Transcript LEFT VENTRICULAR MASS: Measurement, Significance and

LEFT VENTRICULAR MASS:
Measurement, Significance and
Management in CKD/ESRD
Richard J. Glassock, MD, MACP
Geffen School of Medicine at UCLA
ESRD- State-of the Art
Boston
April 23, 2009
20 years after the “Dallas”
meeting the overall Annual
Mortality rate of Dialysis
patients in the USA has
declined by only about 15%
and is still highest of all of the
Countries of the Developed
World
THEME:
LV Mass in CKD/ESRD as a
Paradigm of What is WRONG
with Conventional
Regimens of Treatment
LEFT VENTRICULAR MASS
in CKD/ESRD
How should it be measured?
What are its likely mechanisms?
What are its consequences?
Can it be reversed (or prevented) by
interventions?
 What are key management
principles?
 What are the gaps in knowledge
and directions for future
research?




LV Mass in CKD/ESRD
Measurement
LEFT VENTRICULAR MASS:
Measurement
 Magnetic Resonance Imaging (without
contrast)- Gold Standard
 Computerized Acoustic Cardiography ; 3D
Echocardiography
 Echocardiography- 2D
 Echocardiography-M-mode
 Serum Troponin-T
 Serum Atrial and Brain Natriuretic Peptides
 Electrocardiography (Voltage and DurationVoltage Product)
 Physical examination
INCREASED LV MASS
EKG
(Okin PM, et al J. Electrocardiol 29:256, 1996)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Sensitivity
Specificity
Cornell QRS
Voltage
Cornell QRS
Voltage x
Duration Product
LV MASS in ESRD:
ANP and BNP
(Mallamaci F, et al KI 59:1559, 2001)
100%
80%
60%
40%
20%
0%
ANP
Sensitivity
Positive Predictive Value
BNP
ANP or BNP
Specificity
Negative Predictive Value
INCREASED LV MASS in ESRD:
Echocardiography
(Mark P, et al NDT 22:1815, 2007)
 M-Mode (1 D), 2 D and 3 D Echocardiography
have been commonly used to Quantify LV Mass
in ESRD
 Volume changes occurring with dialysis can lead
to errors in LV Mass estimation by M-Mode/2D
Echocardiography (estimates are based on the
cube of the LV internal diameter and LVID
decreases after HD)
 M-Mode and 2D, but not 3D, Echocardiograms
overestimate LV Mass, due to asymmetric
remodeling in 30% of patients
2D ECHO-Normal
(Courtesy- R. Pecoits-Filho, 2009)
2D ECHO- LVH
(Courtesy-R. Pecoits-Filho, 2009)
LV MASS
Echocardiography (M-Mode or 2D)
Normal Values
 Males= <125-130gms/m2 BSA
 Females= <100gms/m2 BSA
 In Dialysis patients LV Mass
should be indexed to Height
(gms/m2 or gms/m2.71) rather
than BSA due to the weight
fluctuations
LV MASS in ESRD:
Cardiac Magnetic Resonance Imaging
(CMRI)
 Cannot be performed with contrast
(gadolinium) in ESRD
 Requires at least a 1.5 Tesla magnet
 Gives LV Mass values about 65gm/m2
greater than M-mode
Echocardiography
 Pre-post dialysis differences in LV
mass with CMRI are less than those
found with M-mode Echocardiography
(-10gm/m2 vs -26gm/m2)
 3D Echocardiography and CMRI give
equivalent results for LV Mass
LVH in CKD/ESRD:
Measurement-Conclusions
 EKG is an insensitive but specific method of
diagnosis of increased LV Mass
 Troponin-T, ANP and/or BNP levels have excellent
positive predictive value for diagnosis of increased
LV Mass in ESRD
 Cardiac Magnetic Resonance (CMRI) imaging is the
“gold-standard” for measuring LV Mass in ESRD
 M-Mode Echocardiography overestimates the
presence of increased LV Mass (due to volume
changes and geometry in ESRD)
LVH in CKD/ESRD:
Epidemiology and “Natural”
History during CKD and
Conventional ESRD Therapy
LVH in CKD- ECHO
Prevalence of LVH in Non-Diabetic CKD
(Paoletti E, et al AJKJD 46:320, 2005)
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Controls
Stage 1-2
Stage 3-5
Natural History of LVH
in CKD Stages 3/4
(Over two years)
(McMahon LP, et al JASN 15:1624, 2004)
CKD
(Stage 3/4)
↓
Echocardiography
LVH+
(30%)
LVH+
(70%)
LVH(30%)
LVH(70%)
LVH+
(30%)
LVH(70%)
LVH in ESRD
(London GM, et al JASN 12:2759-2767, 2001)
 153 patients receiving “conventional”
HD for >9 months followed for average
of 54 months (10-126 months) with
serial hemodynamic measurements
(including ECHO)
 Outcome parameters (mortality and CV
events) correlated with hemodynamic,
hematological and biochemical
variables
 Response= >10% reduction in LVMI
(gms/m2)
 Baseline- 90% had LVH
LVH in ESRD
(London, et al JASN, 2001)
32%
46%
22%
Regressed
No Change
Progressed
LV Mass in CKD/ESRD:
Epidemiology-Conclusions
 LV Mass steadily increase as CKD
progresses, but not inevitably
 Increased LV Mass in incident ESRD
patients is very common (70-90%),
but will subsequently regress in only
about 50% of patients with
conventional HD or PD.
 Non-regressors on HD/PD have a poor
prognosis
LVH in CKD/ESRD
Mechanisms
Pathogenesis of LVH in CKD/ESRD:
Preload, Afterload and Other Factors
(Ritz E. Kidney Int 75:771-773, 2009)
LVH in CKD/ESRDPathogenetic Mechanisms
 Afterload- (Systemic vascular
resistance, SBP, vascular compliance)
 Preload- (Intravascular volume,
anemia, A-V fistula)
 Non-After or –Preload Factors
LVH IN CKD/ESRD:
Non- After or –Preload Factors








Activation of mTOR
Intra-cardiac RAS
Phosphate retention
Markedly elevated PTH levels
Vitamin D deficiency
Carnitine deficiency
SNS Activation
Cytokine/Hormone/Catechol
production- (aldosterone, endothelin-1, TNFα,
Leptin. Il-1α, Il-6, TGFβ, nor-epinephrine)
 Gender
mTOR and LVH in CKD
(Siedlecki, et al. KI April, 2009)
 A Mouse model of CKD produced
by partial surgical nephrectomy
(SIRI)
 LVH developed in absence of
hypertension or volume
expansion
 ERK and S6 activated (mTORdependent TF)
 Sirolimus abolished LVH (no
effect on BP)
mTOR and LVH
(Siedlecki AM, et al, KI January 2009)
6
5
4
3
2
1
0
LVMI (mg/gm)
SIRI
LV/Tibial length
(mmg/mm)
SIRI + Vehicle
RV/Tibial length
(mg/mm)
SIRI + Rapamycin
Sham
mTOR and LVH:
Post-Renal Transplant
(Paoletti E, et al AJKD 52:324, 2008)
100%
80%
Regression
of LVH
60%
40%
20%
0%
CNI to Sirolimus
CNI
mTOR Inhibition can
ameliorate (or prevent) LVH
in CKD (Independent of
BP/Anemia/Volume)- Not
yet tested in ESRD
Vitamin D and LVH in ESRD
(Achinger SG and Ayus JC. KI 95:s37, 2005)
 Vitamin D deficiency can activate the RAS and
promotes secondary hyperparathyroidism– and
thus promote LVH and elevated blood pressure.
 Retrospective studies have shown regression of
LVH in Vitamin D treated ESRD patients
 Experimentally, activated Vitamin D supplements
(Paricalcitol) reduce LVH, possibly via an effect on
intra-cardiac RAS
 Vitamin D use may reduce CVD mortality in ESRD
patients (observational data primarily)
 No RCT in Humans showing a beneficial effect of
Vitamin D supplementation on LVMI in ESRD has
yet appeared
Hyperphosphatemia
and LVH in ESRD
(Achinger, Ayus, JASN 17:s255, 2006; Strozecki P, et al Ren Fail
23:125, 2001;Galetta F, et al J Intern Med 258:378, 2005)
 Correlations between serum
phosphorous levels and calcium x
phosphorus product and LVH have
been repeatedly noted
 Causality is not proven (absence of
RCT with LVMI as primary end-point)
 Daily HD effectively reduces serum
Phosphorus levels and also improves
LVMI
Parathyroid Hormone and LVH
 PTH levels correlate directly with
LVH in both primary and
secondary hyperparathyroidism
(inconsistently)
 Parathyroidectomy can cause
regression of LVH
 PTH (1-34) can induce LVH (via
MAPK/ERK activation)
PTH and LVH in ESRD
(Fujii H, et al Inter Med. 46:1509, 2007)
200
180
160
140
120
LVMI
100
(g/m2)
80
60
40
20
0
<300pg/ml
>300pg/ml
PTH Levels
>500pg/ml
RAAS and LVH in ESRD
 Angiotensin II directly induces
cardiomyocyte hypertrophy,
independent of afterload
 Local (intra-cardiac) Angiotensin II is
generated by myocardial stretch--But
hypertrophy still occurs in AT1b
receptor KO mice
 Aldosterone (?via TGFβ) may play an
Angiotensin II independent role in
myocardial fibrosis and LVH
LVH in ESRD:
AV Fistula Effects
(in Transplant Recipients)
(Cridlig J, et al Transpl Int 21:948, 2008)
140
120
100
LVMI
(gms/m2)
80
60
40
20
0
AVF+
AVF-
LVH in CKD/ESRD:
Key Factors in Pathogenesis
 Degree of Control of Systemic Arterial
Resistance and Large Vessel
Distensability (Systolic BP, PW Velocity)
 Degree of Control of Hypervolemia
(Ultrafiltration, Interdialytic weight gain,
Interdialytic interval, ?Anemia)
 Preload and Afterload Independent
Factors (mTOR activation, PTH, P04,
Vitamin D, Cardiac RAS)
LVH in CKD/ESRD
Consequences
LVH in ESRD:
Effect on Mortality/Morbidity
(Zoccali C, et al. KI 65:1492, 2004)
100%
80%
Cumulative
Mortality/
CV Events
(%)
60%
40%
20%
0%
Low
Middle
High
Tertiles of LVMI Change (gm/m2.7/month)
All Cause Mortality (3 year)
Fatal/Non-Fatal CV Events (3 year)
LVH in ESRD:
Effect on Mortality and CV Events
(London, et al JASN, 2001)
70%
60%
50%
40%
30%
20%
10%
0%
Mortality
Regression
CV Events
No Regression
LVMI and Mortality in
Hemodialysis
(London GM, et al JASN 12L2759-2767, 2001
)
 A 10% reduction in LVMI in ESRD is
associated with a 22% reduction in
all-cause and a 28% reduction in CV
mortality
 A 1 gm decrease in total LVMI equals
about a 1% decrease in CV mortality
(over 54 months of follow-up)
LVH in ESRD
(London, et al JASN 2001)
30%
20%
10%
0%
-10%
-20%
SBP
Regression
PWV
Hemoglobin
No Regression
LVH in CKD/ESRD:
Cardiovascular Consequences
 Cardiovascular events and death
> Sudden Cardiac Death
(ventricular arrhythmias)
> Dilated Cardiomyopathy and
Congestive Heart Failure
> Aggravation of Ischemic Heart
Disease (acute myocardial infarction)
> Stroke
(hemorrhagic/thrombotic/ischemic)
CARDIAC DEATHS (n=270):
4 D Trial
60%
50%
40%
30%
20%
10%
0%
Sudden Death
Congestive Heart Failure
Acute Myocardial Infarction
Other
LEFT VENTRICULAR HYPERTROPHY4 Year Risk of Sudden Death
(EKG-QRS Criteria)
(4 D Trial- Krane V, et al CJASN 4:394, 2009)
30%
25%
20%
15%
10%
5%
0%
LVH Present
LVH Absent
NT-pro-BNP and Sudden Death
(4-D Trial; Winkler K, et al. Euro Heart J 29:2092, 2008)
30%
25%
20%
15%
10%
5%
0%
1
2
3
Quartile of NT-pro-BNP (pg/ml
4
LVH IN ESRD:
Consequences-Conclusions
 Sudden Cardiac Death is the principal
consequence of increased LV Mass, most
likely due to enhanced risk of fatal
ventricular arrhythmias (electrical
remodeling-arrythmogenic
hypertrophy/fibrosis)
 Systolic and/or Diastolic Dysfunction
due to cardio-myocyte apoptosis, myosin
isoform switch, energy dysmetabolism.
Myofilament slippage and fibrosis also
contribute to the risk of congestive heart
failure (dilated cardiomyopathy)
LVH in CKD/ESRD
 COMMON
 DANGEROUS
 TREATABLE/PREVENTABLE?
LVH in CKD/ESRD-
Effects of Some Interventions
LVH in ESRD:
Effect of EPO therapy
 Seven (7) RCT have been conducted
that examine the effect of EPO
therapy on LVH in CKD/ESRD
 All but one have failed to show any
beneficial effect on LVH of EPO
therapy and correction of hemoglobin
to normal or near normal levels
EPO Therapy in
CKD/ESRD and LVMI:
A Meta-Analysis
(Parfrey PS, et al CJASN 4:755-762, 2009)
 15 unique, non-overlapping studies
involving 1731 subjects (5 of which
were RCT)
 Effect of EPO on LVMI examined in
those with severe anemia (Hemoglobin
<10gm/dl) and those with more
moderate anemia (Hemoglobin
>10<12 gm/dL) at baseline and
according to target Hemoglobin
(lower=≤12gm/dl and higher=
>12gms/dL)
EPO in CKD/ESRD- Change in LVMI:
A Meta-Analysis
10
0
Effect Size
(change in -10
LVMI in -20
gm/m2)
-30
-40
Category
Severe anemia; lower target
Moderate anemia; lower target
Moderate anemai; higher target
LVH and ESRD:
Dialysis mode and Prescription
 Observational (cross-sectional) studies
have shown a lower prevalence of LVH
in PD compared to conventional HD
patients (?effect of residual
confounding; ?better BP/Volume
control; ?AV fistula absence)
 More Frequent/Longer HD sessions are
strongly associated with a much lower
prevalence of LVH (?better volume and
PO4 control) compared to conventional
HD
LVD in ESRD:
HD vs PD
(Tian J-P, et al Ren Fail 30:391, 2008)
70%
60%
50%
Prevalence 40%
of LVH (%) 30%
20%
10%
0%
Hemodialysis
Peritoneal Dialysis
LVH in ESRD:
Hemodialysis Prescription
 One randomized* and one nonrandomized** prospective controlled
studies have been reported
comparing “conventional” (3
x/week) HD with “short-daily” or
“nocturnal” HD and evaluating LVH
(* Culleton BF, et al JAMA 298:1291,
2007;**Ayus JC et al JASN 16:2778,
2005)
LVH in ESRD:
Nocturnal vs Conventional HD
4
2
0
Change
(Baseline -2
to Final)
-4
-6
-8
LVMI
SBP
Nocturnal
PO4
HgB
Conventional
LVH in ESRD:
Short Daily vs Conventional HD
(Ayus JC, et al JASN 16:2778, 2005)
5
0
-5
-10
-15
-20
-25
-30
-35
-40
LVMI
SBP
Short Daily (n=26)
PO4
HgB
Conventional (n=51)
Frequent Hemodialysis Network
Trials
(Suri RS, et al Kidney Int 72:349, 2007)
 Two multi-center randomized trials to
compare Conventional thrice weekly
HD to-1) Daily in-center HD and (MFD)
2) Nocturanl Home HD (NHHD)
 Composite Primary End-point – 12
month change in LVMI (by MRI) and
SF-36 Physical Health Composite
(PHC) scores
LVH in ESRD:
“High Flux” vs “Low-Flux”
Hemodialysis
 Neither the HEMO Study (NEJM, 2002)
nor the MPO Study (JASN, 2009) study
stratified for LVMI
 We do not know if “High-flux” HD is
better than or equivalent to “Low-flux”
HD for LVMI.
 If low serum albumin (<4.0gm/dL) is
associated with an increase in LVMI,
then it is possible that “High-flux” HD
would be superior (MPO study)
LVH in ESRD:
High-flux HD
(Kong CH, et al Bllod Purif 21:163, 2003)
 In patients receiving high-flux HD
failure to “regress” LVH is associated
with:
> Higher inter-dialytic weight gain
> persistence of systolic
hypertension
> higher PTH levels
LVH in ESRD:
Effect of Guideline Adherence
(Covic A, et al J Nephrol 19:783, 2006)
 In a prospective (uncontrolled)
observational study of 103 patients on
HD before and after implementation of
EBPG/KDOQI Guidelines—
> 38% had no regression or had further
progression of elevated LVMI
> Regression of LVH correlated with
improvement of Hgb, PO4 and Ca x
Po4 levels (?causality)
LVMI in CKD/ESRD
Key Management
Principles
LVH in CKD/ESRD:
Key Management Principles- I
 Rigorous control of volume
overload (diuretics, NaCl restriction,
control of inter-dialytic weight gain,
ultra-filtration)
 Meticulous control of 24 hour
blood pressure (targets very
uncertain-?120-130/70-80mmHg;
ACEi/ARB-(tissue penetrating)
preferred; ABPM?
LVH in CKD/ESRD:
Key Management Principles- II
 Replete Vitamin D Stores
(ergocalciferol)
 Maintain serum phosphorous at
3.5-5.0mg/dL (diet and PO4
binders)
 Maintain iPTH levels <500pg/ml
(dialysis)
LVH in CKD/ESRD:
Key Management Principles- III
 If feasible, use More Frequent
Dialysis (nocturnal HD, daily HD)Favor PD over HD as appropriate (?).
 Avoid high-dose EPO- (Maintain
HgB >10 gms/dL but <12gm/dL (?);
maintain Fe stores
 Monitor LVH (LVMI) post-dialysis
every 18 months (by 2D ECHO, 3D
ECHO or CMRI)
LVH in CKD/ESRD:
Key Management PrinciplesUncertainties
 Carnitine Supplementation
 Statins (if CRP elevated and LDL
>120mg/dL)
 Close AV Fistula (transplant)
 Convert to Sirolimus from CNI
(transplant)
 Bilateral nephrectomy
 CAPD instead of HD
 Use Tropinin-T/ANP and/or BNP levels
to monitor LVH
LVH in CKD/ESRD:
Proposed Clinical Targets
 Reduce prevalence of LVH (by
CMRI or 3D ECHO) to <10-15%
 Reduce Prevalence of Sudden
Cardiac Death by >50%
LVH in ESRD:
Knowledge Gaps/Future Research

Can LVH be prevented by aggressive multi-factorial
therapy started early in the course of CKD?- need an
RCT





Can progression of LVH to Dilated Cardiomyopathy be
prevented by interruption of molecular mechanisms?
(e.g. NIX-induced cardio-myocyte apoptosis; inhibition of
fibrosis)
What is (are) the nature of the mTOR activator (s) in
CKD/ESRD?
Can small molecule, non-toxic, cardio-selective mTOR
inhibitors prevent/treat LVH in ESRD (independent of
blood pressure)?
Can fatal cardiac arrhythmias (sudden cardiac death) in
severe LVH be prevented?
Will MFD ameliorate LVMI increase and improve survival
(decrease sudden death)- RCT-Frequent HD Network in
Progress
LVH in ESRD:
How Important is Interdialytic Weight Gain?
How important is the Interdialytic interval?
LVH in CKD/ESRD:
CONCLUSIONS
 Current “conventional” HD (thrice- weekly,
short-duration, long-inter-dialytic interval)
regimens are insufficient to fully correct or
substantially modify LVH in ESRD (despite
“adequate” dialysis dosage)
 Longer (slower) HD regimens with a shorter
inter-dialytic intervals (MFD/NHHD) may
improve LVH (and thereby reduce mortality due
to sudden death)
 Goals of CKD/ESRD therapy should include
modification of LVH as a high priority (including
non-afterload/preload related factors)
LVH in CKD/ESRD
 COMMON
 DANGEROUS
 POORLY UNDERSTOOD AND
POORLY TREATED IN OUR
CURRENT CKD/ESRD TREATMENT
PARADIGMS