Diastolic Dysfunction

1
Diastolic Dysfunction

• The New Devil in the Pandemic

2
Examples of Adverse Remodeling
Stage A
Dilated cardiomyopathy
Hypertensive or diabetic heart disease
Stages B, C, D
Stages B, C, D
LV dilation, globular shape Systolic LV
dysfunction Mitral regurgitation
Normal cavity size, concentric LVH Diastolic
dysfunction Enlarged left atrium
3
Diastole4 phases

• isovolumetric relaxation
• rapid filling
• slow filling
• atrial contraction
• to receive blood during diastole under low
  pressure
• to eject blood commensurate with metabolic
  requirements

4
Determinants of Left Ventricular Filling

• Ventricular relaxation
• complex, energy dependent process
• begins during mid-systole continues 1/3 of
  diastole
• relaxation abnormalities occur early in disease
  states
• Effective chamber compliance
• passive properties of the ventricle
• diastolic suction
• passive filling
• pericardial restraint
• ventricular interaction

Nishimura, Tajik. J Am Coll Cardiol 1997308
5
Diastolic Pressure-Volume Relation in Patients
with Diastolic Heart Failure and in Controls
Zile, M. R. et al. N Engl J Med 20043501953-1959
6
Diastolic CHF definition
Definite DHF

• Definitive evidence of HF
• AND
• Objective evidence of normal LV systolic function
  in proximity to the HF event (within 72 hours
  of event)
• AND
• Objective evidence of LV diastolic dysfunction

Vasan and Levy. Circulation 20001012118
7
Mechanisms and Potential Therapeutic Targets in
LV Remodeling
Ischemic Injury Myocardial Disease Abnormal
Load Genetic Factors
Neurohormones Cytokines Oxidative stress
Altered Molecular Phenotype Ultrastructure
Changes Myocytes hypertrophy Altered Ca
Handling Apoptosis Fibroblast proliferation Collag
en deposition
Konstam et al JCF 2002
8
Effects of Angiotensin II on Growth
Factors/Cytokines and LV Remodeling
Angiotensin II
?TGF-? ?PDGF ?bFGF
Fibroblast proliferation ? Interstitial collagen
Myocyte hypertrophy
LV remodeling
TGF-? transforming growth factor beta PDGF
platelet-derived growth factor bFGF basic
fibroblast growth factor.
9
CHARM Program
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n2028 LVEF 40ACEI intolerant
n2548 LVEF 40ACEI treated
n3025 LVEF gt40ACEI treated/not treated
Primary outcome for each trial CV death or CHF
hospitalization
Primary outcome for Overall Program All-cause
death
10
CHARM-Preserved Primary Outcome CV Death or CHF
Hospitalization

30
366 (24.3)
Placebo
25
333 (22.0)
11 RR
20
Candesartan
15
10
HR 0.89 (95 CI 0.77-1.03), P0.118Adjusted HR
0.86, P0.051
5
0
0
1
2
3
years
3.5
Number at risk Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
11
CHARM-Preserved Primary and Secondary Outcomes
Covariate adjustedP-value
P-value
Candesartan
Placebo
0.89
0.118
0.051
CV death, CHF hosp. 333 366 - CV death 170 170
- CHF hosp. 241 276 CV death, CHF
hosp, 365 399 MI CV death,CHF hosp, 388 429
MI, stroke CV death,CHF hosp, 460 497 MI,
stroke, revasc
0.99
0.918
0.635
0.85
0.072
0.047
0.90
0.126
0.051
0.88
0.078
0.037
0.91
0.123
0.13
0.8
1.0
1.2
candesartan better
Hazard ratio
placebo better
12
Mechanisms and Potential Therapeutic Targets in
LV Remodeling
Ischemic Injury Myocardial Disease Abnormal
Load Genetic Factors
Neurohormones Cytokines Oxidative stress
Altered Molecular Phenotype Ultrastructure
Changes Myocytes hypertrophy Altered Ca
Handling Apoptosis Fibroblast proliferation Collag
en deposition
Konstam et al JCF 2002
13
Structure of the Myocardium in the Normal and
Hypertrophied Heart

Fibrillar Collagen
Myocyte
Vascular Smooth Cells
Cardiac Fibroblast
Coronary Blood Vessel
14
Aldosterones Role in Cardiovascular Disease
Vascular inflammation and injury
Prothrombotic effects
Potassium and magnesium loss
Central hypertensive effects
Myocardial fibrosis
Deleterious effects of aldosterone
Endothelial dysfunction
Catecholamine potentiation
Ventricular arrhythmias
Sodium retention
Cardiovascular disease
McMahon EG. Current Opinion Pharmacol.
20011190-196.
15
Myocardial Histopathology
Aldosterone/NaCl-Treated Hypertensive Rats
Aldo/NaCl
Aldo/NaCl Eplerenone
Rocha R et al. Am J Physiol. 2002283(5)H1802-10.
16
Efficacy in Target Organ Protection LVH Study
Mean Changes from Baseline in LV Mass
Eplerenone Enalapril (n 49)
Enalapril (n 54)
Eplerenone (n 50)
Change inLV Mass (g)
14.5

19.7

27.2

P lt 0.05 vs baseline P 0.007 vs
eplerenone.Pitt B et al. Am J Hypertens.
200215OR-53.
17
Regression of Left Ventricular Hypertrophy (LVH)
Predicts Prognosis
Regressors
Probability of Event-Free Survival ()
Rate of Events (per 100 patient-yr)
P 0.002
Nonregressors
Regressors (n 52) Nonregressors (n 50)
Time to Event (wk)
Nonregressors defined as baseline and follow-up
left ventricular mass index (LVMI) gt 125
g/m2regressors defined as baseline LVMI gt 125
g/m2 and follow-up LVMI lt 125 g/m2. Verdecchia P
et al. Circulation. 19989748-54.
18
Mechanisms and Potential Therapeutic Targets in
LV Remodeling
Ischemic Injury Myocardial Disease Abnormal
Load Genetic Factors
Neurohormones Cytokines Oxidative stress
Altered Molecular Phenotype Ultrastructure
Changes Myocytes hypertrophy Altered Ca
Handling Apoptosis Fibroblast proliferation Collag
en deposition
Konstam et al JCF 2002
19
Mice Lacking the BNP Gene Have Cardiac Fibrosis
Tamura, et al. Proc Natl Acad Sci USA 2000
4239-4244.
20
GC-A Receptor Deficient Mice Have Heart
Failure Hypertension, Ventricular Dilation,
Cardiac Fibrosis and Myocyte Necrosis Oliver et
al. 1997 Proc Nat Acad Sci
21
Regulation of Gene Expression in Human Cardiac
Fibroblasts With BNP and TGF?
BNP
TGFb
Cardiac Fibroblast
gene expression
22
BNP Inhibits TGF-?Induced Fibrosis in Human
Cardiac Fibroblasts
Fibrosis ECM
TIMP3 MATN3 PDGFA COL1A2 CTGF IL11 COL15A PAI-1 MA
GP2 COL7A1 FBN1 COMP
TGF 24hr
TGF 48hr
TGF BNP 24hr
TGF BNP 48hr
BNP 24hr
BNP 48hr
23
Lusitropic Properties of the Natriuretic Peptides
24
The Natriuretic Peptides as Lusitropic Agents
Yamomoto et al, AJP, 97
25
Adhere Database ReportClinical Characteristics
Outcomes in Heart Failure Patients Admitted
withPreserved Systolic Function (HFPSF)
Yancy CW, et al. HFSA 2003.
26
HFPSF Adhere AnalysisStudy Rationale and
Objectives

• Rationale
• 40-50 of acute heart failure is HFPSF
• No consistent description of HFPSF available
• Paucity of data available to guide disease
  management
• Objective
• Evaluate clinical characteristics, medical
  therapy, and outcomes in patients with/without
  HFPSF

Yancy CW, et al. HFSA 2003.
27
HFPSF Adhere AnalysisMethods

• Data from 260 participating hospitals
• September 2001 to June 2003
• 54,639 patient hospitalizations included
• In-hospital LVEF available for 26,776 (49) of
  these patients
• PSF LVEF 40

Yancy CW, et al. HFSA 2003.
28
HFPSF Adhere AnalysisBaseline Demographics
In-hospital LVEF during index episode
40 In-hospital LVEF during index episode
lt40 P-values from Chi square statistic for
categorical variables and from 1-way ANOVA for
continuous variables
Yancy CW, et al. HFSA 2003.
29
HFPSF Adhere AnalysisMedical History
In-hospital LVEF during index episode
40 In-hospital LVEF during index episode
lt40 P-values from Chi square statistic for
categorical variables and from 1-way ANOVA for
continuous variables
Yancy CW, et al. HFSA 2003.
30
HFPSF Adhere AnalysisClinical Presentation
In-hospital LVEF during index episode
40 In-hospital LVEF during index episode
lt40 P-values from Chi square statistic for
categorical variables and from 1-way ANOVA for
continuous variables
Yancy CW, et al. HFSA 2003.
31
The ADHERE Registry 1st Quarter 2003 Benchmark
Report
Clinical Presentation at Registry Hospital
Serum BNP (mean)
Thirty-two percent (n8177) of 25813 patients
received an in-hospital BNP assessment
Represents patients with LVEF assessed at
hospital presentation
32
HFPSF Adhere Analysis Chronic Outpatient
Medication Use
Yancy CW, et al. HFSA 2003.
33
HFPSF Adhere Analysis In-Hospital Medication Use
Yancy CW, et al. HFSA 2003.
34
HFPSF Adhere AnalysisIn-Hospital Course and
Outcomes
In-hospital LVEF during index episode
40 In-hospital LVEF during index episode
lt40 P-values from Chi square statistic for
categorical variables and from 1-way ANOVA for
continuous variables
Yancy CW, et al. HFSA 2003.
35
The ADHERE Registry 1st Quarter 2003 Benchmark
Report
Clinical Status at Discharge
Patients Discharged Improved but Still Symptomatic
36
HFPSF Adhere Analysis Hospital Stay and Mortality
Yancy CW, et al. HFSA 2003.
37
HFPSF Adhere AnalysisConclusions

• HFPSF is common in patients with heart failure
• About half the patients hospitalized for acute
  heart failure have HFPSF
• Patients with HFPSF have less in-hospital use of
  ACE inhibitors, beta-blockers, and IV
  vasoactives, and greater use of IV diuretics than
  those with impaired function
• HFPSF carries a slightly milder clinical impact
  than heart failure with systolic failure
• Shorter hospital stays, less ICU admissions, and
  lower mortality
• Half the patients with HFPSF do not experience
  effective diuresis
• Post-discharge use of ACE inhibitors and
  beta-blockers is less in patients with HFPSF

Yancy CW, et al. HFSA 2003.