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Bradley S. Marino MD, MPP, MSCE

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1 Bradley S. Marino MD, MPP, MSCE
Cardiorenal Syndromes Chronic Kidney Disease in the Fontan Patient: What Does it Tell Us? Bradley S. Marino MD, MPP, MSCE Associate Professor Pediatrics Director, Heart Institute Research Core Attending Physician, Cardiac Intensive Care Unit Divisions of Cardiology and Critical Care Medicine Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine

2 Overview Single Ventricle Palliation Culminating in the Fontan Completion Fontan Outcomes and Multisystem Organ Dysfunction Special Physiologic Considerations in the Fontan Circulation Leading to Various Types of Cardiorenal Syndrome Chronic Kidney Disease in Fontan Survivors Renal Biomarkers Can Predict Cardiac Index by MRI in Fontan Survivors? Multi-Center Retrospective Study Multi-Center Prospective Study

3 Stage I Reconstruction: Modified Norwood Procedure
RV-PA conduit BTS Operative Cardiac Surgery (5th Edition). Editors: TJ Gardner and TL Spray, 2004

4 Mortality After Norwood Palliation
Unpublished Data - Cincinnati Children’s Hospital Medical Center 2012 4


6 Volume Load on Single Ventricle
Superior Cavopulmonary Connection with Takedown of BT or RV-PA Shunt Removes Volume Load on Single Ventricle Bidirectional Glenn Hemi-Fontan


8 Lateral Tunnel Fenestrated Fontan after Hemi-Fontan
Jonas R: Op Tech Card Thorac Surg 2:229,1997

9 Extracardiac Fontan after Bidirectional Glenn
Reddy M et al: Op Tech Card Thorac Surg 2:221,1997


11 The Total Cavopulmonary Connection - Fontan Physiology
Cavopulmonary connections divert systemic venous return into pulmonary vasculature The single ventricle ejects blood to systemic circuit Pulmonary blood flow returns passively to pulmonary vascular bed Fontan pressures 2-3x the normal CVP Increased renal vein pressure and decreased renal perfusion pressure Chronic heart failure is common

12 Increasing Population of CHD Survivors Quebec CHD Mortality
There has been a shift in the present era such that patients with CHD have lower early mortality and are surviving to be ACHD patients. There may be significant adult morbidity and mortality. Khairy, P., et al., Changing mortality in congenital heart disease. J Am Coll Cardiol. 56(14): p Changing mortality in congenital heart disease. Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ. J Am Coll Cardiol Sep 28;56(14): PMID: [PubMed - indexed for MEDLINE] Changing Mortality in Congenital Heart Disease Paul Khairy, MD, PHD,* Raluca Ionescu-Ittu, MSC,†§ Andrew S. Mackie, MD, SM,† Michal Abrahamowicz, PHD,§ Louise Pilote, MD, MPH, PHD,‡§ Ariane J. Marelli, MD† Montreal, Quebec, Canada Objectives This study sought to characterize temporal trends in all-cause mortality in patients with congenital heart disease (CHD). Background Historically, most deaths in patients with CHD occurred in early childhood. Notable advances have since been achieved that may impact on mortality trends. Methods We conducted a population-based cohort study of patients with CHD in Quebec, Canada, from July 1987 to June 2005. A total of 8,561 deaths occurred in 71,686 patients with CHD followed for 982,363 patient-years. Results The proportion of infant and childhood deaths markedly declined from 1987 to 2005, with a reduction in mortality that exceeded that of the general population. Distribution of age at death transitioned from a bimodal to unimodal, albeit skewed, pattern, more closely approximating the general population. Overall, mortality decreased by 31% (mortality rate ratio: 0.69, 95% confidence interval [CI]: 0.61 to 0.79) in the last (2002 to 2005) relative to the first (1987 to 1990) period of observation. Mortality rates decreased in all age groups below 65 years, with the largest reduction in infants (mortality rate ratio: 0.23, 95% CI: 0.12 to 0.47). In adults 18 to 64 years, the mortality reduction (mortality rate ratio: 0.84, 95% CI: 0.73 to 0.97) paralleled the general population. Gains in survival were mostly driven by reduced mortality in severe forms of CHD, particularly in children (mortality rate ratio: 0.33, 95% CI: 0.19 to 0.60), and were consistent across most subtypes. Conclusions Deaths in CHD have shifted away from infants and towards adults, with a steady increase in age at death and decreasing mortality. (J Am Coll Cardiol 2010;56:1149–57) © 2010 by the American College of Cardiology Foundation Khairy et al, JACC, 2010 12

13 The Fontan Circulation: A Spectrum of Heart Failure
Anatomic Risk Factors Procedural Risk Factors Circulatory Risk Factors Underlying 1V Anatomy Staged Procedures Fontan Circulation Primary Prevention Compensated Heart Failure Decompensated Heart Failure Early Intervention End-Stage “Failing Fontan Physiology” Late Intervention Intervention Mortality

14 Dysfunction Functional Impairments
Cardiac Functional Impairments Vascular “Failing Fontan Physiology” Neuro-developmental Pulmonary Multi-system Organ Dysfunction Hepatic Reduced Quality of Life Psychosocial Renal Intestinal Physical Endocrine Hematopoietic

15 Early Contributing Factors
The Fontan Circulation Results in Chronic Heart Failure and Various Types of Cardiorenal Syndrome Early Contributing Factors Multiple episodes of AKI Chronic Volume Load Cyanosis Late Contributing Factors Ventriculo-arterial uncoupling Systolic Dysfunction Diastolic Dysfunction Activation of Renin-Angiotensin-Aldosterone System and increased SVR

16 Types of Cardiorenal Syndromes In Fontan Survivors
Type I: Acute Cardiorenal Syndrome Abrupt worsening of cardiac function (e.g. acute cardiogenic shock or acutely decompensated CHF) leading to acute kidney injury Type II: Chronic Cardiorenal Syndrome Chronic abnormalities in cardiac function (e.g. chronic CHF) causing progressive and potentially permanent chronic kidney disease Type III: Acute Renocardiac Syndrome Abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia) Type IV: Chronic Renocardiac Syndrome Chronic kidney disease (e.g. chronic glomerular or interstitial disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events Type V: Secondary Cardiorenal Syndrome Systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction Combined disorders of the heart and kidney are classified as cardiorenal syndromes. The most recent definition includes 5 subtypes reflecting a variety of conditions where there primary failing organ can be either the heart or the kidney leading to secondary dysfunction of the other organ, and a timeframe of disease.

17 Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients

18 Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients (n=1,102)
50% of ACHD Survivors will have Mild or Moderate-Severe Chronic Renal Dysfunction GFR < 89 ml/min/1.73m2 50% of Fontan Survivors will have Mild or Moderate-Severe Chronic Renal Dysfunction GFR < 89 ml/min/1.73m2 Figure 1. Renal dysfunction in patients with ACHD. Distribution of GFR values across the spectrum of ACHD

19 Chronic Kidney Disease is Associated with Increased Morality in ACHD Patients

20 Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors
Background Patients with “failing Fontan” physiology often have multi-system organ dysfunction Identifying biomarkers that predict declining CI prior to clinical manifestations of “failing Fontan” physiology could potentially improve patient outcome by pre-emptively introducing interventions to augment CI A simple non-invasive measure associated with lower CI is needed to maximize outcome in Fontan survivors Serum biochemical and hematopoietic markers are minimally invasive, widely available and may be useful for serial monitoring of Fontan hemodynamics

21 Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors
Study Design Multi-center retrospective case series comparing MRI-derived CI to serum biomarkers Inclusion Criteria Fontan patients age ≥ 6 years of age Fontan patients who had an MRI with phase contrast CO measured in the vena cavae and/or pulmonary arteries Fontan patients who had biochemical and hematopoietic biomarkers obtained ± 12 months from MRI Patient Data Collection Medical history and biomarker values obtained by chart review Biomarkers analyzed: LFTS, serum creatinine, CBC with mean corpuscular volume (MCV) MRI Data Collection Phase contrast technique-derived CO measurements were obtained by the cardiologist/radiologist at each respective site

22 Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors
Statistical Analysis Normal serum biochemical/hematopoietic values vary by gender and age Normal serum biomarker data from QUEST Diagnostics was used to create age and gender specific LMS curves to calculate age-specific z-scores for each biomarker eCrCl was calculated by the Schwartz formula utilizing the serum creatinine Associations between biomarker z-scores and CI were assessed by Spearman Rank correlation Biomarkers that were significantly correlated with CI (i.e. Total Alk Phos, eCrCl, MCV) had Receiver Operating Curves generated separately and as a composite with corresponding AUC estimated Composite index derived from multivariate logistic regression incorporating all three independently significant variables

23 Retrospective Fontan Biomarker Cohort
85 Fontan survivors from 8 tertiary care centers Median age at MRI – 15 years (6-33 years) 57% Male, 75% Caucasian Original Single Ventricle CHD Diagnosis HLHS - 31% Tricuspid atresia - 21% DORV/TGA - 15% Other SV anatomies - 33%

24 Serum Biomarkers Correlate with Lower Cardiac Index in Fontan Survivors

25 Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index
Marino et al, JACC (Abstract), 2011

26 Total Alkaline Phosphatase, eCrCl, and MCV Predict Lower Cardiac Index
Marino et al, JACC (Abstract), 2011

27 Prospective Cross-Sectional Fontan Biomarker Study
Funded by Children’s Heart Foundation 12 centers – 125 Fontan Survivors Lower CI will be associated with: Heart - Higher Brain Natriuretic Peptide Bone - Lower Bone-specific Alkaline Phosphatase Bone Marrow - Higher Mean Corpuscular Volume Kidney - Lower glomerular filtration rate as measured by Cystatin-C Liver - Higher Gamma-Glutamyl Transpeptidase Intestine - Higher Stool Alpha-1 Antitrypsin

28 Summary Successful SV palliation has resulted in a growing population of Fontan survivors 50% will have evidence of chronic renal dysfunction and suffer from Cardio-renal syndrome eCrCl may be a member of a potential “biomarker panel” to risk stratify Fontan survivors for Lower CI More research on primary prevention of cardiorenal syndrome and long-term renal dysfunction in this high-risk population is needed Longitudinal follow-up of renal biomarkers may allow for early intervention to prevent the “Failing Fontan Physiology”

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