Angela Yee-Moon Wang, MD, PhD Department of Medicine Queen Mary - - PowerPoint PPT Presentation

Angela Yee-Moon Wang, MD, PhD Department of Medicine Queen Mary Hospital University of Hong Kong Hong Kong

Disclosures

 Received Speaker Honorarium from Genzyme, Roche Diagnostics and Baxter Corporation.  Received grants from Baxter, Genzyme and Abbott Laboratory.  Advisory Board for Genzyme Asia.  Medical advisory board for Baxter Extramural Grant Program.

Prevalence of Heart Failure in Dialysis Population

Author, year HD/PD N I or P Prevalence Harnett, 1999 HD + PD 432 I 31 Stack, 2001 HD + PD 4024 I 36 Wang, 2002 PD 246 P 38 Cheung, 2004 HD 1846 P 40 Couchard, 2008 PD HD 1530 9285 I I 34 28 Moretti, 2008 PD 298 P 9.9

I, incident; P, prevalent; HD, hemodialysis; PD, peritoneal dialysis; N, number

Heart Failure Increased Risk of Early Death (within 90 days of Dialysis Initiation) in Dialysis Patients

Soucie JM, et al. J Am Soc Nephrol 1996 Factor Level OR (95% CI) Age 45-64 65-74 75+ 2.1 (1.4, 3.3) 4.3 (2.8, 6.6) 5.0 (3.2, 7.8) Gender Male 1.6 (1.3, 1.9) Albumin (g/L) 35-40 31-34 10-30 1.4 (0.9, 2.2) 2.4 (1.5, 3.7) 4.4 (2.8, 6.9) Heart failure Yes 1.5 (1.2, 1.9) Myocardial infarction by age level <45 45-64 65-74 75+ 8.8 (4.2, 18.6) 1.4 (0.8, 2.4) 1.2 (0.8, 1.9) 1.0 (0.6, 1.6) Hypertension Yes 0.7 (0.6, 0.9) Smoking Yes 1.3 (1.0, 1.7) Activity impairment Severe 2.3 (1.4, 3.6)

Baseline History of Heart Failure Increased Long Term Mortality Risk in Dialysis Patients

Harnett JD, et al. Kidney Int 1995

Background Heart Failure Increases Risk of Mortality and Heart Failure in PD Patients

Wang AY, et al. Clin J Am Soc Nephrol 2011

Prevalence of De-novo or Recurrent Heart Failure in Relation to Baseline Heart Status in Dialysis Patients

Wang AY, et al. J Am Soc Nephrol 2007

27.6% 61.6%

Harnett JD, et al. Kidney Int 1995

25% 56% PD patients HD + PD patients

Factors Predicting Heart Failure in PD Patients

P HR (95% CI) Hemoglobin (1 g/dl ↑) 0.064 0.87 (0.76, 1.01) Serum albumin (1 g/L ↑) 0.014 0.94 (0.89, 0.99) Diabetes mellitus 0.115 1.46 (0.91, 2.35) Systolic blood pressure (1 mmHg ↑) < 0.001 1.03 (1.01, 1.04) Atherosclerotic vascular disease 0.026 1.75 (1.07, 2.87) LV mass index (1 g/m2.7 ↑) 0.050 1.006 (1.000, 1.011) Ejection fraction (1 % ↑) 0.014 0.97 (0.94, 0.99)

Wang AY, et al. Kidney Int 2006

Factors Hazard ratios (95% confidence intervals) P-value New onset heart failure - Diabetes mellitus 2.93 (1.46 – 5.87) 0.002 LV mass index (g/m2) 1.005 (1.000 – 1.010) 0.070 LV volume index (ml/m2) 1.027 (1.004 – 1.050) 0.019 Recurrent heart failure - Serum albumin (g/L) 0.91 (0.86 – 0.97) 0.002 Systolic blood pressure (mmHg) 1.04 (1.02 – 1.06) <0.001 LV volume index (ml/m2) 1.012 (1.001 – 1.024) 0.03

Factors Predicting New Onset and Recurrent Heart Failure in PD Patients Over A 4-year Prospective Follow-up

Wang AY, et al. Clin J Am Soc Nephrol 2011

Prevalence of LV Hypertrophy and Cardiac Dysfunction in Dialysis Patients

Author, yr HD or PD I or P No. Prevalence

• f LVH (%)

Prevalence of Systolic Dysfunction (%) Greaves 1994 HD + PD P 84 NS 36 (FS ≤ 25%) Foley 1996 HD + PD I 432 74 18 (FS ≤ 25%) Mallamaci 2000 HD + PD P 254 77 22 (EF ≤ 45%) Wang 2006 PD P 246 95 33 (EF < 50%)

HD, hemodialysis; PD, peritoneal dialysis; P, prevalent; I, incident; LVH, left ventricular hypertrophy, FS, fractional shortening, EF, ejection fraction; NS, not stated.

Wang AY, et al. Hypertension 2010 cTnT ≤ 0.01 µg/L cTnT between 0.01 – 0.99 µg/L cTnT ≥ 0.1 µg/L

P=0.001

Systolic ¡Dysfunc.on ¡Predicts ¡Sudden ¡Cardiac ¡Death ¡in ¡ ESRD ¡Pa.ents ¡

Cardiac Hypertrophy and Dilatation

Myocyte Capillary Mismatch in the Heart of Uremic Patients

Amann K, et al. J Am Soc Nephrol 1998

control Essential HT CRF patient

Cardiac Pathology in Hemodialysis Patients with Dilated Cardiomyopathy

Aoki, et al. Kidney Int 2005

Factors Predicting Heart Failure in Multivariable Cox Regression Model

Hb, SAlb, DM, SBP and background AVD Model 1 + LVM index Model 2 + LV EF Model 3 + cardiac troponin T P=0.02 P=0.017 P=0.038 Models

Wang AY, et al. Kidney Int 2006

Cardiac Troponin T Enhances the Predictive Value of Systolic Dysfunction and LV Hypertrophy for Heart failure in PD Patients

TnT > 0.06µg/L, LV EF > 50% TnT ≤ 0.06µg/L, LV EF ≤ 50% TnT > 0.06µg/L, LV EF ≤ 50% Vs ref group: TnT ≤ median (0.06µg/L), LV EF > 50% P 0.034 0.398 <0.001 Adjusted HR* 1.88 1.42 3.10 95% CI 1.05, 3.38 0.63, 3.19 1.71, 5.63 TnT > 0.06µg/L, LVMi < median TnT ≤ 0.06µg/L, LVMi ≥ median TnT >0.06µg/L, LVMi ≥ median Vs ref group: TnT ≤ median (0.06µg/L), LVMi < median P 0.097 0.148 0.003 Adjusted HR** 1.91 1.72 2.68 95% CI 0.89, 4.10 0.83, 3.58 1.39, 5.19

Wang AY, et al. Kidney Int 2006 Adjusting for SBP, atherosclerotic vascular disease, hemoglobin, serum albumin, *LV mass index and **LV EF.

Risk Factors for Left Ventricular Hypertrophy

Old Age Diabetes Anemia Hypertension Extra-cellular volume expansion Abnormal calcium*phosphorus metabolism Uremic milieu

Left ventricular hypertrophy

Arterial stiffening Inflammation Sympathetic Overactivity Asymmetric dimethyl arginine Renin-angiotensin system Local growth factors Myocardial ischemia Vitamin D deficiency Hyperparathyroidism Hypoalbumin

Effect of Sodium and Fluid Removal on Survival of Peritoneal Dialysis Patients

Sodium Removal (mmol/24 h/ 1.73 m2) - group I, <130 group II, 130 to 181 group III, 181 to 232 group IV, > 232

Ates K, et al. Kidney Int 2001

Fluid Removal (mL/24 h/1.73 m2)

• group I, <1265

group II, 1265 to 1570 group III, 1570 to 2035 group IV, > 2035

Worse Echocardiographic Measures in PD Patients with History of Volume Overload

History of volume

• verload (N=98)

No history of volume

• verload (N=152)

P LV mass index (g/m2) 262 ± 89 205 ± 75 <0.001 LV end diastolic diameter (cm) 5.29 ± 0.82 4.84 ± 0.79 <0.001 LV end systolic diameter (cm) 3.70 ± 0.93 3.16 ± 0.76 <0.001 LV ejection fraction 0.65 ± 0.13 0.71 ± 0.11 <0.001 LV fractional shortening 0.31 ± 0.09 0.35 ± 0.08 <0.001 Diastolic Function (%)

• Normal
• Abnormal relaxation pattern
• Pseudo-normal
• Restrictive filling pattern

22 61 1 16 21 77 2 0.001 Wang AY, et al. Am J Clin Nutr 2003

NT-pro-BNP – A Powerful Predictor of Heart Failure in PD Patients

4th Quartile 3rd Quartile 2nd Quartile 1st Quartile

Quartile NT-pro-BNP level 1st ≤ 1927 pg/ml 2nd ≥1928 - 5667 pg/ml 3rd ≥5668 - 17533 pg/ml 4th ≥17534 pg/ml

P<0.001 Variable Adjusted hazard ratios (95% confidence intervals) P-value Diabetes 1.87 (1.19, 2.92) 0.006 Systolic blood pressure (1 mmHg) 1.02 (1.01, 1.04) 0.001 Coronary artery disease 1.68 (1.02, 2.76) 0.041 NT-pro-BNP

• 2nd Quartile versus 1st Quartile

1.98 (0.85, 4.63) 0.114

• 3rd Quartile versus 1st Quartile

2.30 (1.00, 5.32) 0.050

• 4th Quartile versus 1st Quartile

7.17 (3.22, 15.99) <0.001

Wang AY, et al. J Am Soc Nephrol 2007

Konings CJ, et al. Nephrol Dial Transplant 2003

Extra-Cellular Volume Determined by Bromide Dilution in relation to Residual GFR

Association between Residual Renal Function and Cardiac Hypertrophy in Peritoneal Dialysis Patients

P=0.001 P=0.001 P=0.86

Wang AY, et al. Kidney Int 2002

Left Ventricular Filling Pressure (as Denoted by E/E’ ratio) is Inversely Associated with Residual Renal Function and Predicts Mortality in PD Patients

Factors Unit ↑ OR 95% CI P LV volume index 1ml/m2 1.06 1.04 - 1.09 <0.001 Residual GFR 1ml/min per 1.73m2 0.76 0.62 - 0.93 0.009 Age 1 yr 1.05 1.02 - 1.08 0.002 LV ejection fraction 1% 0.94 0.88 - 0.99 0.026 Diabetes mellitus .. 2.06 0.94 – 4.50 0.071

Wang AY, et al. Hypertension 2008

E/E’, ratio of early transmitral inflow velocity to early diastolic mitral annular velocity

Incremental Value of E/Em ratio (a non-invasive marker

• f Left Ventricular Filling Pressure) in Predicting Long-

Term Outcomes of PD Patients

Wang AY, et al. Hypertension 2008

Cardio-Renal Link in PD Patients

Loss of Residual Renal Function

Inflammation ↑ Oxidative Stress

Wang AY, et al. Kidney Int 2006

Anemia Hyperphosphatemia Extracellular volume

• verload

↑ Uremic milieu and middle molecule uremic toxins 25(OH)D deficiency Resting hypermetabolism

Cardiac hypertrophy & dilatation Systolic & diastolic dysfunction Valvular/vascular calcification Arterial stiffening Malnutrition Accelerated atherosclerosis

↑ Overall Mortality and Cardiovascular Death

Hypoalbuminemia

Progression to Heart Failure in ESRD

LV hypertrophy Coronary ischemia Traditional Framingham risk factors Kidney disease-related risk factors

Non-immune factors

? Immune activation

Neurohumoral activation

LV remodeling

Progressive LV dilatation

Heart Failure

Hemodynamic factors Metabolic factors RAS activation

Acute Chronic

Levine B, et al. N Engl J Med 1990

Tumor Necrosis Factor and the Failing Heart

Yokoyama T, et al. J Clin Invest 1993

LV Remodeling and Collagen Content in a Transgenic Mouse Model with Targeted TNF Over-expression

Mann DL, et al. Circ Res 2002

Proinflammatory Cytokines in relation to NYHA Functional Class in Patients with Systolic Heart Failure: ‘SOLVD’ Study

Torre-Amione G, et al, J Am Coll Cardiol 1996

Deswal A, et al. Circulation 2001

Circulating Cytokine levels in Relation to Clinical Outcomes

• f Patients with Advanced Heart Failure

Tumor Necrosis Factor and Interleukin-6 Signaling in Heart Failure

LV dysfunction LV remodeling Cardiomyopathy Myocyte apoptosis β Receptor uncoupling Pulmonary edema Endothelial dysfunction Cachexia and anorexia Insulin resistance iNOS activation

Causes of Immune Activation in Heart Failure

Endotoxin and Immune Activation in Chronic Heart Failure

Niebauer J, et al. Lancet 1999

Causes of Immune Activation in Dialysis Patients

Dialysis-related causes Dialysis-unrelated causes Catheter, graft and fistula infections Reduced renal clearance of cytokines Bioincompatibility of dialyzer membrane Accumulation of uremic toxins Bioincompatibility of peritoneal dialysis fluid Atherosclerosis per se Complement activation Chronic heart failure Back filtration Dental and gingival infections Exposure to endotoxins and other cytokine- inducing substances from dialysate Other infections Peritonitis and exit site infections Malnutrition

Associations between Inflammation, Arterial Stiffening, LV Hypertrophy and Dilatation in Peritoneal Dialysis Patients

hs-CRP level ≤ 1.26mg/L (Lower) 1.26-5.56mg/L (Middle) ≥ 5.56mg/L (Upper) Pulse pressure, mmHg 61 ± 13 66 ± 14 66 ± 14a LV mass index (g/m2) 195 ± 70 230 ± 82 248 ± 92a LV end-diastolic diameter (cm) 4.73 ± 0.73 5.13 ± 0.83 5.17 ± 0.85a Residual GFR, ml/min per 1.73m2 0.75 (0.03, 2.04) 0.74 (0, 2.09) 0 (0, 1.59)b

Wang AY, et al. J Am Soc Nephrol 2003

aP≤0.001, bP<0.05

Systolic and Diastolic Dysfunction are Associated with Inflammation in PD Patients

LVEF ≥ 50% LVEF < 50% P CRP (mg/L) 2.04 (0.73, 6.42) 4.29 (1.37, 12.35) 0.004 IL-6 (pg/mL) 8.8 (4.8, 17.1) 11.3 (6.9, 23.2) 0.003 E/Em ratio < 15 E/Em ratio ≥ 15 P CRP (mg/L) 1.26 (0.61, 4.93) 3.96 (1.29, 11.84) <0.001 IL-6 (pg/mL) 7.6 (4.1, 13.8) 10.9 (6.6, 19.8) 0.001

Wang AY, et al. WCN 2011 median (interquartile range).

E/Em, the ratio of early transmitral flow velocity (E) to early diastolic mitral annular velocity (Em); LVEF, left ventricular ejection fraction.

Inflammation Predicts Higher Mortality in Patients with Systolic Dysfunction

EF <50%, High CRP EF < 50%, Low CRP EF ≥50%, Low CRP EF ≥50%, High CRP P<0.0001 EF <50%, High IL6 EF < 50%, Low IL6 EF ≥50%, High IL6 EF ≥50%, High IL6 P<0.0001 Wang AY, et al. WCN 2011

Inflammation Increased Risk of Heart Failure in PD Patients with Systolic Dysfunction

EF<50%, High CRP EF<50%, Low CRP EF≥50%, Low CRP EF≥50%, High CRP P<0.0001 EF<50%, High IL6 EF<50%, Low IL6 EF≥50%, High IL6 EF≥50%, Low IL6 P=0.001 Wang AY, et al. WCN 2011

Inflammation Predicts Higher Mortality in Patients with Diastolic Dysfunction

E/Em ≥15, High CRP E/Em <15, low CRP E/Em ≥15, low CRP E/Em <15, high CRP

P<0.001

E/Em ≥15, High IL6 E/Em <15, low IL6 E/Em ≥15, low IL6 E/Em <15, high IL6 P=0.014

Wang AY, et al. WCN 2011.

PEW in relation to Episodes of Heart Failure in PD Patients

P=0.017

Wang AY, et al. Am J Clin Nutr 2010

Low Handgrip Strength Reflects Diseased Cardiac Status

Partial correlation coefficient P Background atherosclerotic vascular disease -0.182 0.007 LV mass index (g/m2)

• 0.202

0.003 LV volume index (ml/m2)

• 0.127

0.067 LV ejection fraction (%) 0.125 0.068 LV midwall fractional shortening (%) 0.141 0.040 LV filling pressure as denoted by E/Em ratio

• 0.218

0.001

*adjusted for age, gender and body height.

LV, left ventricular; E/Em, ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity.

Wang AY, et al. Nephrol Dial Transplant 2010.

Multivariable Cox Regression Analysis of Factors Predicting Heart Failure in PD Patients

Factors P-value Hazard ratios 95% confidence intervals LV mass index (g/m2) <0.001 1.005 1.002 – 1.008 Handgrip strength (kg) 0.008 0.96 0.94 – 0.99 LV ejection fraction (%) 0.010 0.97 0.94 – 0.99 Hemoglobin (g/dL) 0.029 0.86 0.75 – 0.99 Male gender 0.062 1.62 0.98 – 2.69 Background atherosclerotic vascular disease 0.090 1.50 0.94 – 2.38 Duration of dialysis (months) 0.097 0.99 0.99 – 1.00

Wang AY, et al. Nephrol Dial Transplant 2010

A lower Handgrip Strength Predicts Higher Risk of Heart Failure in PD Patients with Systolic Dysfunction

Wang AY, et al. Nephrol Dial Transplant 2010

Braunwald E. N Engl J Med 2008

The Cytokine Hypothesis of Heart Failure

Cardiovascular Disease Continuum in End-Stage Renal Disease

Wang AY and Sanderson JE. Am J Kidney Dis 2010

Thank You

 John E Sanderson  Christopher WK Lam  Jean Woo  Mei Wang  Iris HS Chan  Siu-Fai Lui

Acknowledgement

• Hong Kong Health Service Research Fund
• Hong Kong Society of Nephrology Research Grants
• Hong Kong Research Grant Council