantung atas (atrium) ke ruang jantung bawah (ventrikel), dan berperan
menghasilkan denyut jantung. Pada beberapa kasus, adanya blok jantung
membuat denyut jantung terganggu sehingga organ ini tidak mampu
memompa darah ke seluruh tubuh dengan baik. Akibatnya, gejala seperti
pingsan dan kondisi yang lebih berat berupa gagal jantung dapat terjadi
AV Blok merupakan salah satu kondisi gangguan konduksi jantung yang

terjadi bila jalur SA Node ke AV Node (yang membentuk interval PR pada
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EKG) terhambat, maka Interval PR menjadi lebih panjang. Ibarat jalan tol
macet, maka jarak tempuh ke tempat tujuan menjadi lebih lama. AV Blok
dibagi menjadi 3 derajat sesuai tengan tingkat keparahan. (Lippincot,
William, 2011)
Total AV blok merupakan keadaan darurat jantung yang membutuhkan

penanganan segera. Blok biasanya berkembang dari blok derajat I dan II,
tetapi total AV blok dapat juga terjadi tanpa blok parsial sebelumnya atau
interval PR yang bisa normal segera setelah terjadi periode blok total. Letak
blok total sering diperkirakan dengan lebar kompleks QRS dan kecepatan
ventrikel. Jika terjadi distal dari His Bundle kompleks QRS biasanya melebar
dan kecepatan ventrikel biasanya > 50x/ menit.(Hidayat, 2010 ).
(Reference terbaru)
C. Etiologi
1. AV blok derajat 1
Terjadi pada semua usia dan pada jantung normal atau penyakit jantung.
PR yang memanjang lebih dari 0,2 detik dapat disebabkan oleh obat-
obatan seperti digitalis, β blocker, penghambat saluran kalsium, serta
penyakit arteri coroner, berbagai penyakit infeksi dan lesi conginetal.
2. AV blok derajat II
a. AV blok derajat II Mobitz I ( Wenckebach )
Tipe ini biasanya dihubungkan dengan blok di atas berkas His.

Demikian juga beberapa obat atau proses penyakit yang
mempengaruhi nodus AV seperti digitalis atau infark dinding inferior
dari miocard dapat menghasilkan AV Blok tipe ini.
b. AV Blok derajat III
Adanya pola Mobitz II menyatakan blok di bawah berkas His. Ini

terlihat pada infark dinding anterior miokard dan berbagai penyakit
jaringan konduksi.
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3. AV blok derajat III ( komplit )
Penyebab dari tepe ini sama dengan penyebab pada AV blok pada derajat
yang lebih kecil. Blok jantung lengkap atau derajat tiga bias terlihat
setelah IMA. Dalam irama utama ini, tidak ada koordinasi antara
kontraksi atrium dan ventrikel, karena kecepatan ventrikel sendiri sekitar
20-40 kali permenit, maka sering penderita menyajikan tanda-tanda curah
jantung yang buruk seperti hipotensi dan perfusi serebrum yang buruk
( Verdy, 2012 )
4. Peradangan jantung, misalnya demam reumatik, peradangan miokard

(miokarditis karena infeksi).
5. Gangguan sirkulasi koroner (aterosklerosis koroner atau spasme arteri

koroner), misalnya iskemia miokard, infark miokard.
(Reference terbaru)
D. Manifestasi klinis
1. Av blok sering menyebabkan bradikardia, meskipun lebih jarang

dibandingkan dengan klainan fungsi nodus SA.
2. Seperti gejala bradikardia yaitu pusing, lemas, sinkop, dan dapat

menyebabkan kematian mendadak
3. AV blok derajat I
a. Sulit dideteksi secara klinis
b. Bunyi jantung pertama bias lemah
c. Gambar EKG : PR yang memanjang lebih dari 0,2 detik.
4. AV blok derajat II
a. Deyut jantung <40x/menit
b. Pada Mobitz I tampak adanya pemanjangan interval PRhingga

kompleks QRS menghilang.
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c. Blok Mobitz tipe II merupakan aritmia yang lebih serius karena lebih
sering menyebabkan kompleks QRS menghilang. Penderita blok
Mobitz tipe II sering menderita gejala penurunan curah jantung dan
akan memerlukan atropine dalam dosis yang telah disebutkan
sebelumnya
(Reference terbaru)
5. AV blok derajat III ( komplit )
a. Atrium yang berdenyut terpisah dari ventrikel, kadang-kadang

kontraksi saat katup tricuspid sedang menutup. Darah tidak bias
keluar dari atrium dan malah mendorong kembali ke vena leher,
sehingga deyut tekanan vena jugularis (JVP) Nampak jelas seperti
gelombang “meriam (cannon)”.
b. Tampak tanda-tanda curah jantung yang buruk seperti hipotensi dan

perfusi serebrum yang buruk ( Verdy,2012)
(Reference terbaru)
Mhn disertai gambar kelianan ECG an penjelasannnya.........................???????
E. Patofisiologi
Blok jantung adalah perlambatan atau pemutusan hantaran impuls antara

atrium dan ventrikel. Impuls jantung biasanya menyebaar mulai dari nodus
sinus, mengikuti jalur intermodal menuju nodus AV dan ventrikel dalam 0,20
detik (interval PR Normal); depolarisasi ventrikel terjadi dalam waktu 0,10
detik (lama QRS kompleks). Terdapat tiga bentuk blok jantung yang berturut
– turut makin progresif. Pada blok jantung derajat satu semua impuls
dihantarkan melalui sambungan AV, tetapi waktu hantaran memanjang. Pada
blok jantung derajat dua, sebagian impuls dihantarkan ke ventrikel tetapi
beberapa impuls lainnya dihambat. Terdapat dua jenis blok jantung derajat
dua, yaitu Wnckebach (mobit I) ditandai dengan siklus berulang waktu
penghantaran AV yang memanjang progresif, yang mencapai puncaknya bila
denyut tidak dihantarkan. Jenis kedua (mobitz II) merupakan penghantaran
sebagian impuls dengan waktuhantaran AV yang tetap dan impuls yang lain
tidak dihantarkan.
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Pada blok jantung derajat tiga, tidak ada impuls yang dihantarkan ke
ventrikel, terjadi henti jantung, kecuali bila escape pacemaker dari ventrikel
ataupun sambungan atrioventrikuler mulai berfungsi. Blok berkas cabang
adalah terputusnya hantaran berkas cabang yang memperpanjang waktu
depolarisasi hingga lebih dari 0,10 detik
(Reference terbaru)
F. Pathway
?????????? Etiologi
??????????
????
Irama abdormal dari pacu jantung, pergeseran pacu jantung dari nodus sinus
ke bagian lain dari jantung, gangguan keseimbangan elektrolit dll
Perlambatan atau pemutusan hantaran implus antara atrium dan ventrikel
Depolarisasi Ventrikel lebih lama
Gagal transmisi implus Total Atrium Ventrikel Blok
Sebagian miokardum mengalami blok total

Denyut ventrikel tidak efisien Pengobatan
Curah jantung
Kurang
informasi
Hipertrofi Penurunan Kongesti pulmonal

ventrikel Defisit
suplai O2 pada
pengetahuan
otot dan Tekanan
Pemendekan jaringan hidrostatik >>
miokard Tekanan osmotic
Kelemahan
Pengisian LV otot Transisi cairan ke
menuru ruang intersisiel
Sesak nafas
Penurunan
curah
jantung Ketidakefektifan
pola nafas
14
Penjelasan woc atao algoritma????????????????
G. Pemeriksaan Penunjang
1. EKG : menunjukkan pola cedera iskemik dan gangguan konduksi.

Menyatakan tipe/sumber disritmia dan efek ketidakseimbangan elektrolit
dan obat jantung.
2. Monitor Holter : Gambaran EKG (24 jam) mungkin diperlukan untuk

menentukan dimana disritmia disebabkan oleh gejala khusus bila pasien
aktif (di rumah/kerja). Juga dapat digunakan untuk mengevaluasi fungsi
pacu jantung/efek obat antidisritmia.
3. Foto dada : Dapat menunjukkan pembesaran bayangan jantung

sehubungan dengan disfungsi ventrikel atau katup.
4. Skan pencitraan miokardia : dapat menunjukkan aea iskemik/kerusakan

miokard yang dapat mempengaruhi konduksi normal atau mengganggu
gerakan dinding dan kemampuan pompa.
5. Tes stres latihan : dapat dilakukan utnnuk mendemonstrasikan latihan

yang menyebabkan disritmia.
6. Elektrolit : Peningkatan atau penurunan kalium, kalsium dan magnesium

dapat mnenyebabkan disritmia.
7. Pemeriksaan obat : Dapat menyatakan toksisitas obat jantung, adanya obat

jalanan atau dugaan interaksi obat contoh digitalis, quinidin.
8. Pemeriksaan tiroid : peningkatan atau penururnan kadar tiroid serum dapat

menyebabkan.meningkatkan disritmia.
9. Laju sedimentasi : Penignggian dapat menunukkan proses inflamasi akut

contoh endokarditis sebagai faktor pencetus disritmia. 10. GDA/nadi
oksimetri : Hipoksemia dapat menyebabkan/mengeksaserbasi disritmia.
(Reference terbaru)
H. Penatalaksanaan
1. Terapi medis
a. Obat antiaritmia
Reseptor Klas Obat Cara kerja obat
Saluran 1A Procainamide, - Mencegah

Na+, K+ Quinidine, masuknya Na ke
Amiodarone dalam sel
Saluran 1B Lidocaine, - Menghambat

Na+ Phenitoin konduksi,
memperlambat masa
pemulihan (recovery)
dan mengurangi
kecepatan otot jantung
untuk discharge secara
spontan
- Class 1A
memperpanjang aksi
potensial
ß- 2 Esmolol, - Anti
adrenergik Metoprolol, simpatetik, mencegah
Propanolol, efek katekolamin pada
Sotalol*, aksi potensial
Amiodarone
- Termasuk
golongan ß-adrenergik
antagonis
Saluran K+ 3 Sotalol*, Memperpanjang

Bretylium, waktu aksi potensial
Ibutilide,
Dofetilide
Saluran 4 Verapamil, - Mencegah

Ca+ Diltiazem, masuknya Ca ke
Amiodarone dalam sel otot jantung
- Mengurangi
waktu plateau aksi
potensial, efektif
memperlambat
konduksi di jaringan
nodal.
b. AV blok derajat I
1) Tidak ada tindakan yang diindikasikan.
2) Interval PR harus dimonitor ketat terhadap kemungkinan blok lebih

lanjut,
3) Kemungkinan dari efek obat juga harus diketahui
c. AV blok derajat II Molitz I
1) Tidak ada tindakan yang diindikasikan. Kecuali menghentikan obat

jika ini merupakan agen pengganggu
2) Monitor klien terhadap berlanjutnya blok.
3) Tipe ini biasanya tidak diterapi kecuali sering kompleks QRS

menghilang dengan akibat gejala klinis hipotensi dan penurunan
perfusi serebrum. Bila ada gejala ini maka pada penderita bisa
diberikan 0,5 sampai 1,0 mg atropine IV sampai total 2,0 mg.
d. AV blok derajat II Molitz II
1) Observasi ketat terhadap perkembangan menjadi blok jantung derajat

III.
2) Obat seperti atropine atau isopreterenol, atau pacu jantung mungkin

diperlukan bila pasien menunjukkan gejala-gejala atau jika blok
terjadi dalam situasi IMA akut pada dinding anterior.
e. AV blok derajat III (komplit)
1) Atropin (0,5 sampai 1 mg) bisa diberikan dengan dorongan IV. Bila
tidak ada kenaikan denyut nadi dalam respon terhadap atropine maka
bisa dimulai tetesan isoproterenol 1 mg dalam 500 ml D5W dengan
tetesan keciluntuk meningkatkan kecepatan denyut ventrikel.
Penderita yang menunjukkan blok jantung derajat tiga memerlukan
pemasangan alat pacu jantung untuk menjamin curah jantung yang
mencukupi (Boswick, 1988).
2) Pacu jantung diperlukan permanen atau sementara
(Reference terbaru)
BAB III
ASUHAN KEPERAWATAN
Buat askep teori ssengan mengunakan format kritis, B1, B2.............................??????
A. PENGKAJIAN:
IDENTITAS KLIEN
Nama : Tn. P Umur : 58 th
Agama : Islam Pendidikan : SMA
Status : Kawin Pekerjaan : Wirausaha
Tgl masuk :- No reg : 657XXX
Alamat : Sumbersari, Jember
IDENTITAS PENANGGUNGJAWAB
Nama : Ny. A.
Pendidikan : SMA
Hubungan dgn klien : Istri
Alamat : Sumbersari, Jember
1. Keluhan utama:
Keluhan utama yang biasa terjadi pada pasien dengan ganggguan
blok jantung adalah jantung berdetak secara lambat dan tidak
teratur, sehingga mengganggu aliran darah.
2. Alasan masuk ICU/ICCU

Karena kondisi kesehatannya tiba-tiba memburuk atau mengalami
gangguan fungsi organ tubuh. Misalnya, mereka tidak bisa
bernapas dengan baik
3. Riwayat kesehatan:
a. Riwayat kesehatan sekarang
Keluhan utama yang biasa terjadi pada pasien dengan
ganggguan blok jantung adalah jantung berdetak secara
lambat dan tidak teratur, sehingga mengganggu aliran
darah.
b. Riwayat kesehatan dahulu
Klien mengatakan pernah mengalami penyakit jantung pada

tahun 2017 dan pernah dirawat dengan penyakit jantung dan
tidak terkontrol, klien juga ada riwayat hipertensi. Klien
mengatakan tidak ada memiliki alergi makanan maupun obat.
Klien dulunya merupakan perokok aktif dan baru berhenti
merokok 2 tahun ini.
c. Riwayat kesehatan keluarga
Klien mengatakan tidak ada keluarga yang mengalami penyakit

yang sama dengan klien.
4. Sekudery survey
a. Kepala :
Pusing, berdenyut selama tidur atau saat terbangun,
tampak perubahan ekspresi wajah seperti meringis atau
merintih, terdapat atau tidak nyeri pada rahang
b. Mata :
Kedua mata simetris, ukuran pupil ± 2 mm, konjungtiva
tampak berwarna merah muda, tidak ada terdapat
udema pada palpebra dan tidak ada peradangan pada
mata klien
c. Hidung:
Hidung tampak bersih, tidak ada pembengkakan pada
hidung klien, tidak ada terdapat perdarahan pada
20
hidung klien. Klien menggunakan oksigen nasal kanul
dengan 4 L.
d. Telinga :
Telinga bersih bentuk telinga normal
e. Leher :
Tampak distensi vena jugularis, terdapat atau tidak
nyeri pada leher
f. Dada :
1) Paru
a) Inspeksi : gerakan dinding dada sumetris kanan dan
kiri, tidak terdapat luka, warna kulit sawo
matang
b) Palpasi : Vokal fremitus simetris kiri dan kanan
c) Perkusi : Sonor
d) Palpasi : vasikular (+/+), Ronkhi (-/-)
2) Jantung :
a) Inspeksi : Ictus cordis tidak terlihat, CRT < 3 detik,
tidak ada perubahan warna kulit, nadi 101
x/i
b) Palpasi : Ictus cordis teraba di ICS ke V, tidak ada
nyeri tekan.
c) Perkusi : Batas jantung kanan atas: ICS II linea para
sternalis dextra. Batas jantung kanan
bawah: ICS IV linea para sternalis
sinistra dextra. Batas jantung kiri atas: ICS
II linea para sternalis sinistra. Batas jantung
kiri bawah: ICS IV linea medio clavicularis
sinistra.
d) Auskultasi : BJ 1, BJ 2 irama teratur dan tidak ada

suara tambahan.
i. Abdomen
1) Inspeksi : Bentuk tampak datar, simetris kiri dan
kanan, umbilikus bersih, tidak ada tampak
luka atau bekas operasi pada abdomen
klien
2) Auskultasi : Bising usus terdengar 12x/i
3) Palpasi : Tidak ada nyeri tekan, dan massa.
4) Perkusi : Timpani
j. Genetalia : Terpasang kateter jenis foley catheter
k. Kulit : Akral Dingin

l. Ekstrimitas :
Ekstremitas atas : Terpasang infus RL 21 cc/jam di

sebelah kanan dn terpasang manset tensi di sebelah kiri
Ekstremitas bawah : Tidak ada tampak udem maupun

fraktur Rentang kekuatan otot : 5
B. Analisis Data
NO DATA FOKUS ETIOLOGI PROBLEM

1. DS : Perubahan Penurunan curah
1. Klien mengatakan kontraktilitas jantung
merasakan sesak
nafas
2. Klien mengatakan
kepala pusing
3. Klien badan terasa
lemas
DO :
1. Tanda-tanda vital :
TD: 160/117 mmhg
RR: 26 x/i SpO2: 99
% N: 101 x/i S: 360C
2. Hasil foto thorax AP
terlihat adanya
pembesaran jantung
compensated
DD/posisi. Efusi
pleura sinistra.
3. Klien terpasang
monitor
4. Gambaran EKG
terdapat: SR, P wave:
0,06 , PR Interval
0,16, QRS Complex
0,08, T Inverted I,
AVL, V1- V2.
5. Valsartan 1 x 160 6.
Lasix 2 x 1 7.
23
Spironolactone 1 x 25
mg
2. DS : Hambatan upaya Ketidakefektifan
napas: nyeri saat pola nafas
1. Klien mengatakan
bernapas
merasakan sesak
nafas
2. Klien mengatakan
kepala pusing
3. Klien badan terasa

lemas
4. Klien mengatakan
batuk
DO :
1. Tanda-tanda vital :
TD: 160/117 mmHg

RR: 26 x/i SpO2: 99
% N: 101 x/i S: 36 0C
2. Klien berkeringat
dingin
3. Klien tampak
gelisah
4. Klien tampak
menggunakan otot
bantu nafas
5. Klien tampak lemas

dan sesekali batuk
24
6. Klien terpasang
oksigen 4 L
DS : klien mengatakan tidak kurang pengetahuan Defisit

3.
mengetahui tentang penyakit pengetahuan
dan pengobatannya
DO :
6. pasien menyakan
penyakitnya itu
bagaimana dan cara
pengobatannya
7. pasien tambak bigung
C. DIAGNOSA KEPERAWATAN
1. Ketidakefektifan pola nafas berhubungan dengan hambatan upaya napas

(mis: nyeri saat bernapas, kelemahan otot pernapasan)
2. Penurunan curah jantung berhubungan dengan perubahan kontraktilitas
3. Defisit pengetahuan berhubungan dengan kurang pengetahuan
25
D. Intervensi Keperawatan
Tujuan dan
Hari/Tanggal Diagnosa Intervensi Paraf
Kriteria Hasil
Penurunan Penurunan 1. Auskultasi

nadi apikal.
curah jantung curah jantung
Catat
pasien teratasi penilaian
denyut
dalam waktu
jantung dan
3x24 jam irama
jantung
Kriteria Hasil 2. Catat bunyi
jantung
3. Palpasi
1. tanda-
denyut nadi
tanda perifer
4. Pantau
vital
tekanan
dalam darah
5. Kaji kulit
rentang
terhadap
normal pucat dan
sianosis
2. Wajah 6. Kolaborasi
dengan
Tampak tenaga
rileks kesehatan
lainnya
dalam
pemberian
oksigen
tambahan
Ketidakefektifan pola nafas 1.Anjurkan

untuk posisi
pola nafas klien teratasi
semi fowler
dalam waktu 2.Ajarkan
latihan nafas
2x24 jam
dalam
3.Ciptakan
Kriteria Hasil : lingkungan
yang nyaman
1. Tanda – 4. Observasi
tanda vital tanda – tanda
26
dalam vital
batas 5. Observasi
normal pola napas
2. Tidak 6. Berikan
tampak informasi
gelisah pola napas
3. Tidak tidak efektif
mengguna 7. Kolaborasi
kan otot dengan tenaga
bantu kesehatan
pernafasan yang lain
4. Tidak dalam terapi
oksigen
terpasang
O2
Defisit pengetahuan 1. Kaji tingkat

pengetahuan pasien teratasi pengetahuan
dalam waktu klien
1x24 jam
2. berikan
kriteria hasil : informasi
dalam
1. pasien
berbagai
dan
varian proses
keluarga
pembelajaran
menyatak
an paham 3. berikan
tentang penjelasan
penyakit, tentang
kondisi faktor risiko,
dan pembatasa
program aktivitas,
pengobat obat dan
an gejala.
2. pasien
dan
keluarga
27
mampu
menjelask
an
kembali
apa yang
dijelaskan
perawat/ti
m
kesehatan
lainnya
28
BAB III
PENUTUP
A. Kesimpulan
Blok jantung adalah suatu kondisi medis berupa tersumbatnya aliran listrik
yang menyuplai jantung. Normalnya, aliran listrik jantung berasal dari ruang
jantung atas (atrium) ke ruang jantung bawah (ventrikel), dan berperan
menghasilkan denyut jantung. Pada beberapa kasus, adanya blok jantung
membuat denyut jantung terganggu sehingga organ ini tidak mampu
memompa darah ke seluruh tubuh dengan baik. Akibatnya, gejala seperti
pingsan dan kondisi yang lebih berat berupa gagal jantung dapat terjadi
Pemeriksaan penunjang terdiri dari EKG, Monitor Holter, foto thorak dan
lain-lain
29
DAFTAR PUSTAKA
Hidayat,Alimul A,.A. 2010. Metode Penelitian Kesehatan Paradigma Kuantitatif.

Jakarta:Health Books
Morton, Patricia Gonce.Et al.2011.Keperawatan Kritis. Jakarta : EGC
Penulisan dafta pustaka????????????
(Reference terbaru)
30
doi: 10.2169/internalmedicine.2563-18
Intern Med 58: 2041-2044, 2019
http://internmed.jp
【 CASE REPORT 】
Cardiac Magnetic Resonance Identified the Fibrotic Lesion

Associated with Syncope Attack Due to Complete
Atrioventricular Block in a Patient with
Hypertrophic Cardiomyopathy and Aortic Stenosis
Takayuki Kawamura, Yoshitaka Iwanaga, Takashi Nakamura, Masakazu

Yasuda, Takashi Kurita and Shunichi Miyazaki
Abstract:
An 84-year-old man presented with syncope. Prior to admission, ambulatory electrocardiogram had demon-
strated non-sustained ventricular tachycardia. Echocardiography showed severe aortic stenosis. He was also
diagnosed with hypertrophic cardiomyopathy (HCM) by cardiac magnetic resonance (CMR) showing remark-
able inhomogeneous left ventricular hypertrophy and extensive late gadolinium enhancement (LGE) in the le-
sions at the upper border and right-ventricular side of the basal-mid septal wall. Finally, he showed complete
atrioventricular (AV) block followed by a long pause and syncope several times after admission. In this case
with several possible causes of syncope, the CMR findings suggested a clue concerning the etiology of his
syncope: complete AV block in HCM.
Key words: cardiac magnetic resonance, complete atrioventricular block, hypertrophic cardiomyopathy,
late gadolinium enhancement, syncope
(Intern Med 58: 2041-2044, 2019)

(DOI: 10.2169/internalmedicine.2563-18)
2041
no history of coronary artery disease. His family history
Introduction showed a sister with pacemaker implantation, a brother with
heart failure, and a daughter with cardiac hypertrophy.
Ventricular arrhythmia is a major cause of syncope and An examination revealed a blood pressure of 135/80
sudden death in hypertrophic cardiomyopathy (HCM). Myo- mmHg and a heart rate of 84 bpm. A grade 3/6 systolic
cardial fibrosis is a pathological hallmark of HCM and is murmur was best heard in the third intercostal space, right
considered a substrate for ventricular arrhythmia. Recently, of the sternum. An electrocardiogram (ECG) showed first-
cardiac magnetic resonance (CMR) has helped visualize degree AV block with left bundle branch block.
myocardial fibrosis and scarring in vivo through late gad- Echocar- diography showed severe aortic stenosis (AS) with
olinium enhancement (LGE), and the prognostic role of the a peak velocity of 4.5 m/s and an aortic valve area of 0.72
presence of LGE has been demonstrated. However, complete 2
and 0.67 cm by the continuity equation and planimetry,
atrioventricular (AV) block in HCM is a relatively rare com- respectively (Fig. 1A and B). It also showed inhomogeneous
plication, and the details concerning the etiology are un- remarkable LV hypertrophy with a septal thickness of 26
clear (1). mm and no left ventricle outflow tract (LVOT) pressure-
gradient. The LV cavity dimensions and systolic function
Case Report were within normal limits (Fig. 1C and D). The ambulatory
ECG prior to admission showed the non-sustained ventricular
An 84-year-old man was referred to our hospital for the tachycardia (VT). CMR showed remarkable
evaluation of new-onset recurrent syncope attacks. He had inhomogeneous LV hy-
pertrophy with extensive LGE. Namely, LGE lesions
were
Division of Cardiology, Department of Internal Medicine, Kindai University Faculty of Medicine, Japan
Received: December 24, 2018; Accepted: January 23, 2019; Advance Publication by J-STAGE: March 28, 2019
Correspondence to Dr. Yoshitaka Iwanaga, yiwanaga@med.kindai.ac.jp
2042
Intern Med 58: 2041-2044, 2019 DOI: 10.2169/internalmedicine.2563-
18
Figure 　 1. 　 Standard transthoracic echocardiography. Continuous-wave Doppler measurement of

peak aortic transvalvular velocity (A), aortic valve area (AVA) by planimetry (B), parasternal long-
axis view (C), and M-mode recording at the mitral valve level (D).
Figure 　 2. 　 Cardiac MR images with late gadolinium enhancement (LGE) (A-D) and T2-weighted
images (E, F). Basal (A, E) and basal-mid short-axis images (B, F), and long-axis images (C, D). The
arrowheads indicate LGE at the upper border of the ventricular septum, the thin arrows indicate
LGE at the right-ventricular side of the basal-mid septal wall, and the thick arrows indicate the high-
signal-intensity area of T2 images.
18
Figure 　 3. 　 Continuous ECG-monitoring records when a syncope attack occurred (A, arrow). Com-
plete AV block with a ventricular pause for 19 seconds was noted (B). Representative images stained
with Hematoxylin and Eosin staining or Masson’s trichrome of myocardial tissues removed at sur-
gery (C). ECG: electrocardiogram, AV: atrioventricular
18
apparent at the upper border of the ventricular septum just aortic-valvular malfunction or LV dysfunction, including
below the membranous septum and right-ventricular side of LVOT obstruction. His clinical course has been uneventful
the basal-mid septal wall, and subsequent T2-weighted im- without syncope, VT events, or HF symptoms for six and a
aging showing high signal intensity (Fig. 2). Cardiac cathe- half years following the DDD pacemaker implantation and
terization showed no LVOT pressure gradient, and coronary surgery.
angiography showed no significant coronary stenosis. How-
ever, after admission, he presented with complete AV block Discussion
followed by long pause and syncope several times
(Fig. 3A and B). Patients with HCM frequently have arrhythmia and hemo-
He successfully underwent permanent dual-chamber dynamic abnormalities and are prone to syncope and sudden
(DDD) pacemaker implantation to prevent syncope due to death. Complex ventricular tachyarrhythmias are usually as-
complete AV block, followed by aortic valve sociated with syncope, but LVOT obstruction must be con-
replacement with septal myocardial resection for the AS and sidered as another potential cause of syncope. While appar-
HCM. His- tology showed remarkable myocardial ent LVOT obstruction was not shown by
hypertrophy and dis- array with extensive interstitial and echocardiography or catheterization in the present case, the
perivascular fibrosis (Fig. 3C). After the surgery, patient was com- plicated by severe AS and was difficult to
echocardiography showed no diagnose. Eventu-
18
18
ally, the development of complete AV block was revealed to the branching portion of the His bundle and the upper por-
be the cause of syncope. We discussed whether DDD pace- tion of the left bundle branch. CMR findings suggest that
maker or implantable cardioverter defibrillator (ICD) im- our case may correspond to these feline cases with regard to
plantation would be more appropriate in this case and ulti- histology. In addition, the findings in our case may be simi-
mately chose a DDD pacemaker because he developed syn- lar to those in cases of complete AV block occurring after
cope with complete AV block repeatedly. We therefore diag- septal myectomy or septal alcohol ablation in HCM patients.
nosed his syncope as being due to complete AV block. We However, the pathological process may instead be related to
also concluded that his non-sustained VT on ambulatory the aging phenomenon seen in elderly patients with idi-
ECG did not suggest a high risk for sudden death because opathic or primary heart block.
he lacked any other major factors indicating a high risk, Although the literature suggests that patients with HCM
such as a family history, LVOT obstruction, wall thickness may rarely develop AV block, this combination must be
30 mm, and abnormal blood response to exercise (2). considered in the differential diagnosis of syncope, as it af-
The incidence of arrhythmia in HCM is well docu- fects the approach to the treatment. During the long-term
mented (3). Life-threatening VT is associated with syncope follow-up of patients with HCM, it is prudent to be alert for
and sudden cardiac death in HCM. In contrast, reports about the development of abnormal AV conduction. When patients
AV-conduction disease are rare. However, Fananapazir et al. with HCM show bundle block, it may suggest the possible
reported an abnormal His-Purkinje conduction in 23% of development of AV block in the future. In addition,
HCM patients who survived sudden cardiac death (4). It CMR with LGE and T2-weighted imaging may be helpful for
suggests that some patients with HCM may have syncope or as- sessing the possibility of AV block development. While
sudden cardiac death related to complete AV block. The the presence of LGE by CMR is generally associated with
cause and etiology of AV block in HCM are unclear. ventricular arrhythmia and its prognosis, it may also be
Spe- cific mutations concerning AV block have not been useful for detecting conduction abnormalities.
identified in studies on genetics of HCM. Several
histopathologic reports in patients with HCM accompanied The authors state that they have no Conflict of Interest (COI).
by advanced AV conduction disorders have shown interstitial
fibrosis or myocardial necrosis in the conduction system
and abnormalities in the small intramural coronary arteries Reference
s
with thickened walls and luminal narrowing (5). Myocardial
ischemia, auto- nomic dysfunction, and an abnormal vascular 1. Yesil M, Bayata S, Susam I, Dinçkal H, Postaci N. Rare
response may also be underlying mechanisms of complete association of hypertrophic cardiomyopathy and complete
AV block. CMR facilitates the visualization of myocardial atrioventricular block with prompt disappearance of outflow
gradient after DDD pacing. Europace 1: 280-282, 1999.
fibrosis and scarring in vivo by virtue of LGE. 2. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guide-
In addition, T2-weighted imaging presents the visualiza- lines on diagnosis and management of hypertrophic cardiomyopa-
tion of edematous myocardium or inflammation in vivo, thy: the Task Force for the Diagnosis and Management of Hy-
which may be indicative of recently sustained myocyte in- pertrophic Cardiomyopathy of the European Society of Cardiology
jury in HCM (6). In the present case, CMR showed inhomo- (ESC). Eur Heart J 35: 2733-2779, 2014.
3. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ.
geneous remarkable LV hypertrophy with extensive LGE, Spectrum and prognostic significance of arrhythmias on ambula-
which was apparent in the lesions at the upper border of the tory Holter electrocardiogram in hypertrophic cardiomyopathy. J
ventricular septum and right-ventricular side of the basal- Am Coll Cardiol 45: 697-704, 2005.
mid septal wall; the former may correspond to the branching 4. Fananapazir L, Epstein SE. Hemodynamic and electrophysiologic
evaluation of patients with hypertrophic cardiomyopathy surviving
portion of the His bundle and upper portion of the left bun-
cardiac arrest. Am J Cardiol 67: 280-287, 1991.
dle branch, and the latter may correspond to the proximal 5. Rosen KL, Cameron RW, Bigham PJ, Neish SR. Hypertrophic
portion of the right bundle branch. High signal intensity on cardiomyopathy presenting with 3rd-degree atrioventricular block.
T2-weighted imaging suggested ongoing inflammation or Tex Heart Inst J 24: 372-375, 1997.
myocardial injury of the AV conduction system, leading to 6. Gommans DF, Cramer GE, Bakker J, et al. High T2-weighted
signal intensity is associated with elevated troponin T in
development of complete AV block. Interestingly, since fe-
hypertrophic cardiomyopathy. Heart 103: 293-299, 2017.
line cardiomyopathies, including HCM, are occasionally as- 7. Kaneshige T, Machida N, Itoh H, Yamane Y. The anatomical
sociated with complete AV block, Kaneshige et al. basis of complete atrioventricular block in cats with hypertrophic
examined the conduction systems histologically in 13 feline cardiomyopathy. J Comp Pathol 135: 25-31, 2006.
cases of HCM and complete AV block (7). They reported
The Internal Medicine is an Open Access journal distributed under the Creative
the anatomical basis of complete AV block, where marked
Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To
degen- eration and fibrous replacement of the AV view the details of this license, please visit (https://creativecommons.org/licenses/
conduction sys- by-nc-nd/4.0/).
tem were consistently observed in the combined regions of

18
Ⓒ 2019 The Japanese Society of Internal Medicine

Intern Med 58: 2041-2044, 2019
International Journal of Cardiology 207 (2016)
349–358
Contents lists available at ScienceDirect
International Journal of Cardiology
journa l homepage : www.elsevi er.com/ locate/ijcard
Targeted resequencing identifies TRPM4 as a major gene predisposing

to progressive familial heart block type I
Xavier Daumy a,b,c,1, Mohamed-Yassine Amarouch d,1,2, Pierre Lindenbaum a,b,c,e, Stéphanie Bonnaud
a,b,c,e
, Eric Charpentier a,b,c, Beatrice Bianchi d, Sabine Nafzger d, Estelle Baron a,b,c, Swanny Fouchard d,
Aurélie Thollet d, Florence Kyndt a,b,c,e, Julien Barc a,b,c, Solena Le Scouarnec a,b,c, Naomasa Makita f,
Hervé Le Marec a,b,c,e, Christian Dina a,b,c,e, Jean-Baptiste Gourraud a,b,c,e, Vincent Probst a,b,c,e, Hugues Abriel
⁎ , Richard Redon a,b,c,e,1, Jean-Jacques Schott a,b,c,e,⁎⁎,1
d, ,1
a
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France
b
Centre National de la Recherche Scientifique (CNRS) UMR 6291, l'institut du thorax, Nantes, France
c
Université de Nantes, l'institut du thorax, Nantes, France
d
Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland
e
Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France
f
Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
a r t i c l e i n f o a b s t r a c t
Article history: Background: Progressive cardiac conduction disease (PCCD) is one of the most common cardiac
Received 15 July 2015 conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A,
Received in revised form 5 November SCN1B, TRPM4, LMNA and GJA5.
2015 Methods and results: In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated
Accepted 1 January 2016
patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently
Available online 11 January 2016
absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise
role and im- portance in cardiac conduction and disease is still debated. One novel variant, TRPM4-p.I376T, is
Keyword
carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a
s: TRPM4
total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus
Atrio-ventricular block
only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293
PFHBI
cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4-p.I376T results in an increased
Gain-of-function mutation
current density concom- itant to an augmented TRPM4 channel expression at the cell surface.
Conclusions: This study is the first extensive NGS-based screening of TRPM4 coding variants in patients
with
PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I
and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of
the
TRPM4 ion channel.
© 2016 Published by Elsevier Ireland Ltd.
1. Introduction conduction system. It is one of the most common cardiac conduction

disturbances characterized by a progressive alteration of cardiac con-
Progressive cardiac conduction defect (PCCD) was first described duction through the His-Purkinje system with right or left bundle
in the sixties by Lenègre [1] and Lev [2] as a fibrosis process affecting branch block (RBBB or LBBB) and widening of QRS complexes, leading
the to complete atrioventricular block (AVB), syncope and sudden death.
Familial cases of PCCD have been reported with an autosomal
dominant inheritance and causally related to rare mutations in genes
⁎ Correspondence to: H. Abriel, University of Bern, Department of Clinical
Research, Murtenstrasse, 35, 3010 Bern, Switzerland.
involved in cardiac impulse propagation (SCN5A [3,4], SCN1B [5] and
⁎⁎ Correspondence to: J.-J. Schott, Inserm UMR 1087, l'institut du thorax IRT- TRPM4 [6,7]), in the structure of the nuclear lamina (LMNA [8,9]) and
UN, 8 quai in cell-to-cell communication (GJA5 [10]).
Moncousu, 44007 Nantes, France. Among these genes, TRPM4, encoding a calcium-activated cationic
E-mail address: Hugues.Abriel@dkf.unibe.ch (H. Abriel), jjschott@univ- channel that is expressed in Purkinje fibers and nodal tissue [6,7], has
nantes.fr
first been linked to progressive familial heart block type I (PFHBI) in
(J.-J. Schott).
1
These authors contributed equally to this work. two large pedigrees, respectively from South Africa [6] and Lebanon
2
Current affiliation: Materials, Natural Substances, Environment &
Modeling Laboratory, University of Sidi Mohamed Ben Abdellah- Fes,
Multidisciplinary Faculty of Taza, Taza, Morocco.
http://dx.doi.org/10.1016/j.ijcard.2016.01.052
0167-5273/© 2016 Published by Elsevier Ireland Ltd.
350 X. Daumy et al. / International Journal of Cardiology 207 (2016) 349–358
[7]. PFHBI is associated with a progressive impairment of the His Nanodrop instrument (Ther- mo Scientific). DNA integrity was
bundle branches conduction, typically starting with RBBB and then assessed by separation in a E-Gel®
left anterior hemiblock (LAHB) and that may progress to a complete 96 Agarose Gels, 1% (Life Technologies, G700801). For multiplex
AVB. QRS duration increases with time while PR and QTc intervals amplification, we used the HaloPlex™ Target Enrichment System
remain constant [11–13]. (Agilent Technologies, 1–500 kb, ILMFST, 96 reactions, G9901B),
Conduction defects in TRPM4-dependent familial cases were Protocol Version D.2 (November, 2012). We applied a custom
shown to be related to gain-of-function mutations proposed to be HaloPlex™ design enabling high-throughput sequencing of the
caused by a reduction of the deSUMOylation of TRPM4 channels and coding regions of 45 genes previously linked to cardiac arrhythmias
an impaired endocytosis resulting in stabilization and or conduction defects and/or
overexpression of mutant channels at the plasma membrane [6,7].
Since these two seminal reports, eighteen gain- or loss-of-function
variants have been identified as causing diverse forms of cardiac
conduction defects and/or Brugada syndrome [14–16].
Here, using next generation sequencing (NGS) technologies, we
report novel TRPM4 variants including one (c.T1127C; p.I376T)
segregat- ing with the third largest reported PCCD family. This
missense mutation segregates in 39 relatives of a 4-generation
pedigree and was observed to lead to gain-of-expression and
function of the mutant channel. These findings strongly support a
central role of TRPM4 in cardiac conduction and cardiac conduction
disorders.
2. Methods
2.1. Patient
phenotyping
The study was conducted according to the French guidelines for

genetic research and approved by the ethic committee of the Nantes
University Hospital. A written consent was obtained for each family
member who accepted to participate in the study.
The investigation included a physical examination with particular
attention to the cardiovascular system and a 12-lead ECG. Heart rate,
PR interval, QRS, QTc duration, P and QRS axes were measured
automat- ically at rest (Mac Vu Marquette Inc., Milwaukee, Wisconsin,
USA). Con- duction defects were defined using the conventional
classification [17,
18]. Two expert physicians, blinded to the clinical status,
independently and systematically reviewed the ECG parameters.
Because of the prevalence of minor conduction defects in the
general population and in order to decrease the risk of
misclassification, only the most obviously affected patients were
considered as affected. QRS axis was classified as normal when its
value was between −30° and +90°. PR duration shorter than 210 ms
was considered as normal. Patients were considered as affected if
they have been implanted with a pacemaker (PM) for PCCD or if
they have an ECG showing a major conduction defect (complete
AVB, complete RBBB, complete LBBB, parietal block (PB) defined as a
QRS wider than 115 ms without morphology of RBBB or LBBB, LAHB
or left posterior hemiblock (LPHB)). Given the progressive nature of
the disease, only patients older than 45 without any conduction
defect were considered as unaffected. All the other patients were
considered as undetermined and not included for the evaluation of
the ECG parameters. Cardiac morphological diseases were excluded
by echocardiography in all patients.
2.2. Targeted
sequencing
Genomic DNA was extracted from peripheral blood lymphocytes

by standard protocols. The DNA yields were assessed by
measurements using Quant-IT™ dsDNA Assay Kit, Broad Range (Life
Technologies, Q33130). The purity of the DNA was assessed by
spectrophotometry (OD 260:280 and 260:230 ratios) using a
sudden cardiac death, including 19 genes known or suspected to be the Exome Aggregation Consortium (ExAC) data (60,706 unrelated
involved in PCCD. In this study we focused solely on the relevant 19 individuals including more than 33,300 non-Finnish European
PCCD genes including SCN5A, SCN1B, TRPM4, GJA5 and LMNA that have individuals, release v1, downloaded from
already been associated with isolated cardiac conduction defects ftp://ftp.broadinstitute.org/pub/ExAC_ release).
together with GJA1, GJC1, SCN10A, NKX2-5, TBX5, SNTA1, PRKAG2, RYR2, In case of missense variants SIFT [20] and PolyPhen-2 (PPH-2) [21]
EMD, BMP2, BMPR1A, GATA4, MSX2 and TNNI3K as likely candidate were used to predict the impact of the amino acid substitutions.
genes. The targeted coding regions (exons) ± 10 bp correspond to Filter- ing was performed using Knime4Bio [22].
141 kb of genomic sequence.
Target enrichment and sequencing were performed as previously
described [19]. First, 200 ng of gDNA samples were digested in eight
different restriction reactions, each containing two restriction
enzymes, to create a library of gDNA restriction fragments. These
gDNA restriction fragments were hybridized to the HaloPlex probe
capture library. Probes are designed to hybridize and circularize
targeted DNA fragments. During the hybridization process, Illumina
sequencing motifs including index sequences were incorporated into
the targeted fragments. The circularized target DNA biotinylated
HaloPlex probe complexes were captured on magnetic streptavidin
beads. We proceeded to a liga- tion reaction of the circularized
complexes followed by an elution reaction before PCR amplification.
The amplified target DNA was purified using AMPure XP bead
(Beckman Coulter, A63881). To validate enrichment of target DNA
in each library sample by microfluidics analysis, we used the 2200
TapeStation (Agilent Technologies, G2964AA), with D1K ScreenTape
(Agilent Technologies, 5067–5361), and D1K Reagents (Agilent
Technologies, 5067–5362). We ensured that the majority of
amplicons range from 175 to 625 bp. Finally we quantified each
library by qPCR using KAPA Library Quantification Kit (Clinisciences,
KK4854). Libraries were pooled to an equimolar concentration and
DNA was then denatured with NaOH. Finally libraries pool was
diluted to a 4 pM final concentration before proceeding to 100 bp
paired-end Illumina sequencing on HiSeq.
2.3. Detection of rare coding variation in

TRPM4
Raw sequence reads were aligned to the human reference

genome (GRCh37) using BWAMEM (version 0.7.5a) after removing
sequences corresponding to Illumina adapters with Cutadapt v1.2.
GATK was used for indel realignment and base recalibration,
following GATK DNAseq Best Practices. Variants were called for each
sample separately using GATK UnifiedGenotyper (version 2.8) and
Samtools mpileup (version 0.1.19), and variants were considered for
further analyses if found by both GATK and Samtools with a
minimum quality score of 25.
Variants were considered of interest if: 1—They present a
potential pathogenicity as predicted by Variant Effect Predictor
(Ensembl). Variants were considered as having a potential functional
consequence if they were annotated with one or more of the
following SO terms for at least one RefSeq transcript:
“transcript_ablation” (SO:0001893), “splice_ donor_variant”
(SO:0001575), “splice_acceptor_variant” (SO:0001574),
“stop_gained” (SO:0001587), “frameshift_variant” (SO:0001589),
“stop_lost” (SO:0001578), “initiator_codon_variant” (SO:0001582),
“inframe_insertion” (SO:0001821), “inframe_deletion”
(SO:0001822), “missense_variant” (SO:0001583),
“transcript_amplification” (SO:0001889); 2—They were rare that is
if the minor allele frequency (MAF) was b 1% compared to the 1000
genomes phase 1 data (379 individuals of European origin,
integrated release v3, downloaded from
ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20110521), to the
NHLBI GO Exome Sequencing Project (ESP) data – Exome Variant
Server (EVS) (4300 individuals of European origin, ESP6500SI-V2 re-
lease, downloaded from http://evs.gs.washington.edu/EVS), and to
X. Daumy et al. / International Journal of Cardiology 207 35
(2016) 349–358 1
(2016) 349–358 1
2.4. Segregation the input. The beads were subsequently washed five times with 1X
analysis lysis buffer before elution with 50 μl of 2X NuPAGE sample buffer
(Invitrogen, Carlsbad, California, USA) plus
Familial segregation analyses were carried out by bidirectional 100 mM DTT at 37 °C for 30 min. These biotinylated fractions were
direct sequencing of amplified genomic DNA amplicons with analyzed as TRPM4 expressed at the cell surface. The input fractions,
variant-specific primers (forward: CCTCCATCCCTTTGGACAG; analyzed as total expression of TRPM4, were resuspended with 4X
reverse: CAGGCCAGGA AAGGTGTCTA) using the “Big Dye Terminator NuPAGE Sample Buffer plus 100 mM DTT to give a concentration of 1
v3.1 Cycle Sequencing Kit” (Applied Biosystems - Life Technologies) mg/ml and incubated at 37 °C for 30 min.
following the manufacturer's recommendations. The capillary
sequencing was performed on Applied Biosystems 3730 DNA
Analyzer using standard pro- cedures provided by Applied
Biosystems (Life Technologies).
The RefSeq NM_017636.3 transcript has been used to compare
our sequencing data.
Linkage was assessed between the variant I376K and the disease
using standard method comparing likelihood under a recombination
fraction of 50% (no linkage) and 0% (full linkage). LOD score [23]
calculation was performed with Superlink-Online SNP version 1.1
(http:// cbl-hap.cs.technion.ac.il/superlink-snp/main.php) [24].
We postulated a rare causal variant (frequency set at 1/10,000)
and dominant model with high penetrance (80%). The prevalence is
5% and therefore, the phenocopy rate is 0.0499.
A LOD score higher than 3 is considered as significant for linkage.
2.5. Cell culture and

transfection
Human embryonic kidney (HEK293) cells were cultured with

DMEM medium supplemented with 4 mM Glutamine, 10% FBS and a
cocktail of streptomycin–penicillin antibiotics. For the
electrophysiolog- ical studies, the cells were transiently transfected
with 80 ng of HA- TRPM4 WT or HA-TRPM4 p.I376T in a 35 mm dish
mixed with 4 µl of JetPEI (Polyplus transfection, Illkirch, France) and
46 μl of 150 mM NaCl. The cells were incubated for 24 h at 37 °C
with 5% CO2. All trans- fections included 400 ng of cDNA encoding
CD8 antigen as a reporter gene. Anti-CD8 beads (Dynal®, Oslo,
Norway) were used to identify transfected cells, and only CD8-
displaying cells were analyzed. Cells were used 24 h after
transfection.
For the biochemical studies, HEK 293-cells were transiently
transfected with 960 ng of either HA-TRPM4 WT, HA-TRPM4 p.I376T
variants or empty vector (pcDNA4TO) in a P100 dish (BD Falcon,
Dur- ham, North Carolina, USA) mixed with 30 μl of JetPEI (Polyplus
transfection, Illkirch, France) and 250 μl of 150 mM NaCl. The
cells were incubated for 48 h at 37 °C with 5% CO2.
2.6. Cell surface biotinylation

assay
Following 48 h of incubation, transiently transfected HEK293 cells

were treated with EZlinkTM Sulfo-NHS-SS-Biotin (Thermo Scientific,
Rockford, Illinois, USA) 0.5 mg/ml in cold 1X PBS for 15 min at 4 °C.
Sub- sequently, the cells were washed twice with 200 mM glycine in
cold 1X PBS and twice with cold 1X PBS to inactivate and remove the
excess biotin, respectively. The cells were then lysed with 1X lysis
buffer (50 mM HEPES pH 7.4; 150 mM NaCl; 1.5 mM MgCl2; 1 mM
EGTA pH 8.0; 10% Glycerol; 1% Triton X-100; 1X Complete Protease
Inhibitor Cocktail (Roche, Mannheim, Germany)) for 1 h at 4 °C. Cell
lysates were centri- fuged at 16,000 g; 4 °C for 15 min. Two
milligram of the supernatant was incubated with 50 μl Streptavidin
Sepharose High Performance beads (GE Healthcare, Uppsala,
Sweden) for 2 h at 4 °C, and the remain- ing supernatant was kept as
(2016) 349–358 1
2.7. Western blot already been associated with isolated cardiac conduction defects
experiments together with GJA1, GJC1, SCN10A, NKX2-5, TBX5, SNTA1, PRKAG2,
RYR2, EMD, BMP2, BMPR1A, GATA4, MSX2 and TNNI3K. A graphical
Protein samples were analyzed on 9% polyacrylamide gels, trans- representation of the mean coverage obtained for the 5 major genes
ferred with the TurboBlot dry blot system (Biorad, Hercules, CA, USA) is provided in Supplemental Fig. 1.
and detected with anti-TRPM4 (generated by Pineda, Berlin, When selecting only genetic variants with a potential
Germany), anti α-actin A2066 (Sigma-Aldrich, St. Louis, Missouri, pathogenicity as predicted by Variant Effect Predictor (see methods)
USA) antibodies using SNAP i.d. (Millipore, Billerica, MA, USA). The and an MAF below 1% in public databases, we identified a total of 45
anti-TRPM4 antibody was generated by Pineda (Berlin, Germany) variants in 43 patients: 11 novel variants and 34 rare variants (see
using the following peptide sequence: NH2- Supplemental Table 1). Among these variants, 13 have already been
CRDKRESDSERLKRTSQKV- CONH2. A fraction of the antisera, which associated with cardiac pathologies such as the Brugada
was subsequently used in this study, was then affinity purified. syndrome and cardiac
2.8. Cellular
electrophysiology
For patch-clamp experiments in whole-cell configuration, glass

pi- pettes (tip resistance, 1.5–3 MΩ) were filled with an intracellular
solution containing (in mM): 100 CsAsp, 20 CsCl, 4 Na2ATP, 1
MgCl2, 10
EGTA, and 10 HEPES. The pH was adjusted to 7.20 with CsOH, and
the
free Ca2+ concentration at 100 μM with CaCl2 using WEBMAXCLITE
program (http://www.stanford.edu/~cpatton/downloads.htm).
Access resistance ranges was from 3 to 5 MΩ. Extracellular solution
contained (in mM): 156 NaCl, 1.5 CaCl2, 1 MgCl2, 6 CsCl, 10
glucose and 10
HEPES. The pH was adjusted to 7.40 with NaOH. Patch-clamp
recordings
were carried-out in the whole-cell configuration at room
temperature (23–25 °C). TRPM4 currents were investigated using a
ramp protocol. The holding potential was −60 mV. The 400 ms
increasing ramp from
− 100 to +100 mV ends with a 300 ms step at + 100 mV then
300 ms at − 100 mV. A new ramp was performed every 2 s. Before
seal formation, liquid junction potential was compensated to keep
the baseline at 0 mV. Using a Digidata 1440 A analog-digital inter-
face (Axon Instruments,Inc.), currents were filtered at 5 kHz and the
sampling frequency was at 50 kHz. Current densities were obtained
by dividing the peak current recorded at −100 mV by the cell
capacitance (17 ± 2 pF and 16 ± 1 pF, respectively transfected with
WT and I376T- TRPM4 channels). Of note, capacitances and series
resistances were not compensated.
2.9. Data analysis and statistical

methods
Currents were analyzed with Clampfit software (Axon

Instruments, Inc). Data were analyzed using a combination of
pClamp10, Excel (Microsoft) and Prism (Graphpad).
Comparisons between groups were performed with impaired
two- tailed Student's t test. Data are expressed as mean + SEM. A
p-value b0.05 was considered significant.
3. Results
3.1. Mutational
screening
Ninety-five patients with PCCD were recruited through the

French National Referral Center for Sudden Cardiac Death as
previously described [25]. Nineteen genes known or suspected to be
involved in conduction defects were sequenced in these patients
using the HaloPlex™ System, resulting in a mean coverage depth
of 578 × per sample: SCN5A, SCN1B, TRPM4, GJA5 and LMNA that have
2
35
Table 1
Characteristics of identified amino acid variants in TRPM4.*
No. Patient Exon Nucleotide Amino Effect Genotype Other SIFT | PPH-2 dbSNP141 EUR_AF EVS_UAMAF AllelicFreq_NFE ECG Phenotype
Acid variant(s) in database id (1000 (%) (ExAC) (%) morphology
susceptibility genomes)
genes (%)
(2016) 349–358
X. Daumy et al. / International Journal of Cardiology 207
1.1 35 6 c.755 GNA R252H [16] missense_variant Heterozygous 0 deleterious(0.01) | rs146564314 0 0.63 0.818 RBBB type 2 AVB 2°
possibly_damaging(0.772)
1.2 36 6 c.755 GNA R252H [16] missense_variant Heterozygous 0 deleterious(0.01) | rs146564314 0 0.63 0.818 LBBB type 2 AVB 2°
1.3 37 6 c.755 GNA R252H [16] missense_variant Heterozygous 0 deleterious(0.01) | rs146564314 0 0.63 0.818 Normal type 2 AVB 2°
2 13 7 c.858 GNA T286T splice_region_variant & Heterozygous 1 (GJA5) | 0 0.00 0.001 Normal AVB 3°
synonymous_variant
3 9 9 c.1127 TNC I376T missense_variant Heterozygous 0 deleterious(0.02) | benign(0.323) 0 0.00 0 RBBB + LAHB Normal
4 4 11 c.1294 GNA A432T [7,15,16] missense_variant Heterozygous 2 (TRPM4 deleterious(0) | rs201907325 0.13 0.10 0.056 LBBB AVB 3°
and RYR2) probably_damaging(0.97)
5 24 11 c.1324 CNT R442C missense_variant Heterozygous 1 (SCN5A) deleterious(0) | rs148867331 0 0.02 0.018 RBBB + LAHB Normal
probably_damaging(0.996)
6.1 21 12 c.1682 ANC D561A [16] missense_variant Heterozygous 1 (SCN1B) tolerated(0.22) | benign(0.086) rs56355369 0.13 0.55 0.618 RBBB AVB 3°
6.2 28 12 c.1682 ANC D561A [16] missense_variant Heterozygous 1 (SCN5A) tolerated(0.22) | benign(0.086) rs56355369 0.13 0.55 0.618 RBBB AVB 3°
7 4 13 c.1744 GNA G582S [15,16] missense_variant & Heterozygous 2 (TRPM4 tolerated(0.34) | benign(0.037) rs172149856 0.13 0.10 0.060 LBBB AVB 3°
splice_region_variant and RYR2)
8.1 38 16 c.2209 GNA G737R [15] missense_variant & Heterozygous 0 tolerated(0.59) | benign(0.007) rs145847114 0.4 0.17 0.180 LBBB AVB 1° + type 2
splice_region_variant AVB 2°
8.2 39 16 c.2209 GNA G737R [15] missense_variant & Heterozygous 0 tolerated(0.59) | benign(0.007) rs145847114 0.4 0.17 0.180 RBBB + LPHB AVB 1°
splice_region_variant
9 40 17 c.2531 GNA G844D⁎ [7,16] missense_variant Homozygous 0 tolerated(0.2) | rs200038418 0.13 0.16 0.431 RBBB + LAHB AVB 2/1, 3/1
10 41 17 c.2561 ANG Q854R [15,16] missense_variant Heterozygous 0 probably_damaging(0.945)
tolerated(0.29) | benign(0.029) rs172155862 0.26 0.12 0.289 LAD type 2 AVB 2°
11 3 18 c.2674 CNT R892C missense_variant Heterozygous 3 (TNNI3K, deleterious(0) | rs147854826 0 0.10 0.081 Normal AVB 3°
SCN1B and probably_damaging(0.985)
RYR2)
12 10 18 c.2675 GNA R892H missense_variant Heterozygous 1 (SCN5A) deleterious(0.02) | benign(0.252) 0 0.00 0 RBBB + LAHB AVB 3°
13.1 42 24 c.3611 CNT P1204L [15,16] missense_variant Heterozygous 0 tolerated(0.21) | unknown(0) rs150391806 0.13 0.33 0.505 Normal AVB 3°
13.2 43 24 c.3611 CNT P1204L [15,16] missense_variant Heterozygous 0 tolerated(0.21) | unknown(0) rs150391806 0.13 0.33 0.505 RBBB + LAHB AVB 1°
RBBB: Right Bundle Branch Block; LBBB: Left Bundle Branch Block; LAHB: Left Anterior HemiBlock; LPHB: Left Posterior HemiBlock; LAD: Left Axis Deviation; AVB: AtrioVentricular Block
Variants already described in some articles are noted: [7] Liu et al., [16] Stallmeyer et al., [15] Liu et al.
⁎ The patient 40 has been identified as homozygous for this variant (G844D).
(2016) 349–358 3
Fig. 1. The TRPM4-p.I376T variant is responsible for PFHBI. (A) Distribution of rare coding variation detected among 95 patients with PCCD in the TRPM4 channel. Novel
variants are shown in red, low-frequency ones in blue. The two rare variants previously reported as causing PFHBI [6,7] are indicated in green. (B) Capillary
sequencing of the exon 9 of TRPM4 for the patient 9 confirms the presence of a novel variant resulting in the p.I376T substitution. (C) Family tree of patient 9 (the
proband, IV-5). Plus symbols (+) denotes p.I376T mutation carriers and minus symbol (−) non-carriers. ‘PM’ indicates patients implanted with a pacemaker, ‘LVNC’
stands for Left Ventricular Non-Compaction and ‘C′ indicates congenital forms of conduction defects.
(2016) 349–358 3
conduction defects (and one with Small Fiber Neuropathy; see Seven of these variants (54%) are located in the intracellular N-
Supple- mental Table 1). terminal region (Fig. 1a). Two of them – p.I376T and p.R892H – are
absent from public databases and thus considered as novel.
3.2. TRPM4 is the most frequently affected gene The TRPM4-p.I376T missense variant, which resides in the intracel-
lular N-terminal domain (Fig. 1a), was identified in the male patient
The most frequently affected gene is TRPM4, with a total of 13 9 (Fig. 1b). No other rare variant altering any other known
rare variants identified and then validated by capillary sequencing PCCD- susceptibility genes could be identified in this patient. The
(Table 1). affected
Fig. 2. The ECG profile of the proband IV-5. This patient presented with a heart rate of 69 bpm, a complete right bundle branch block and a left anterior hemiblock
enlarging the QRS complex to 170 ms. ECG was recorded at a 25 mm/s paper speed and 0,1 mV/mm signal amplitude. A premature ventricular beat can also be
observed in the first QRS complex of the precordial lead.
Table 2
Clinical data of the affected family members.
Patient no. Age at last Heart rate (bpm) PR (ms) QRS (ms) QTc (ms) ECG morphology Conduction PM (age)
clinical
IV-5 (proband) examination
32 69 160 170 474 RBBB + LAHB Normal 32 y.o.
II-1 85 63 138 126 439 RBBB Normal
III-2 60 81 170 128 439 PB Normal
III-3 50 35 200 120 336 RBBB + LAHB type 2 AVB 2° 50 y.o.
III-4 51 55 188 158 439 RBBB + LAHB Normal
IV-8 33 59 180 168 436 RBBB + LAHB Normal 31 y.o.
IV-9 25 76 170 166 504 RBBB + LAHB Normal
IV-25 40 74 200 130 434 RBBB + LAHB AVB 1°
V-16 8 45 148 398 RBBB + LAHB type 2 AVB 2° at birth
and AVB
V-18⁎ 12 35 LBBB 3° AVB 3° at birth
V-21 11 73 136 123 441 RBBB Normal
VI-1 0 62 144 90 439 RBBB + LAHB type 2 AVB 2° 8-month-old
RBBB: Right Bundle Branch Block; LAHB: Left Anterior HemiBlock; PB: Parietal Block; LBBB: Left Bundle Branch Block; AVB: AtrioVentricular Block.
⁎ This patient presented with a left ventricular non-compaction phenotype.
amino acid is located in a highly conserved region across vertebrates (90.9%) carried the TRPM4 variant versus only 1 out of 21 unaffected
as indicated by its Genomic Evolutionary Rate Profiling score [26] of family members (4.8%). The twelfth patient suffering from cardiac
4.24 (Supplemental Fig. 2). It is predicted as deleterious (0.02) by conduction disease (patient VI-1) was born in 2012 and thus was
SIFT [20] but benign (0.323) by PolyPhen-2 (PPH-2) [21]. not geno- typed given his young age. The two-point logarithm of the
The TRPM4-p.R892H variant has been identified in the patient 10, odds ratio (LOD) score was estimated at 4.1182 for this locus -
who presents with a complete AVB. We found that the same patient assuming a disease allele frequency of 0.01%, a disease penetrance of
also carries a rare missense variant in SCN5A (p.A572D), suggesting 80% and a recombination fraction of 0%. These findings indicate a
that the TRPM4-p.R892H variant alone may not be responsible for the genotype–phenotype co- segregation in an autosomal dominant
observed cardiac conduction defects. Another substitution affecting manner in this large French family affected by PFHBI. The patient III-
the same amino acid - TRPM4-p.R892C - was detected in a second pa- 2, while appearing as a phenocopy, may show conduction defects
tient (patient 3), but was also reported at an MAF below 1% in public caused by a previous anterior myocardial infarct while the patient V-
databases (Table 1). 17 (born in 1994) was still young at recruitment time (17 years
old), which may explain the absence of conductance disturbance for
3.3. Familial this variant carrier. This patient will be subjected to regular clinical
recruitment
follow-up since carrying the putative causal variant may confer
higher risk to develop PCCD with aging.
Patient nine carrying the TRPM4-p.I376T variant (patient IV-5 in
the pedigree) was diagnosed with complete RBBB and LAHB (Fig. 2)
and was implanted with a PM for conduction disorders at the age of 3.4. The p.I376T variant induces a gain-of-function of TRPM4
32. Fa- milial investigation has been undertaken for this patient, channel
indicated as the proband IV-5 on Fig. 1c.
A total of 96 family members could be identified, among which 57 To investigate the effect of the p.I376T variant on TRPM4
have been recruited (Fig. 1c). Twelve patients were diagnosed with expression levels, we performed Western blot and cell surface
conduction defects, of which six (50%) were implanted with a PM biotinylation experiments. As previously published [27], we
(Table 2). Ten of the 12 patients presented with RBBB, among which observed that the TRPM4 channel is expressed in fully and core
8 showed LAHB. The eleventh patient (V-18) exhibited an isolated glycosylated forms (Fig. 3). In the presence of the p.I376T variant, we
LBBB; the last one (III-2) PB (Table 2). observed an increased expression of these two forms at the cell
Two patients (V-16 and VI-1) exhibiting at birth 2:1 AVB with membrane (Fig. 3). The functional consequences of the p.I376T
RBBB and LAHB QRS morphology alternant with complete AVB were variant were investigated using the whole-cell configuration of the
classified as patients with a congenital AVB, as well as the patient V- patch-clamp technique. As reported by our group [28], TRPM4
18 who exhibited a permanent complete AVB with a 30 bpm currents recorded over time show two distinct phases (Fig. 4a). After
ventricular escape rhythm with a complete LBBB QRS morphology. the membrane rupture, a fast transient phase is observed; it is
This patient also met the magnetic resonance image diagnostic followed by a plateau phase in which the current amplitude is
criteria for a left ventricular non compaction while echocardiography stable (Fig. 4a). The functional characterization of the p.I376T variant
had failed to identify this phenotype (Fig. 1c). Note that the patient shows in this condition an increase of TRPM4 current densities in
IV-6 presented with minor conduction defects (QRS duration of both transient and plateau phases, (Table 4, Fig. 4b, c and d).
118 ms) and a slight left axis deviation (−14°), but was not
considered as affected following our criteria and thus was classified
as ‘unknown’.
Age at last clinical evaluation (34 ± 25 vs 22 ± 16, ns), PR (169 Table
3
±
Comparison of age at last clinical evaluation, heart rate, PR, QRS and QTc
24 ms vs 138 ± 20 ms, P b 0.001), QRS (138 ± 26 ms vs 88 ± 13 durations between affected and unaffected members of the family.
ms, P b 10−10) and QTc (438 ± 42 ms vs 417 ± 22 ms, P b 0.05)
Affected Unaffected p value
durations were higher in the affected members compared to
(affected vs
non-affected members while the heart rate was lower in the affected
unaffected)
group (61 ±
16 bpm vs 77 ± 16 bpm, P b 0.01) (Table Patients (N) 12 45
3). Age (years) 34 ± 25 24 ± 16 NS
The novel TRPM4-c.T1127C variant (TRPM4-p.I376T) was Heart rate (bpm) 61 ± 16 75 ± 17
systemat- b 0.01
PR (ms) 169 ± 24 140 ± 21 b 0.001
−10
ically assessed among family members (Fig. 1c). We were able to test QRS (ms) 138 ± 26 90 ± 13 b10
QTc (ms) 438 ± 42 415 ± 24 b 0.05
39 family members: 10 out of the 11 affected patients that we
tested
(2016) 349–358 355
Fig. 3. Expression of the WT and p.I376T TRPM4 channels. (A) Western blots showing the expression of TRPM4 at the total (left panel) and surface levels (right panel)
with white and black arrowheads representing fully glycosylated and core-glycosylated forms of TRPM4, respectively. (B) Quantification of the Western blots is shown
as relative intensity of protein bands for both fully- and core-glycosylated forms of TRPM4 in each fraction. *P b 0.05, **P b 0.01.
4. Discussion
In the present study, thirteen variants in the TRPM4 gene were with PCCD. Eleven of these variants were previously listed in at least
identified using NGS technologies upon screening of a cohort of 95 one of the used public databases. Two of them (p.A432T and
patients p.G844D) were previously reported in familial autosomal conduction
block and were shown as deleterious [7]. Five other variants
(p.R252H, p.D561A,
356 X. Daumy et al. / International Journal of Cardiology 207
(2016) 349–358
Fig. 4. Whole cell patch clamp recording for the WT and p.I376T TRPM4 channels. (A) Time course recording of the TRPM4 current. (B) Individual current traces of
the WT and p.I376T TRPM4 channels recorded as transient and plateau phases. (C) Quantification of current density of the WT and p.I376T TRPM4 channels for both
phases. The current densities are measured at the pic current at −100 mV. (D) Current–voltage relationships of the WT and p.I376T TRPM4 channels. *P b 0.05, **P b
0.01, ***P b 0.001.
p.G582S, p.Q854R and p.P1204L) have been reported in sporadic splicing of the seventh intron p.T286T) have not been causally
cases presenting with conduction disorders and/or Brugada related to conduction disorders and/or arrhythmia so far.
syndrome [15, Another variant, TRPM4-p.R892H, is novel since absent from public
16]. Of interest p.R252H was identified in 3 unrelated patients all of databases. However, as the patient carrying this variant also carries
which exhibiting a type 2 second-degree AVB (patients 35, 36 and an SCN5A-p.A572D variant, no conclusion could be drawn on the
37). The four other variants (three missense variants p.R442C, relative pathogenicity of each of these two variants.
p.G737R and p.R892C and one synonymous variant predicted to The last variant identified in TRPM4 (p.I376T) is also novel. Familial
affect investigations led to the identification of 96 members including 12
patients with conduction disorders. This is the third largest pedigree
diagnosed with PFHBI in which a TRPM4 mutation significantly
segregates in an autosomal dominant manner with the pathology.
Table 4
TRPM4 WT TRPM4 p.I376T Thus, this study
represents the first NGS-based detection of a TRPM4 variant that has
The functional characterization of the I376T variant.
Current density −161 ± 31 −678 ± 113 led to the recruitment of a large 4-generation pedigree from the pro-
of Transient Phase n = 12 n=9 band (patient IV-5 on Fig. 1c) carrying the mutation p.I376T. Of
(pA/pF) Current density −772 ± 138 −1390 ± 134 interest,
of plateau phase (pA/pF) n =8 n=7
domain as the 2 causal variants previously identified in large pedigrees
(2016) 349–358 357
(Fig. 1a) [11,18]. Noteworthy, 6 out of the 11 low-frequency variants pedigree. This work confirms that gain-of-function mutations in the
identified in this study also reside in the same intracellular N- intracellular N-terminal region of TRPM4 are responsible for PFHBI
terminal domain, thus suggesting that this domain could be a and further underline the crucial role of TRPM4 channel in cardiac
preferential site for PFHBI causing mutations. conduction disorders.
In the present family, a large majority of affected members Supplementary data to this article can be found online at
present with RBBB and anterior hemiblocks, without any LBBB. This http://dx. doi.org/10.1016/j.ijcard.2016.01.052.
pattern is similar to the clinical descriptions of the families
previously linked to mutations in TRPM4 [6,7], which corresponds to
the PFHB type IB defini- tion. Our study, in combination with
previously published works [6,7,
16] strongly support the prominent role of this cardiac TRP channel
in this subtype of conduction disease. The clinical onset of
conduction disturbances tends to occur at an early age among
affected patients. In particular, the presence of three cases of
congenital AVB implanted with a PM during the first year of life also
suggests an important role of heritability in disease severity.
Furthermore, the observation that these three congenital AVB
patients are first- or second-degree relatives suggests that additional
genetic factors are strengthening the disease susceptibility in these
patients.
Expression and functional analyses were performed using
HEK293 cells, in whole-cell patch-clamp configuration and Western
blotting. The TRPM4 p.I376T results in an increased current density
that may be caused by an augmented TRPM4 channel expression at
the cell surface as previously described [6,7]. The underlying mecha-
nisms leading to conduction block caused by TRPM4 dysfunction
are not yet understood. It has been proposed [15,29] that gain-of-
function mutations may depolarize the cells of the conduction sys-
tem, reduce the availability of the cardiac sodium channels and cur-
rent and thereby alter the normal impulse propagation in Purkinje
fibers. This model is consistent with the large QRS complexes ob-
served in PFHBI patients. Conversely, loss-of-function mutations of
TRPM4 may lead to a hyperpolarization of the membrane potential,
and so reduce cellular excitability and conduction. A detailed analy-
sis of the molecular mechanisms leading to the mutation-induced
gain of expression and function was out of the scope of the present
work. These findings, however, strongly support the role of TRPM4
gain-of-function in slowed cardiac impulse propagation.
5. Limitations
Next generation-based targeted resequencing such as HaloPlex™

System allows high-throughput genetic screening in a large number
of individuals but some target sequences may be uncovered due to
biases in DNA digestion by restriction enzymes. Thus some relevant
variations may be missed in small subsets of coding regions: this
problem is inher- ent to sequencing strategies based on DNA
enrichment.
Furthermore this high-throughput candidate-gene approach was
used to screen 19 candidate genes in 95 unrelated patients. Except
for the patient carrying the TRPM4-p.I376T variant (patient 9) for
which a familial recruitment, segregation tests and a LOD score
calculation strongly suggest an association between this variant and
the phenotype, the implication of variants in other unknown
involved genes cannot be excluded in isolated PCCD cases.
6. Conclusion
In this study we identified one large family with 10 members

diagnosed with PFHBI and carrying a TRPM4 gain-of-expression and
function mutation. This represents the first NGS-based detection
of a TRPM4 variant that has led to the recruitment of a large PCCD
Authors' contributions [10] N. Makita, A. Seki, N. Sumitomo, et al., A Connexin40 mutation associated
with a ma- lignant variant of progressive familial heart block type I,
Circ. Arrhythm. Electrophysiol. 5 (2012) 163–172.
XD, MYA, HA, RR and JJS conceived the study, wrote the [11] J.M. Combrink, W.H. Davis, H.W. Snyman, Familial bundle branch block, Am.
manuscript and are the guarantors of the project; PL, EC, JB and SLS Heart J.
contributed to the data processing; SB and EB performed the 64 (1962) 397–400.
sequencing; BB and SN contributed to the functional and biochemical [12] A.J. Brink, M. Torrington, Progressive familial heart block–two types, S. Afr.
Med. J. 52 (1977) 53–59.
analyses; SF, AT and FK recruited the patients; HLM, NM, JBG and VP [13] E. Stéphan, Hereditary bundle branch system defect: survey of a family with
provided expert clinical advice; CD led the statistical analysis. All four af-
fected generations, Am. Heart J. 95 (1978) 89–95.
authors interpreted the data, contributed and commented on drafts
of the article, and approved the final version.
Fundings
This work was supported by the Fondation pour la Recherche

Médicale (FRM grant DEQ20140329545) to Jean-Jacques Schott; by
the Institut National de la Santé et de la Recherche Médicale
(INSERM, ATIP-Avenir program), the ANR-14-CE10-0001-01
(GenSuD) and the French Regional Council of Pays-de-la-Loire to
Richard Redon; by the Centre National de la Recherche et de la
Santé (CNRS grant — PRC CNRS/JSPS) to Jean-Jacques Schott and
Naomasa Makita; by the French Ministry of Health (grant from the
Clinical Research Hospital Program PHRC-I PROG11/33 in 2011) and
the Fédération Française de Cardiologie (grant no. RC13_0012 in 2012)
to Vincent Probst; and by the Swiss Na- tional Science Foundation to
Hugues Abriel (310030B_14706035693), and the TransCure NCCR
network, the Berne University Research Foundation.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We would like to thank the French clinical network against

inherited cardiac arrhythmias as well as the patients who
participated to this study for participation. We are also grateful to
the members of the Genomics and Bioinformatics Core Facility of
Nantes (Biogenouest) for their technical expertise.
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MAKALAH GANGGUAN BLOK JANTUNG

Disusun untuk memenuhi tugas mata kuliah

1. Nike Chandra Bella 1711011013

UNIVERSITAS MUHAMMADIYAH JEMBER

FAKULTAS ILMU KESEHATAN

PROGRAM STUDI S1 ILMU KEPERAWATAN

Jember, 28 Maret 2020

KATA PENGANTAR ........................................................................... 2

DAFTAR ISI .......................................................................................... 3

BAB I PENDAHULUAN ..................................................................... 5

A Latar Belakang ............................................................................. 5

B Rumusan Masalah ........................................................................ 5

D. Manifestasi klinis ........................................................................ 12

G. Pemeriksaan Penunjang .............................................................. 15

BAB III ASUHAN KEPERAWATAN .............................................. 19

C Diagnosis Keperawatan .................................................................. 25

D Intervensi Keperawatan ................................................................. 26

DAFTAR PUSTAKA ........................................................................... 30

A. Anatomi Fisiologi Jantung

Jantung dilapisi oleh selaput yang disebut pericardium, yang terbagi

a. Parikardium parietalis yaitu lapisan luar yang melekat pada tulang

b. Pericardium viseralis, yaitu lapisan permukaan dari jantung itu sendiri,

Diantara kedua lapisan selaput tersebut terdapat sedikit cairan pelumas

Dinding jantung terdiri dari 3 lapis yaitu :

a. Epikardium ataupericardium, merupakan lapisan yang paling luar dari

b. Miokardium, merupakan lapisan tengah yang berotot yang paling tebal.

Jantung terdiri atas 4 ruang yaitu :

1) Anterium kanan berfungsi sebagai penampung darah yang

2) Atrium kiri berfungsi menerima darah yang kaya oksigen dari

1) Ventrikel kanan, menerima darah dari atrium kanan dan

2) Ventrikel kiri, menerima darah dari atrium kiri dan dipompakan

a. Katup atrioventrikuler, terletak antara antrium dan ventrikel, yaitu :

1) Katup tricuspid, mempunyai 3 buah daun katup yang terletak

2) Katup bicuspid atau katup mitral, mempunyai 2 buah daun

1) Katup pulmonal, terletak pada arteri pulmonalis

2) Katup aorta, terletak pada antara ventrikel kiri dan aorta

Didalam otot jantung terdapat jaringan khusus yang bias

a. Otomatisasi : kemampuan untuk menimbulkan implus secara

b. Irama : kemampuan untuk membentuk implus yang teratur

c. Konduksi : kemampuan untuk menyalurkan implus

d. Rangsangan : kemampuan untuk bereaksi terhadap rangsangan.

1) SA Node ( Nodus Sino-Atrial )

Terletak diantara batas vena cava superiordan atrium kanan,

Berfungsi menghantarkan implus dari nodur SA ke nodus

Menghantarkan implus dari nodus SA ke atrium kiri

4) AV Node ( Nodus Atrio-Ventrikuler )

Terletak didalam dinding septum atrium sebelah kanan,

Berfungsi menghantarkan implus dari AV ke system Branch

6) System bundle branch

Merupakan lanjutan dari “bundle of HIS” yang bercabang

a) Right Bundle branch ( RBB/cabang kanan ) : mengirim

b) Left bundle brach ( LBB/cabang kiri ) yang terbagi

AV Blok merupakan salah satu kondisi gangguan konduksi jantung yang

Total AV blok merupakan keadaan darurat jantung yang membutuhkan

a. AV blok derajat II Mobitz I ( Wenckebach )

Tipe ini biasanya dihubungkan dengan blok di atas berkas His.

b. AV Blok derajat III

Adanya pola Mobitz II menyatakan blok di bawah berkas His. Ini

4. Peradangan jantung, misalnya demam reumatik, peradangan miokard

5. Gangguan sirkulasi koroner (aterosklerosis koroner atau spasme arteri

1. Av blok sering menyebabkan bradikardia, meskipun lebih jarang

2. Seperti gejala bradikardia yaitu pusing, lemas, sinkop, dan dapat

a. Sulit dideteksi secara klinis

b. Bunyi jantung pertama bias lemah