Download Coronary artery disease

Coronary atherosclerosis in CKD
• Atherosclerosis plaque is the central feature of coronary
arteries
• Lead to MI, CHF, death
• Term ASCVD replace CAD
• Evidence of atherosclerosis in CKD
• Autopsy
• angiography
KDOQI commentary on the 2012
KDIGO clinical practice guideline for the
Evaluation and management of CKD
www. Kdigo.org
1. All people with CKD be considered at increased risk for CVD
2. Level of care for ischemic heart disease ,CHF should be
offered to CKD patients
3. Antiplatelet to CKD at risk for atherosclerotic events
Pathobiology of uremia and its consequences for the pathogenesis of
atherosclerosis
McCullough P.A. Curr Opin Nephrol Hypertens;2004:591-600
1. Traditional risk factors
2. Non-traditional risk factors
Traditional CVD
risk factor
Nontraditional CVD
risk factors
Diabetes
Oxidative Stress
AGEs
Hypertension
ADMA
Dyslipidemia
Inflammation
Smoking
Cellular senescence
Atherosclerotic
cardiovascular disease
in CKD patient
Risk factors for CVD specific to patients with CKD or that occur more frequently or
with greater levels in patients with CKD
Roberts et al. Am J Kid Dis ;2006:341-360
Major cardiovascular risk factors and cardiovascular outcomes
Major risk factors
Hypertension
Diabetes mellitus
Cigarette smoking
Obesity (BMI>30)
Microalbuminuria or estimated
GFR < 60 ml/min
Physical inactivity
Dyslipidemia
Age (men > 55 years, women > 65 years) Family history of premature
cardio-vascular disease (men < 55 years, women < 65 years)
Target-organ damage
Heart
LV hypertrophy
Angina or prior MI
Brain
Stroke or transient ischemic attack
Prior coronary revascularization
Chronic kidney disease
Heart failure
Peripheral arterial disease
Retinopathy
McCullough P.A. Curr Opin Nephrol Hypertens;2004:591-600
Kidney International (2017)
Pathophysiology
• Calcification plaque accelerated by CKD (medial layer)
• Contributed by secondary HPTH, uremic process
• Degree calcification by spiral CT scan correlated with serum PO4, total
calcium phosphorus product
• Increase stimulation of macrophage
• Release inflammatory mediator (TNF alpha)
• Vascular smooth muscle death, impaired vascular reactivity, increase
plaque rupture
• Independent CAC score between site of aortic calcification and tracer
uptake
Coronary artery calcification (CAC)
• Is a feature of CKD
• Association with higher time integrated mean serum PO4 level, cumulative
exposure to Ca containing oral phosphate binder
• ESRD and advanced CKD associated with extensive calcification of coronary
arteries and higher CAC score than without CKD
• Presence of coronary atheroma, higher CAC score in ESRD
Noninvasive detection ASCVD
• Symptom, EKG, cardiac stress test is less reliable in CKD
patients
• Symptom
• Chest pain is still most common presentation in CKD
• Atypical symptom more common than in non-CKD, esp SOB
• EKG
• ST elevation in EKG is less common in CKD
• Cardiac stress test
• More likely to have positive cardiac stress test in CKD
• Stronger correlation of atypical angina symptoms and true
CAD in CKD
Echocardiography
KDOQI recommend : Echo after 1-3 month after RRT and every
3 years regardless of symptoms
-
GFR declines   Incidence of obstructive CAD
-
Diffuse multi-vessel involvement with coronary calcification
-
Increased mortality
-
Limitation of diagnostic studies
Exercise stress test
CAG, contrast risk
Radionuclide scan : less sensitivity
EKG
Exercise-pharmacological myocardial perfusion
Myocardial Necrosis
Troponin C , I ,T ( CTnI, c TnT )
Trop C : associate with actinomysin of the cardiac and skeletal muscle
CTnI , cTnT : cardiac specific
GFR
- Troponin
In HD patient , CTnT predicts mortality and cardiovascular events, poor
outcome
Strict glycemic control
BP control
Uncertain in
CKD stage 5
Life style modification
-
ASA: should be given in individual with GFR < 45 ml/min per
1.73 m2 and CKD 5D
Statin: SHARP Trial: Simvastatin + Ezetimibe
Reduce CVD 17% but not overall mortality
Management
• Medication
• 1.statin
• Based on 3 trials : Die Deutsche Diabetes Dialysis, An Assessment of
Survival and Cardiovascular Events, Study of Heart and Renal
Protection
• No benefit to primary, secondary prevention using statin in ESRD
• Reduction in MACE in CKD not on dialysis, simvastatin+ezetimibe,
but no different in mortality outcome
• Meta-analysis : reduction in mortality and cardiovascular events
• KDIGO : use on all patients with CKD >50yr and those with high risk
for ASCVD aged 18-49 yr
Management
• 2.antiplatelet
• Higher reactivity of platelets to adenosine diphosphate in CKD
• Less reduction in platelet reactivity to P2Y12 inhibitors, limit
efficacy of P2Y12 and ASA
• Reduction in benefit following PCI esp. stent thrombosis
• High risk for thrombotic events and bleeding event
• ASA for primary prevention in SIHD is limited in CKD to
prevention of MI but not for mortality
• Newer P2Y12 inhibitors have not been adequately studied in
CKD patients
- Use of ASA
Clopidogrel
β blockers
ACEi/ARB
Same as in non-CKD patients
- PTCA should be used
No benefit from PCI and medication
In 320 patients with CKD stage 3-4
No difference in primary end point
(death, MI, Stroke) between PCI and CABG in CKD
patients
SHARP Trial : No efficacy of statin in CKD stage 5D
IV Thrombolysis : Benefit in stroke if given within 4-5 hr of
symptom onset
Management
• Revascularization for SIHD
• COURAGE and Bypass Angioplasty Revascularization
Investigation 2 Diabetes (BARI2D)
• PCI, CABG not superior to medical therapy in reducing all cause
mortality, MI
• BARI2D excluded all patients with Cr>2
• COURAGE enrolled 16 patients with GFR<30(5%)
• Hage et al, 260/2287 had GFR<60 evaluation for KT, neither
presence nor severity of CAD on angiography affected
survival, revascularization had survival benefit in TVD
• Limitation : underpower with GFR<60, prospective cohorts
CKD have better outcome with DES than bare metal stents
CABG in CKD :  risk of operative complication
PCI : additional risk of radiocontrast
Management
• Renal transplant
• Improve CV outcomes in ESRD
• US Renal Data Service
• Never wait listed or KT: 3.4 times to experience hospitalization for
ACS than who wait listed
• Wait listed and transplanted had rate ratio 0.34 for ACS hospitalization
compared with who were wait listed and never underwent transplant
• Even older had KT lead to improved survival
Congestive heart failure
Pathophysiology
Abnormal calcium and phosphate metabolism
Risk for vascular calcification in CKD
1CRP,
C-reactive protein
Cannata-Andia et al. J Am Soc Nephrol ;2006:S267-S273
•
•
High Phosphorus
 Potent stimulus to differentiation
of smooth vascular cells into osteoblast-like cells
 Mineralization
Sites: All calibers : high-caliber arteries
aorta
medium vessels
small-size vessels
cardiac valve
Non traumatic fraction
Strategies to reduce vascular calcifications :
• Control serum phosphate
• Sevelamer
Reduce the progression of both coronary and aortic calcifications
Fetuin A
• Circulating inhibitor of vascular calcification
• Low level predict cardiovascular event and mortality
Vitamin D analog
: Effect on proliferation
cardiovascular
Immune disorder
Calcium mimetics :
Bisphosphonates : Potential role in the management of vascular calcification
Increase bone mass
Reduce bone nontraumatic fragilily fractures
Reduce vascular calcification in experiment
Diet Control:
Dialysis Prescription : Short daily , nocturnal
Vitamin D Protection Mechanism
15
27
Neutrophil gelatinase - associaled lipocalin
Kidney injury molecule- 1
Interleukin-18
Mid-regional proadrenomedultin
Catalytic iron
Media of oxidative stress
Specific CV biomarkers and potential interventions that may be indicated if levels are
abnormal
Roberts et al. Am J Kid Dis ;2006:341-360
Asymmetric dimethylarginine (ADMA)
•
•
•
•
Elevated ADMA levels predict acute coronary events
ADMA accumulates in the patient with CKD
Predict all-cause mortality and cardiovascular events
Correlate with left ventricular mass index and negatively with
ejection fraction
ADMA
Cardiac troponin : Strong predictor of all cause mortality in
CKD 5D
BNP : associate with LVH
LV dysfunction
Interleukin – 6
Stimulate CRP secretion from the liver
Increase as GFR decrease
Tumor necrosis factor α
Proinflammatory cytokine
Greater in patients with decreases GFR
Fibrinogen
Produced by hepatocyte
Significantly predict CVD event in CKD patient
Oxidative stress
• Imbalance between oxidant and antioxidant compounds
• Antioxidant therapy dose not reduce cardiovascular event in large
trials
• Treatment :
Vitamin E
N - acelylcysteine
Sympathetic Nervous System Activation
Neuropeptide Y
• associated with LVH , systolic dysfunction
• Predicts cardiovascular events but not mortality
• Plasma norepinephrine predicts mortality and CVD events
• Therapy : Blocking sympathetic nervous system
Homocysteine
Sulfhydryl containing aminoacid from methionine
Proatherogenic
- Oxidative stress
- Alteration in endothelial antithrombotic mechanism
- Direct damage to the vascular matrix
GFR
Homocystine level
Treatment :
Folate
Vitamin B6
Vitamin B12
But did not reduce cardiovascular event
C – reactive Protein
PREVEND study
•
ESRD patient : CRP strongly associated with CVD events and death
•
plasma fibrinogen directly associated with left atrial volume
•
(CREED) data base
C-reactive protein (CRP)
• Best studied cardiovascular biomarkers of inflammation
• Produced by hepatocyte under the control of IL-6
CRP provide overall measure of systemic inflammatory activity
Inflammation
Atherosclerosis is an inflammatory disease
-  Oxidative stress
-  Clearance of proinflammatory substances
( advanced glycosylation end products )
-
Inflammation has been linked to alteration in protein metabolism
Hyperhomocysteinemia
May trigger renal damage
Level increase as renal function
( 20-50 µmol/L in ESRD patients )
Wald et al : 5% homocysteine
42% high CVD risk
Glycosylation of proteins
Advanced glycation end products ( AGEs )
• Nonenzymatic modification of proteins level correlate with GFR
• Independent risk factor for death in HD patients
Left Ventricular structure and function
• Cardiac ventricles produces B-type natriuretic peptide (BNP)
• BNP leave to active C-terminal end (BNP-32)
• Inactive N-terminal end (pro BNP1-76)
• BNP32 correlated with
• HT
• Coronary artery disease
• predict cardiovascular death
• Pro BNP1 predict
• combined end point of CVD events
• progression of kidney disease mortality
Therapy
• Reduce left ventricular wall tension
• Ultrafiltration by dialysis treatment
• Angiotensin-converting enzyme inhibitor
• β-blocker
Dietary salt restriction
Diuretic – aldosterone antagonist
: ACEi, ARB : little evidence in CKD
CKD increase risk of stroke 1.4 times
Stage 5D increase risk of stroke 5-10 times
Overall stroke rate 4% per year
(CHOICE Trial)
Independent predictor : age and diabetes
Prevention : BP lowering
Antiplatelet
Statin
Carotid endarterectomy
Stroke in HD
• Retrospectively examined 1671 incident
• hemodialysis patients with atrial fibrillation
• warfarin use compared with nonuse
• increased risk of stroke (HR, = 1.93; 95% CI1.29 to 2.90)
Warfarin
• Warfarin for prevent stroke
• selection of patients with NVAF
• not proven to be beneficial in ESRD and NVAF
• Warfarin has thin margin of benefit over risk in patients with ESRD
• Meta-analysis of warfarin in NVAF and ESRD
•
•
•
•
warfarin had no effect on
risks of stroke (hazard ratio, 1.12; 95%CI, 0.69 to 1.82; P=0.65) or
mortality (hazard ratio, 0.96; 95%CI, 0.81 to 1.13; P=0.60)
but was associated with increased risk of major bleeding (hazard ratio, 1.30; 95%CI, 1.08 to 1.56; P<0.01).
Guideline
• The 2005 KDIGO/ KDOQI guidelines
• not recommend warfarin anticoagulation for primary prevention of stroke
• in patients with ESRD and NVAF receiving dialysis
• Canadian Cardiovascular Society suggested
• patients with ESRD (eGFR,15 ml/min per 1.73 m2)
• not routinely receive anticoagulation or acetylsalicyclic acid
• for stroke prevention in atrial fibrillation
Prevalence 15-20% in dialysis patients
Increase incidence of stroke
Cerebral embolism
CHADS 2 score
CHF
Hypertentsion
Age older than 75
Diabetes
Score >1   Risk for stroke and need warfarin
Warfarin for primary prevention : questionable in CKD 5D
- Direct Thrombin Inhibitor : dabigatran 150 mg twice daily
Can use in CKD Stage 3
RE-LY Study (Randomized Evaluation of long-Term anticoagulation
Therapy)
Coagulation cascade of oral anticoagulant
• apixaban is the most likely drug to move forward in patients with ESRD and NVAF
• Apixaban was associated with
• less major bleeding than dabigatran and rivaroxaban
• but not edoxaban in patients with moderate renal impairment
CKD is an independent risk factors for PAD
CKD and peripheral arterial disease
• we recommend that adults with CKD be regularly examined for
signs of peripheral arterial disease and be considered for usual
approaches to therapy
• We suggest that adults with CKD and diabetes are offered regular
podiatric assessment
Screening CKD 5D at the time of dialysis initiation
- The Ankle – Brachial Index
< 0.5 = diagnostic value
- Stop smoking
- Antiplatelet
- Statins
- ACEi
- Cilostagol (phosphodiesterase inhibitor)
 Risk of SCD with declining of GFR
Arrhythmia
Metabolic derangement
In CKD 5D : Frequent, long, slow HD
β blockers
Implantable cardioverter defibrillators.
- Correcting anemia, minimize vascular calcification
- Adequate ultrafiltration in CKD-5D
Anemia and Erythropoietin therapy
Anemia
Increase mortality due to
LVH
Vasodilatation
Increase cardiac output
Relative risk for mortality 5-6% lower for every 1 g/dl greater Hb
concentration
Summary
• Atherosclerotic plaque is central feature of disease coronary
arteries
• CKD is an ASCVD equivalent
• CKD have medial calcification
• Diagnosis test in ASCVD in CKD is less reliable
• CAC scores have been demonstrated to identify CKD at
higher risk for ASCVD
• Statin recommended in CKD age > 50yr
• Antiplatelets less efficacy in CKD
• Revascularization not superior benefit than medication
• TVD in ESRD may benefit from CABG than PCI
• Renal transplant improve in cardiovascular outcome in CKD