Gangguan jantung fungsional

Divisi PsikosomatiDivisi PsikosomatikkBagian Ilmu Penyakit Dalam RSMHBagian Ilmu Penyakit Dalam RSMH

Gangguan jantung fungsional kadang menyerupai penyakit jantung organik.

Pada sisi lain pasien penyakit jantung organik sering kali disertai gangguan psikis.

Dapat menyebabkan terjadinya kesalahan diagnosis.

Pengetahuan dan pemahaman tentang gangguan jantung fungsional diperlukan agar dapat melakukan pengobatan yang lebih tepat.

GANGGUAN JANTUNG FUNGSIONALGANGGUAN JANTUNG FUNGSIONAL

Sindroma Da Costa menjadi masalah kembali pd PD I yang kemudian disebut sebagai Soldier’s Heart.

Sir Thomas, 1917 Effort syndrome karena gejala-gejala tsb timbul terutama bila melakukan aktifitas .

Culpin hub. antara effort synd, ansietas dan fobia, th/ pd penyakit dasar (neurosis disorders) dan bukan pada jantungnya.

Ada juga yg menyebut sbg disorders action of the heart.

Oppenheimer neurocirculatory asthenia yaitu suatu sindrom ditandai dgn gejala-gejala nervous dan gejala2 sirkulasi yg kemudian menimbulkan kelelahan

Da Costa, 1971 mengevaluasi 300 tentara perang

gejala utama sesak nafas, palpitasi dan nyeri dada tanpa kelainan organis jantung = Irritable Heart

Gejala lain : fatig, sakit kepala, pusing, konfuse dan gangguan tidur.

Beard, 1880 neurasthenia Kel. gejala menonjol : gejala kardiovaskular dan fatig. Freud, 1899 menyebutnya ansietas neurosis karena gejala cemas menonjol disamping gejala2 kardiak. Pada perjalanan penyakitnya dapat menjadi fobia.

Berkcman menyebutnya sebagai cardiac phobia.

Setelah PD I Istilah neurosis kardiak mulai banyak digunakan menggambarkan suatu sindrom ditandai oleh suatu rasa khawatir berlebihan akan adanya penyakit jantung, tidak hanya thd ggn jantung fungsional saja tp juga thd peny. jantung organik .

Masih banyak istilah diagnosis : War neurosis ( Mc Kenzi ), Hyperkinetic heart syndrome ( Gorlin ), Effort phobia ( Jones ), dll. Istilah diagnosis apapun digunakan

merupakan gangguan jantung fungsional dgn gejala2 utama pd sistem kardiovaskular khususnya jantung dan berkaitan erat dengan fungsi psikis seseorang.

Epidemiologi

Pusat rujukan yang mempunyai senter jantung gangguan jantung fungsional berkisar 10-20% dari semua kasus rujukan yang diduga mempunyai kelainan organik.

Pada praktek umum dari semua pasien datang dengan keluhan berhubungan dengan jantung : sekitar 75% merupakan gangguan jantung fungsional.

Penelitian : rata-rata 2/3 penderita hiperventilasi pd ansietas intermiten memperlihatkan penurunan PaCO2.

Hiperventilasi kronis adaptasi fisiologis

pusat pernafasan terhadap PaCO2 rendah dengan PH normal,

Tetapi bila terjadi penurunan PaCO2 lebih lanjut akibat perubahan emosi seperti rasa takut, sedih dll, gejala-gejala seperti tersebut diatas dapat timbul kembali.

Stres psikis selain merupakan faktor risiko penyakit jantung dan dapat menyebabkan lambatnya penyembuhan pasien penyakit jantung kekambuhan dan mortalitas penyakit jantung struktural atau organik.

Skintigrafi : stres iskemia miokard pada orang sehat dan lebih bermakna pd pasien peny. jantung koroner, disamping dpt menimbulkan mikrotrombus dan perubahan tonus vagal. Mempermudah terjadinya nyeri dada berkepanjangan, gangguan elektris, gangguan konduksi,aritmia, dan meluasnya area infark sehingga terjadi gagal jantung, sampai dengan kematian

Faktor-faktor psikososial, keadaan stres dapat menyebabkan angina pektoris, menimbulkan awitan IM prematur dan memicu timbulnya IM.

IM terjadi sesaat setelah adanya stresor psikososial dan pada angiografi koroner pasien-pasien ini tidak menunjukkan penyempitan koroner yang nyata.

Pada pasien gangguan psikis seperti ansietas panik dapat ditemukan adanya prolaps katup mitral yang secara klinis tidak membahanyakan.

Gejala-gejala klinik sangat bervariasi Secara umum dapat dikelompokkan menjadi

gejala-gejala psikis dan somatik dengan derajat dan intensitas yang ringan sampai yang berat .

Episode simptomatik umumnya ditandai adanya faktor pencetus berkaitan stres emosi, tetapi dapat juga timbul tiba-tiba tanpa stresor yang jelas.

Gejala dapat mereda dalam waktu beberapa menit, tetapi dapat segera timbul kembali sehingga menambah kecemasan pasien dan keyakinan akan adanya sakit jantung organik.

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Stimulasi saraf simpatik akibat stres psikis dapat menyebabkan peningkatan kontraksi miokard dan denyut jantung Konsumsi oksigen meningkat, sementara aliran darah koroner menurun akibat vasospasme koroner.

Untuk mempertahankan aliran darah koroner diimbangi oleh vasokontriksi arteriole sistemik mengganggu fraksi ejeksi ventrikel.

Mekanisme ini dapat menerangkan terjadinya iskhemia miokard akibat stres psikis.

Stimulasi saraf simpatik akibat stres psikis dapat menyebabkan peningkatan kontraksi miokard dan denyut jantung Konsumsi oksigen meningkat, sementara aliran darah koroner menurun akibat vasospasme koroner.

Untuk mempertahankan aliran darah koroner diimbangi oleh vasokontriksi arteriole sistemik mengganggu fraksi ejeksi ventrikel.

Mekanisme ini dapat menerangkan terjadinya iskhemia miokard akibat stres psikis.

Psikofisiologi dan PatologiPsikofisiologi dan Patologi

Konsep psiko-neuroendokrinologi

Menjelaskan bahwa melalui jalur hipotalamik-hipofisis, stres menstimulasi medulla adrenal memproduksi katekolamin dan korteks adrenal memproduksi kortisol.

Kedua hormon ini akan meningkatan tekanan darah, denyut jantung, konsumsi oksigen, penurunan kalium terutama pada otot jantung, nilai ambang elektris ventrikel turun, tonus vasculer meningkat, otot mjd tegang (‘pegel’) bahkan kerusakan serabut otot

Konsep psiko-neuroendokrinologi

Menjelaskan bahwa melalui jalur hipotalamik-hipofisis, stres menstimulasi medulla adrenal memproduksi katekolamin dan korteks adrenal memproduksi kortisol.

Kedua hormon ini akan meningkatan tekanan darah, denyut jantung, konsumsi oksigen, penurunan kalium terutama pada otot jantung, nilai ambang elektris ventrikel turun, tonus vasculer meningkat, otot mjd tegang (‘pegel’) bahkan kerusakan serabut otot

Psikofisiologi dan PatologiPsikofisiologi dan Patologi

Disamping itu stres dapat meningkatkan jumlah trombosit, agregasi dan adhesi trombosit.

Katekolamin merupakan agregan yang poten in vitro,

Gregnani dkk stres emosi dapat meningkatkan trombosit, baik dengan ADP ataupun kolagen.

Percobaan binatang stres emosi dapat menimbulkan mikrotrombus pada pembuluh-pembuluh darah kecil jantung.

Gangguan psikofisiologis dan metafisiologis ini dapat berlangsung beberapa hari sampai bertahun-tahun.

Stres psikis dpt hiperventilasi akibat pengaruh B adrenergik

Hiperventilasi penurunan PaCO2 alkalosis respiratorik.

Mula-mula vasodilatasi arteriol beberapa menit kemudian vasokontriksi termasuk arteri koronaria.

Sehingga pada hiperventilasi dapat terjadi sakit dada, baik karena peningkatan kerja otot, pernafasan atau akibat aliran darah koroner yang berkurang.

EKG= sinus takhikardia, aritmia, elevasi atau depresi segmen ST, dugaan penderita hiperventilasi mempunyai kelainan jantung struktural.

Pada penderita dengan aterosklerosis koroner, hiperventilasi mempermudah terjadinya iskhemia myokard, bahkan pada sebagian penderita dilaporkan dapat mencetuskan IM akut.

Keluhan dan gejala dpt terbatas pd gejala tertentu (palpitasi / takikardia) atau dengan gejala sangat kompleks berbagai macam diagnosis, bahkan salah interprestasi sbg gangguan jantung organik ataupun sebaliknya.

Spektrum gejala kardiovaskular selain palpitasi /takikardia, sering juga sesak napas, nyeri dada, keringat dingin, lekas capai, sakit kepala sampai dengan pingsan.

Anamnesis dan pemeriksaan fisis teliti dapat mendiagnosis ada tidaknya gangguan jantung Psikosomatik, memmbedakan antaara gangguan fungsional dan organis.

Sesak napas- Sering terjadi saat aktifitas (effort, exercise), namun tidak

sesuai dengan beratnya aktifitas. - Tidak puas mengambil napas sehingga harus

mengambil napas dalam (sighing), bisa diikuti gejala

hiperventilasi Palpitasi

- Saat aktifitas ringan, terkejut atau istirahat. - Palpitasi saat tidur miring kekiri suara detak jantung sendiri terdengar- Biasanya akibat VES atau takikardi paroksismal.- Gelisah hebat dan sering timbulnya gangguan tidur.

Nyeri dada- Nyeri tidak spesifik, tapi dapat menyerupai angina pektoris.- Timbul saat aktifitas, tetapi tidak hilang dengan istirahat.- Lokasi di apeks kordis, 25 % dada kanan & kiri

Fatique- Intermiten atau terus menerus. - Terutama pagi hari dan berkurang pada siang hari.- Berkurang/hilang bila melakukan aktifitas menyenangkan. - Pada penyakit jantung organik timbul pada siang atau sore hari setelah melakukan aktifitas

Cemas- Cemas berlebihan akan adanya penyakit jantung

Pusing atau melayang terutama saat berdiri atau berjalan, tetapi jarang terjadi sinkop.

Sakit kepala biasanya ringan, tetapi dapat pula berdenyut.

Rasa panas, banyak keringat dingin, tremor, parestesi, gemetar dan gelala fisik lain

EKG umumnya normal, tapi dpt dijumpai gambaran sinus takikardia, atau ventrikel ekstra sistole .

Sebagian kecil kasus sinus aritmia, takikardi atrial, atrial flutter, dan lain-lain.

Dapat jg tjd ggn konduksi spt PR interval memanjang. PR interval memanjang tsb dpt menghilang dgn pemberian atropin membuktikan ggn tsb berkaitan dgn meningkatnya tonus vagal.

Dapat jg dijumpai depresi atau inversi gel T pd lead II, III dan lead precordial yg dpt dikurangi atau dihilangkan dgn pemberian ergotamin menunjukkan keadaan ini dipengaruhi akifitas syaraf simpatis.

Bisa jg depresi segmen ST-T pd lead II, III. V4,V5,V6, jarang pd lead I dan AvL, tapi umumnya tidak > 2 mm.

Beberapa kasus elevasi segmen ST yang tidak khas.

Perubahan EKG ini disebabkan spasme pembuluh darah koroner menyebabkan iskemia miokard relatif.

Dapat membahayakan terutama pd penderita yang sudah ada aterosklerosis koroner sebelumya dapat menjadi pencetus timbulnya serangan infark miokard akut.

Pemeriksaan fisik : tampak dalam keadaan cemas.

Keringat dingin biasanya hanya pd telapak tangan dan kaki.

Walaupun jarang, pd EKG bisa didapatkan takikardia atrial, takikarddia ventrikel paroksismal atau perubahan gel. ST-T.

Dalam keadaan demikian perlu eveluasi lebih mendalam untuk menentukan ada tidaknya peny jantung organik.

Pada ekokardiografi bisa didapatkan prolaps katups mitral. Kurang lebih 5% pasien ansietas panik didapatkan adanya prolaps katup mitral.

Non farmakologis : edukasi dan bimbingan dpt membantu mempercepat penyembuhan.

Antara lain menjelaskan tentang gejala yang timbul dengan tepat tanpa menakutkan paien yang dapat memperburuk penyakitnya, meluruskan pola pikir pasien yang salah tentang penyakit jantung

Bila mungkin membantu memecahkan masalah yang sedang dihadapinya.

Terapi kognitif dan perilaku sangat membantu dlm mengoreksi perilaku yang salah yang dapat merupakan faktor risiko penyakitnya dan mengajukan untuk berpola hidup sehat.

Pengobatan farmakologis : dpt simptomatik seperti anti angina atau anti nyeri, analgetik, vasodilator koroner.

Dapat juga diberikan obat golongan benzodiazepin seperti diazepam, alprazolam untuk mengurangi kecemasan.

Terapi simptomatik lain dapat diberikan sesuai indikasi, tidak berlebihan dan menghindari obat yang dapat memperburuk keadaan.

Pengobatan lebih khusus sesuai dengan gangguan psikis atau organis yang dijumpai.

TERIMA KASIH

1. Dimensi bio-organik

2. Dimensi psiko-edukatif

3. Dimensi sosio-kultural

1. Dimensi Bio-organik

Pem fisik lengkap & teliti Menghilangkan pikiran kalau ia tidak sakit berat atau tak dapat diobati.

Obati kelainan fisik atau cacat bawaan dgn bedah plastik/kosmetik menghilangkan rasa rendah diri.

Dengan obat-obatan :a. Simptomatisb. Sesuai penyakit yg diderita, misal ulkus peptik, asma

bronkial, angina pektorisc. Obati psikis dengan transquilizer, anxiolitik, anti

depresi, dllld. Th/ neural dg Impletol Healty habits

Hubungan Dokter-PasienTherapeutic relationship, kepercayaan pasien-dokterVentilasiMemberi kesempatan mengutarakan konflik dan isi hatinya Puas, lega & mengurangi ketegangannya.Re-edukasi

Memberi keyakinan & pengertian tentang sebab penyakitnya, sambil memperbaiki pendapat yg salahAgamaMelihat masalah dari sudut agama dan penyelesaian nya secara agama

3. Dimensi Sosio-Kultural

Perbaiki kondisi sosial ekonomi. Beri jalan keluar, saran, pandangan, sesuai kemampuan yang ada pada pasien

Kapasitas adaptasi

Tingkatkan kemampuan penyesuaian diri pasien thd lingkungan atau keluarganya

Manipulasi lingkungan lingkungan dan orang-orang yg bergaul dg pasien perlu psikoterapi demi kepentingan pasien.

sympathetic; parasympathetic activity: increased catecholamines (e.g. NA)lower threshold for ischemia, ventricular tachycardia, ventricular fibrillation, sudden death in CHD pts.

heart rate; heart rate variability baroreceptor sensitivity QT tid ved depresion

Carney et al; Psychosomatic Medicine 2005; 67 [Suppl. 1]: s29-s33Udupa K, et al. J Affect Disord. 2006 Nov 17; [Epub ahead of print]

• Elevated values were observed in patients with co-morbid panic disorder (P = 0.006).

• Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD.

Cytokines may lead to sickness-behaviour (lethargia, anorexia, paresthesia, irritability, social withdrawal, impaired concentration, sleep problems, decreased libido; particularly TNF-alfa and IL-6 may induce depression, anxiety and memory impairment)

In non-melancholic depression elevated levels of -IL-6 (mediates activation of the HPA axis), -NK cells (acute stage)-leucocytes/lymphocytes (acute stage)

In melancholic depression:- decreased (in vitro) production of IL-2; IFN-g; IL-10 (acute stage), but normal cell counts

•Schwarz . Dialogues in Clin Neurosciences 2003; 5: 139-153

Higher depression scores were associated with a prospective increase in incidence of cardiac related hospitalizations and/or death (p = .037).

Lesser IFN-gamma/IL-10 expressing CD4+ T cell ratios were related to higher depressive symptom scores at baseline (p = .005) and a prospective increased incidence of cardiac related hospitalization or death over a two-year period (p = .05).

Conclusion: A shift in the Th1/Th2 ratio may play a role in the association between depressive symptoms and morbidity and mortality in CHF patients, suggesting broader immune dysregulation than previously considered

Redwine et al, Psychosom Med 2007 Jan-Feb;69(1):23-9

The relationship between central nervous system correlates of depression and

immune system parameters is bidirectional, mediated by neurohormonal and

parasympathetic pathways. Depressive symptoms primarily affect the transition

from stable CAD to acute coronary syndromes via plaque activation and

prothrombotic processes (solid line) and may adversely affect the initial response

to injury at early stages of coronary atherosclerosis (dashed line).

Kop: Psychosom Med 2005; 67 [Suppl 1]: s37-s41

5% increase in HRV in SSRI treated pts compared with a 9% decrease in SDNN over the 22-week study period in the placebo group

SSRIs reduce platelet activity. SSRI (sertraline) was associated with substantially less release of platelet/endothelial biomarkers: PF4, βTG, platelet/endothelial cell adhesion molecule 1, P selectin, thromboxane B2, 6-keto prostaglandin F1a, vascular cell adhesion molecule 1, and E selectin.

•Jiang W, Davidson JRT. Am Heart J 2005; 150: 871-881 (nov)

• SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008).

No effect on mortality in overall sample No effect on mortality in subgroups:

- Depression- Low social support- Minority- Non-minority

Trend to worse outcome in women Those on SSRI had less mortality

•Sertraline Antidepressant Heart Attack Trial (SADHART) •Glassman et al. JAMA. 2002;288:701-709.

Episodes of MDD that began prior to ACS responded more frequently to sertraline than to placebo (63% vs 46%, respectively; odds ratio, 2.0; 95% confidence interval, 1.13-3.55) whereas depression with onset beginning after hospitalization showed a high placebo response rate (69% vs 60%, respectively) and low sertraline-placebo response ratio (1.15).

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•Glassmann et al, Arch Gen Psychiatry 2006 Mar;63(3):283-8

Copyright restrictions may apply.

Tiihonen, J. et al. Arch Gen Psychiatry 2006;63:1358-1367.

Relative risk and 95% confidence interval of total mortality obtained by using medication as a time-dependent variable

Copyright restrictions may apply.

Lesperance, F. et al. JAMA 2007;297:367-379.

Adjusted Mean Baseline to 12-Week Changes in Depression and Other Outcomes*

Copyright restrictions may apply.

Glassman, A. H. et al. Arch Gen Psychiatry 2007;64:1025-1031.

Natural Logarithm of Heart Rate Variability by Treatmenta

Copyright restrictions may apply.

Glassman, A. H. et al. Arch Gen Psychiatry 2007;64:1025-1031.

Heart rate variability (HRV) recovery following myocardial infarction in the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) and studies by Jokinen et al37 and McFarlane et al

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•Source: A. Steptoe et al. (2004), Psychosomatic Medicine, 66: 323-329.

-903 men; 473 women: post-MI;- intervention or usual care; one yearResults:Men: No effect Women: Treatment group higher cardiac and all-cause mortality

•Frasure-Smith et al, Lancet 1997

A figurative interdependence between the heart and sadness has long existed in language and in literature.

In 1628, English physician William Harvey noted “every affection of the mind that is attended either with pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart”

1970s-epidemiologists start to associate/correlate heart disease and depression.

Review some of the literature regarding: -the course of depression following cardiac events

-depression as a risk factor for cardiac events -the links between depression and heart disease Review evidence for treatment of

depression in pts with CHD Review the ACC AHA guidelines Discuss the professional recommendations

with ramifications relevant to local health care system and evironment

DSM-IV requires that five of the following are present:

• Depressed mood most of the day• Anhedonia• Significant change in weight• Insomnia or hypersomnia• Psychomotor agitation or retardation• Fatigue or loss of energy• Feelings of worthlessness or guilt• Impaired concentration, indecisiveness• Recurring thoughts of death or suicide

Further, one of the symptoms must be either depressed mood or anhedonia. The symptoms must be present nearly every day for 2 weeks, and occur through most of the day.

Symptoms must cause impairment of functioning.

S sleepI interestG guilt or worthlessnessE energyC concentrationA appetiteP psychomotor changesS SI

502 pts with >10PVC/hr or >5 NSVT episodes evaluated

Results indicated that higher levels of depression and lower pulse rate reactivity were significant risk factors for death or cardiac arrest, after adjusting statistically for a set of known clinical

predictors of disease severity.

•AJC 1990;66:59-62

To evaluate if MDD in patients hospitalized after MI would have an independent impact on mortality during 6month follow-up

Prospective evaluation of 222 patients with MI using DIS

78% male. Ages 24-88. EF 12-76%. 82 pts with previous MI.

Depression was a significant predictor of mortality with HR 5.74, p=0.0006.

Controlling for LVEF, Killip class, previous MI, HR 4.29, p=0.013

•JAMA 1993; 270(15) 1819-1825

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18month follow-up showed that both DIS and BDI scores consistent with depression were significantly related to 18month cardiac mortality, after controlling for other predictors of mortality including Killip class, PVCs, previous MI. (OR 3.64, p=0.012 and OR 7.82, p=0.0002 with adjusted OR6.64, p=0.0026)

The deaths that occurred in 18month follow-up were concentrated among depressed patients with PVCs >10/hr.

•Circ 1995; 91:999-1005.

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1250 patients with CAD assessed for depression and followed for 15.2 years to evaluate the long-term mortality risk.

Pts were enrolled at the time of LHC and followed at 6 and 12 months then annually with SDS.

•Am J Cardiol 1996;78:613-617

Higher depression scores were associated with increased risk of subsequent cardiac death (p=0.002) and total mortality (p<0.001) after controlling for initial disease severity and treatment.

Pts with moderate to severe depression had a 69% greater odds of cardiac death and a 78% greater odds of mortality from all causes than nondepressed patients.

Pts with higher scores had a higher risk of cardiac death >5 yrs later (p<0.005)

Compared with nondepressed pts, those with moderate to severe depression had an 84% greater risk at 5-10yrs later and a 72% greater risk after >10yrs.

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Prospective observational study of 284 patients hospitalized with MI

Any depression at the time of MI was not associated with mortality at 8 years.

However, increased mortality was statistically significant in the short term (4 months).

•AJC 2008;101:602-606

•No Depression

•Any Depression

•Years

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•Any Depression

•No Depression

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Of note, this was a small observational study of 284 hospitalized pts over age 63 with multiple comorbidities.

425 pts hospitalized for ACS completed the BDI and SF-12 in hospital, 6- and 12 months later.

Only patients with persistent symptoms of depression were at risk for poorer physical health.

Patients with newly developed depressive symptoms after ACS had a trend toward worse physical health, whereas patients with transient

depressive symptoms were not at increased risk.

•AJC 2008;101:15-19

What about patients with no history of heart disease?

Observational study of 1190 male medical students enrolled from 1948 to 1964 followed for 40 years

Incidence of depression was 12%. In multivariate analyses, these men were at greater risk for subsequent CAD (RR 2.12) and MI (RR 2.12).

The increased risk associated with depression was present even for MIs occurring 10 yrs after the first MDE (RR 2.1)

The association did not change when time-dependent smoking, EtOH, and coffee use were added to models, nor when BMI, FH of MI, baseline cholesterol, and time-dependent HL were added.

In a model with the strongest RF, the risk of CHD from depression was still significant with RR of 1.7

•Arch Int Med 1998;158:1422-1426

Clinical depression was associated with a greater risk of total mortality according to both unadjusted and adjusted analyses.

Clinical depression was significantly related to CVD mortality in unadjusted analyses, with a trend toward increased CVD mortality in adjusted analyses.

The association of clinical depression with CVD mortality was stronger than the association of clinical depression with other causes of death,

exclusive of suicide.

5006 women and 2888 men who completed the CES-D were followed over 10 years.

17.5% of women were depressed and 9.7% of men were depressed.

The mean poverty index was lower in depressed patients.

Women had 187 nonfatal and 137 fatal events. Men had 187 nonfatal and 129 fatal events.

•Arch Int Med 2000;160:1261-1268

The RR of nonfatal CHD among women with scores of 23 or higher on CES-D was 2.09

Adjusted RR with final model taking into consideration poverty, DM, HTN, smoking, and BMI was 1.73.

The adjusted RR for nonfatal CHD in depressed men was 1.71.

Adjusted RR for CHD mortality was 2.34. Adjusted all-cause mortality RR was 1.69.

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Pathophysiologic changes Behavioral issues Medication Adherence Medication Side Effects

Physiological pathways

• Cardiovascular autonomic dysregulation

E.g., low heart rate variability (HRV)

• Pro-inflammatory processes

E.g., elevated CRP, IL-6

• Pro-coagulant processes

E.g., elevated fibrinogen, PF4, BTG

• Shared genetic factors

E.g., TNFA, IL1B, 5-HTT, 5-HT2A, 5-HT2B

sympathetic; parasympathetic activity: increased catecholamines (e.g. NE)lower threshold for ischemia, ventricular tachycardia, ventricular fibrillation, sudden death in CHD pts and may contribute to endothelial injury

resting heart rate; heart rate variability baroreceptor sensitivity QT interval/impaired repolarization, variable

repol

•Psychosom Med 2005;67:S1:S29-33.

Elevated catecholamines may also promote procoagulant processes by potentiating platelet activation through agonist effects, by increasing hemodynamic stress on vascular walls, or by inhibiting vascular eicosanoid synthesis.

•Psychosom Med 2005;67:S1:S34-36.

Cytokines may lead to sickness-behavior (lethargia, anorexia, paresthesia, irritability, social withdrawal, impaired concentration, sleep problems, decreased libido; particularly TNF-alfa and IL-6 may induce depression, anxiety and memory impairment)

In non-melancholic depression elevated levels of -IL-6 (mediates activation of the HPA axis), -NK cells (acute stage)-leucocytes/lymphocytes (acute stage)

In melancholic depression:- decreased (in vitro) production of IL-2; IFN-g; IL-10 (acute stage), but normal cell counts

•Schwarz . Dialogues in Clin Neurosciences 2003; 5: 139-153

•Kop: Psychosom Med 2005; 67 [Suppl 1]: s37-s41

•The relationship between central nervous system correlates of depression and

•immune system parameters is bidirectional, mediated by neurohormonal and

•parasympathetic pathways. Depressive symptoms primarily affect the transition

•from stable CAD to acute coronary syndromes via plaque activation and

•prothrombotic processes (solid line) and may adversely affect the initial response

•to injury at early stages of coronary atherosclerosis (dashed line).

SSRIs reduce platelet activity. SSRI (sertraline) was associated with substantially less release of platelet/endothelial biomarkers: PF4, βTG, platelet/endothelial cell adhesion molecule 1, P selectin, thromboxane B2, 6-keto prostaglandin F1a, vascular cell adhesion molecule 1, and E selectin.

•Jiang W, Davidson JRT. Am Heart J 2005; 150: 871-881

SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008).

•Barton et al. J Hypertens. 2007 Oct;25(10):2117-2124.

Copyright restrictions may apply.

Glassman, A. H. et al. Arch Gen Psychiatry 2007;64:1025-1031.

Heart rate variability (HRV) recovery following myocardial infarction in the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) and studies by Jokinen et al and McFarlane et al

-20

-10

0

10

20

30

40

Ch

ang

e in

HR

V, %

•n=416 •n=11

•n=12•n=125

•n=133 •n=15

•Patients Without

•Depression

•Prescribed

•Sertraline

•Given

•Placebo

•Patients With Depression

•A

•B

•Jokinen et al•SADHART•McFarlane et al

Behavioral pathways

• Smoking

High prevalence of smoking in depression & vice versa

Depression decreases smoking cessation rates.

• Physical inactivity

Depression is inversely associated with exercise, participation in cardiac rehabilitation

• Poor diet and obesity

• Nonadherence to prescribed medications

14% of depressed pts vs 9% of nondepressed pts reported not taking their medications as prescribed (OR 2.8, p<0.001)

Twice as many depressed pts as nondepressed pts reported forgetting to take their medications (OR2.4, p<0.001)

9% depressed pts and 4% nondepressed pts reported deciding to skip their medications (OR 2.2 p=0.009)

•Archives 2005;165:2508-2513

0

2

4

6

8

10

12

14

16

18

20

Pe

rce

nta

ge

of

Pa

rtic

ipa

nts

Depressed (n=204) Not Depressed (n=736)

Not as Prescribed(P <.001)

Forgot to Take(P <.001)

Decided to Skip(P <.01)

Reason for Nonadherence

Depression was associated with medication nonadherence in a gradient fashion.

15% of nondepressed pts, 29% of mildly depressed pts, and 37% of mod-severely depressed pts took ASA <80% of the time.

Change in depressive symptoms over the study period were linearly related to changes in adherence.

•JACC 2006;48:2218-22

381 pts, 127 without BB and 254 matched pts with BB at discharge after MI

There were no significant differences in BDI at baseline, 3, 6, or 12 months after MI.

•JACC 2006;48:2209-14

Does treatment of depression, then, improve outcomes in patients with CAD?

369 pts with MDD randomized to sertraline (50-200mg/day) or placebo for 24 weeks

Pts were hospitalized with ACS in the past 30 days and met DSM-IV criteria for MDD.

The study involved 7 countries from 04/1997-04/2001.

Primary outcome was change from baseline EF.

Secondary measures included cardiovascular adverse events, HAM-D scores, CGI-I scores

•JAMA 2002;288(6) 701-709

No difference between drug and placebo in:

• LVEF

• Blood pressure

• Resting ECG (HR, QRS, QT)

• 24-Hour Holter ECG

VPCs

HRV (time & frequency domain)

Severe Recurrent MDD Subgroup*Severe Recurrent MDD Subgroup*

OutcomeOutcome

SertralineSertraline

(n=50)(n=50)

PlaceboPlacebo

(n=40)(n=40) pp

HAM-D, mean (SD)HAM-D, mean (SD) -12.3 (0.9)-12.3 (0.9) -8.9 (1.0)-8.9 (1.0) .01.01

All Randomized PatientsAll Randomized Patients

OutcomeOutcome

SertralineSertraline

(n=186)(n=186)

PlaceboPlacebo

(n=183)(n=183) pp

HAM-D, mean (SD)HAM-D, mean (SD) -8.4 (0.4)-8.4 (0.4) -7.6 (0.4)-7.6 (0.4) .14.14

• HAM-D: Hamilton Rating Scale for Depression

• * 2 prior episodes plus HAM-D score 18.

Sertraline had no significant effect on mean LVEF, incidence of PVCs, or QTc interval.

The incidence of severe CV adverse events was 14.5% with sertraline and 22.4% with placebo.

CGI-I but not HAM-D favored sertraline. In the groups with preexisting depression,

both CGI-I and HAM-D measures were significantly better in those assigned to sertraline.

Sertraline appears to be a safe medication for use following ACS.

In patients with recurrent depression and CAD, sertraline was efficacious in the treatment of depression.

2481 MI patients at 8 centers enrolled from 10/1996 to 04/2001.

Pts had major or minor depression by DSM IV criteria.

Randomized to usual medical care or CBT based therapy with primary endpoints of death or nonfatal MI.

•JAMA 2003;289(23) 3106-3116.

Cognitive behavior therapy

• Behavioral activation, cognitive restructuring, social skills training, social network.

• Up to 6 months of CBT with trained therapist

Sertraline added for severely depressed patients and for those who did not respond sufficiently to CBT within 6 weeks

5,1

-10,1

3,4

-8,4

-15

-10

-5

0

5

10

ESSI score Hamilton depressionscore

InterventionUsual care

•ENRICHD Social Support Instrument (ESSI) scores reported for patients with low social support only; Hamilton depression scores reported for depressed patients only.

0

10

20

30

40

50

60

70

80

BDI 10-15 BDI 16-23 BDI 24+

% R

emis

sion

of

Dep

ress

ion Usual Care

Intervention

•RL*=1.35

•p<0.006

•RL=1.80

•p<0.0008

•RL=2.58

•p<0.0015

•(N=346)

•(N=313)

•(N=200)•*Relative Likelihood of Remission

•The ENRICHD Intervention Did

•Improve Late Survival (>6 Months)

•Late survival

•depended on

•whether depression

•improved over the

•course of the

•intervention.

•Carney et al., Psychosom Med 2004;66(4):466-474.

Improvements in psychosocial outcomes favored treatment at 6 months.

There was no difference in event-free survival.

Of note, treatment with anti-depressants was 4.8% to 20.6% in the usual care group and 9.1% to 28% in the treatment arm.

284 patients with CAD and DSM-IV criteria for MDD with HAM-D scores >20.

Pts randomized to (1) 12 weekly sessions of interpersonal psychotherapy plus clinical mgmt vs clinical mgmt only and (2) 12 weeks citalopram or matching placebo

•JAMA 2007;297(4) 367-379

Citalopram was superior to placebo in reducing 12 week HAM-D scores (p=0.005)

No benefit was seen of IPT over clinical mgmt (p=0.06)

Similar to the results of SADHART, response to SSRI was more pronounced in pts with a history of recurrent depression.

522 patients enrolled in cardiac rehab and a control group not enrolled evaluated over 4 years

•AJM 2007;120:799-806

•Effect of Cardiac Rehab on Depression in 552 patientsEffect of Cardiac Rehab on Depression in 552 patients

•17%17%

•6%6%

•15%

•20%

•10%

•0•BeforeBefore •AfterAfter

•5%

•Milani RV, Am J Med 2007

•BeforeBefore

•AfterAfter

•Actuarial cumulative hazard plot for survival time

•based on depression status upon completion of cardiac rehabilitation

•Milani RV, Am J Med 2007

•DepressedDepressed

•Non-Non-depresseddepressed•0

•0.05

•0.10

•0.15

•0.20

•0.25

•0.30

•0.35

•0 •1 •2 •3 •4 •5

•Time (Years)Time (Years)

•Prevalence of Prevalence of DepressionDepression Before and After Cardiac Rehab Before and After Cardiac Rehab

•23%23%

•19%19%

•30

•20

•0•YoungYoung •ElderlyElderly

•10 •6%6%•4%4%

•BeforeBefore

•AfterAfter

•Lavie CF, Arch Int Med, 2006

What are the treatment recommendations regarding depression in patients with CHD?

Lichtman JH, Bigger JT, Blumenthal JA, Frasure-Smith N, Kaufmann PG, Lespérance F, Mark DB, Sheps DS, Taylor CB, Froelicher ES.

Circulation 2008;118;1768-1775

Routine screening for depression in patients with CHD in various settings, including the hospital, physician’s office, clinic, and cardiac rehabilitation center.

The opportunity to screen for and treat depression in cardiac patients should not be missed, as effective depression treatment may improve health outcomes.

•Lichtman et al., Circulation 2008;118;1768-1775

•Over the past 2 weeks, how often have you been bothered by any of the following problems?

•(1) Little interest or pleasure in doing things.

•(2) Feeling down, depressed, or hopeless.

•Positive screen = “yes” to either question.

•Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606–613.

•Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606–613.

•Over the past 2 weeks, how often have you been bothered by any of the

•following problems?

•(1) Little interest or pleasure in doing things.

•(2) Feeling down, depressed, or hopeless.

•(3) Trouble falling asleep, staying asleep, or sleeping too much.

•(4) Feeling tired or having little energy.

•(5) Poor appetite or overeating.

•(6) Feeling bad about yourself, feeling that you are a failure, or feeling

• that you have let yourself or your family down.

•(7) Trouble concentrating on things such as reading the newspaper or

• watching television.

•(8) Moving or speaking so slowly that other people could have noticed.

• Or being so fidgety or restless that you have been moving around a

• lot more than usual.

•(9) Thinking that you would be better off dead or that you want to hurt

• yourself in some way.

Patients with positive screens should be evaluated by a professional qualified in the diagnosis and management of depression.

Patients with cardiac disease who are under treatment for depression should be carefully monitored for adherence to their medical care, drug efficacy, and safety with respect to their cardiovascular as well as mental health.

•Lichtman et al., Circulation 2008;118;1768-1775

Monitoring mental health may include, but is not limited to, the assessment of patients receiving antidepressants for possible worsening of depression or suicidality, especially during initial treatment when doses may be adjusted, changed, or discontinued.

•Lichtman et al., Circulation 2008;118;1768-1775

MDD occurs in 15-23% of patients with coronary disease and is an independent RF for morbidity and mortality.

RCTs in the 1990s and 2000s show RR of MI and CV mortality of 1.5-2 in pts with preexisting depression.

In persons with established IHD, depression is associated with a 3-4 fold increase in the risk of subsequent CV morbidity and mortality.

Treatment of depression in patients with CAD is safe and somewhat efficacious

Rehabilitation is associated with a 50% decrease in depressive symptoms in pts with CHD

•Depression & Anxiety, 2006

•http://www.ca.uky.edu/hes/?p=6http://www.ca.uky.edu/hes/?p=6

•Mental Health Shortage Area, 2000

•http://www.ca.uky.edu/hes/?p=6http://www.ca.uky.edu/hes/?p=6

•Primary Care Shortage Area, 2000

•http://www.ca.uky.edu/hes/?p=6http://www.ca.uky.edu/hes/?p=6

•Population Uninsured, 2000

•http://www.ca.uky.edu/hes/?p=6http://www.ca.uky.edu/hes/?p=6

•Lavie CF, Arch Int Med, 2006

•Prevalence of Prevalence of HostilityHostility Before and After Cardiac Rehab Before and After Cardiac Rehab

•13%13%

•5%5%

•30

•20

•0•YoungYoung •ElderlyElderly

•10

•2%2%

•6%6%

•BeforeBefore

•AfterAfter

2320 men from the Beta blocker heart attack trial With other important prognostic factors controlled

for, the patients classified as being socially isolated and having a high degree of life stress had more than four times the risk of death of the men with low levels of stress and isolation.

An inverse association of education with mortality in this population was noted.

•NEJM 1984; 311:552-559

588 pts evaluated for the time prior to MI and at 12 months with HADS and followed for 8 years.

Multivariate predictors of death included age, previous MI, Killip class, medications prescribed on dc.

Depression was not associated with cardiac mortality whether detected imediately before MI (p=0.48), 12 months after (p=0.27), or at both times (p=0.97).

120

125

130

135

140

morn

ing

noon

afte

rnoon

even

ing

mm

Hg

overcommitment +,occup. position -

overcommitment +,occup. position +

overcommitment -,occup. position +

overcommitment -,occup. position -

•Source: A. Steptoe et al. (2004), Psychosomatic Medicine, 66: 323-329.

282 post MI patients interviewed in hospital and at 3-4 months

3-4 months after infarction, 33% of patients met criteria for depression. The large majority of patients who initially met criteria for major but not minor depression showed evidence of depression at 3 months and most patients with major depression had not returned to work by 3 months.

Treatment of major depressive syndromes after myocardial infarction may reduce chronicity and disability, while minor depressive syndromes may be similar to normal grief and tend to be self-limited.

•Arch Intern Med. 1989;149(8):1785-1789.

• Elevated values were observed in patients with co-morbid panic disorder (P = 0.006).

• Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD.

•Barton et al. J Hypertens. 2007 Oct;25(10):2117-2124.