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Thessaloniki, October 30, 2015
Comorbidities in Heart Failure
Filippos Triposkiadis, MD, FESC, FACCProfessor of CardiologyDirector, Department of CardiologyLarissa University HospitalLarissa, Greece
Definition of Comorbidity
Several definitions have been suggested for comorbidity based on differentconceptualizations of a single core concept: the presence of more than 1distinct conditions in an individual. Although always used as a person-levelconstruct, 4 major types of distinctions are made:• the nature of the health conditions• the relative importance of the co-occurring conditions• the chronology of presentation of the conditions• the expanded conceptualizations
Definition of Comorbidity
Feinstein AR. J Chronic Dis. 1970;23:455-468Angold A, et al. J Child Psychol Psychiatry. 1999;40:57-87
Valderas JM, et al. Ann Fam Med 2009;7:357-363
Chronologic Aspects of Comorbidity
Time span
Sequence
Comorbidity Constructs
Patient’s complexity
Non health-related individual attributes
Morbidity burden
Disease 1 (index) Disease 2 Disease n
Comorbidity of index disease
Multimorbidity
Sex Age Frailty
Health-related individual attributes
Valderas JM, et al. Ann Fam Med 2009;7:357-363
Risk factor 1 Risk factor 2
Risk factor 1
Risk factor 1
Risk factor 2
Risk factor 2
No etiologicalassociationThere is no etiologicalassociation between thediseases.
Direct causationOne of the diseases maycause the other, eg,Disease 1 (D1) = diabetesmellitus, Disease 2 (D2) =cataracts.
Associated risk factorsThe risk factors for eachdisease are correlated, eg,Risk Factor 1 (RF1) = smoking;Risk Factor 2 (RF2) = alcohol;D1 = chronic pulmonaryobstructive disease;D2 = liver cirrhosis.
Risk factor 1 Risk factor 2
Risk factor 1 Risk factor 2
Etiological Models of Comorbid Diseases
Disease 1
Disease 1
Disease 1
Disease 1
Disease 1
Disease 2
Disease 2
Disease 2
Disease 2
Disease 2 Disease 3
Valderas JM, et al. Ann Fam Med 2009;7:357-363
Disease 1 Disease 2 Disease 3
HeterogeneityThe risk factors for eachdiseases are notcorrelated, but eachone of them can causeeither disease, eg, RF1= smoking; RF2 = age;D1 = ischemic heartdisease; D2 = lungcancer.
Risk factor 3
IndependenceThe presence of the diagnostic features of each disease is actuallydue to a third distinct disease, eg, D1 = hypertension; D2 = tensionheadache; D3 = pheochromocytoma.
Disease 1 Disease 2
Cardio-Kidney-Damage (C-K-D)
El Nahas M. Kidney International 2010; 78: 14-18
Prevalence of Comorbiditiesin Heart Failure
Multimorbidity in Heart Failure:A Community Perspective
Chamberlain AM, et al. The American Journal of Medicine 2015; 128: 38-45
Prevalence of Individual Chronic Conditionsin HFpEF and HFrEF
Chamberlain AM, et al. The American Journal of Medicine 2015; 128: 38-45
Co-Morbidities in Patients with Heart Failure:the European Heart Failure Pilot Survey
van Deursen, et al. European Journal of Heart Failure 2014; 16: 103–111
A total of 3226 European outpatients with chronic HF were included in this analysis of the European Society ofCardiology (ESC) Heart Failure Pilot Survey. The following co-morbidities were considered: diabetes, hyper- andhypothyroidism, stroke, COPD, sleep apnoea, chronic kidney disease (CKD), and anaemia.
Overall (I-squared = 33.6%, p = 0.068)
Tribouilloy
CHARM
MEDICARE
EFFECT
DIG
DOSE
Study
SHS
SENIORS
MAYO
RELAX-AHF
CHS
OPTIMIZEEURO HF
GWTG
ADHERE
Worchester
ECHOESVeteransOlmsteadFramingham
DIAMOND-CHF
1.49 (1.30, 1.70)
3.08 (1.70, 5.59)
1.85 (1.05, 3.26)
1.42 (0.79, 2.55)
1.27 (0.73, 2.22)
1.83 (1.05, 3.21)
1.31 (0.64, 2.71)
OR (95% CI)
0.39 (0.18, 0.85)
3.14 (1.70, 5.81)
1.84 (1.05, 3.24)
2.53 (0.99, 6.45)
1.13 (0.64, 1.99)
1.63 (0.88, 3.03)1.44 (0.82, 2.52)
1.56 (0.81, 3.00)
1.50 (0.80, 2.82)
1.25 (0.70, 2.26)
1.13 (0.65, 1.98)1.50 (0.83, 2.71)1.44 (0.68, 3.06)1.13 (0.65, 1.98)
1.12 (0.58, 2.14)
100.00
3.46
%
4.90
5.25
6.12
5.00
3.55
Weight
5.93
3.24
4.93
1.63
6.33
4.405.69
4.00
4.40
5.51
6.374.993.156.37
4.79
1.49 (1.30, 1.70)
3.08 (1.70, 5.59)
1.85 (1.05, 3.26)
1.42 (0.79, 2.55)
1.27 (0.73, 2.22)
1.83 (1.05, 3.21)
1.31 (0.64, 2.71)
OR (95% CI)
0.39 (0.18, 0.85)
3.14 (1.70, 5.81)
1.84 (1.05, 3.24)
2.53 (0.99, 6.45)
1.13 (0.64, 1.99)
1.63 (0.88, 3.03)1.44 (0.82, 2.52)
1.56 (0.81, 3.00)
1.50 (0.80, 2.82)
1.25 (0.70, 2.26)
1.13 (0.65, 1.98)1.50 (0.83, 2.71)1.44 (0.68, 3.06)1.13 (0.65, 1.98)
1.12 (0.58, 2.14)
100.00
3.46
%
4.90
5.25
6.12
5.00
3.55
Weight
5.93
3.24
4.93
1.63
6.33
4.405.69
4.00
4.40
5.51
6.374.993.156.37
4.79
1.1 1 10
HYPERTENSION
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.647)
OPTIMIZE
DIAMOND-CHF
Worchester
DOSE
Veterans
MEDICARE
SHS
Study
CHARM
RELAX-AHF
EURO HF
EFFECT
DIG
ADHERE
MAYO
Tribouilloy
SENIORS
CHSECHOES
GWTG
OlmsteadFramingham
0.48 (0.42, 0.55)
0.52 (0.30, 0.92)
0.39 (0.21, 0.71)
0.44 (0.25, 0.78)
0.50 (0.28, 0.88)
0.55 (0.31, 1.01)
0.43 (0.23, 0.81)
0.41 (0.22, 0.77)
OR (95% CI)
0.57 (0.32, 1.00)
0.57 (0.33, 1.00)
0.65 (0.36, 1.16)
0.32 (0.17, 0.62)
0.54 (0.31, 0.95)
0.56 (0.30, 1.04)
0.63 (0.36, 1.12)
0.45 (0.19, 1.06)
0.54 (0.30, 0.95)
0.39 (0.21, 0.72)0.20 (0.11, 0.38)
0.73 (0.42, 1.27)
0.56 (0.32, 0.99)0.34 (0.19, 0.61)
100.00
5.00
5.16
5.33
5.08
4.36
4.49
4.54
Weight
4.85
4.86
4.23
4.84
4.86
4.09
4.50
2.45
4.83
4.906.58
4.35
4.785.93
%
0.48 (0.42, 0.55)
0.52 (0.30, 0.92)
0.39 (0.21, 0.71)
0.44 (0.25, 0.78)
0.50 (0.28, 0.88)
0.55 (0.31, 1.01)
0.43 (0.23, 0.81)
0.41 (0.22, 0.77)
OR (95% CI)
0.57 (0.32, 1.00)
0.57 (0.33, 1.00)
0.65 (0.36, 1.16)
0.32 (0.17, 0.62)
0.54 (0.31, 0.95)
0.56 (0.30, 1.04)
0.63 (0.36, 1.12)
0.45 (0.19, 1.06)
0.54 (0.30, 0.95)
0.39 (0.21, 0.72)0.20 (0.11, 0.38)
0.73 (0.42, 1.27)
0.56 (0.32, 0.99)0.34 (0.19, 0.61)
100.00
5.00
5.16
5.33
5.08
4.36
4.49
4.54
Weight
4.85
4.86
4.23
4.84
4.86
4.09
4.50
2.45
4.83
4.906.58
4.35
4.785.93
%
1.1 1 10
MYOCARDIAL INFARCTION
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.716)
MAYO
RELAX-AHF
OPTIMIZE
Tribouilloy
Veterans
DIAMOND-CHFEURO HF
MEDICARE
Olmstead
CHSGWTG
EFFECT
SENIORSDOSE
ADHERE
CHARM
Framingham
Study
1.36 (1.17, 1.58)
1.70 (0.95, 3.06)
1.69 (0.97, 2.97)
1.27 (0.69, 2.32)
1.25 (0.70, 2.26)
1.00 (0.56, 1.79)
1.18 (0.62, 2.24)1.12 (0.58, 2.14)
1.31 (0.73, 2.37)
0.95 (0.53, 1.73)
3.35 (1.17, 9.62)1.32 (0.73, 2.42)
1.49 (0.80, 2.78)
1.09 (0.61, 1.95)2.53 (1.41, 4.52)
1.30 (0.64, 2.64)
1.16 (0.62, 2.16)
1.45 (0.76, 2.75)
OR (95% CI)
100.00
5.79
6.34
6.35
6.72
7.70
5.765.84
6.50
7.47
%
1.446.25
5.52
7.374.87
4.55
6.25
5.29
Weight
1.36 (1.17, 1.58)
1.70 (0.95, 3.06)
1.69 (0.97, 2.97)
1.27 (0.69, 2.32)
1.25 (0.70, 2.26)
1.00 (0.56, 1.79)
1.18 (0.62, 2.24)1.12 (0.58, 2.14)
1.31 (0.73, 2.37)
0.95 (0.53, 1.73)
3.35 (1.17, 9.62)1.32 (0.73, 2.42)
1.49 (0.80, 2.78)
1.09 (0.61, 1.95)2.53 (1.41, 4.52)
1.30 (0.64, 2.64)
1.16 (0.62, 2.16)
1.45 (0.76, 2.75)
OR (95% CI)
100.00
5.79
6.34
6.35
6.72
7.70
5.765.84
6.50
7.47
%
1.446.25
5.52
7.374.87
4.55
6.25
5.29
Weight
1.1 1 10
ATRIAL FIBRILLIATION
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.956)
CHS
ADHERE
CHARM
OPTIMIZE
ECHOES
DIG
Framingham
SENIORS
Tribouilloy
Veterans
Worchester
SHS
MEDICARE
EFFECT
RELAX-AHF
MAYO
DOSE
DIAMOND-CHF
Study
GWTG
EURO HF
Olmstead
0.95 (0.83, 1.08)
1.24 (0.65, 2.35)
1.23 (0.70, 2.15)
0.95 (0.52, 1.76)
1.18 (0.67, 2.07)
0.49 (0.22, 1.10)
1.05 (0.57, 1.94)
0.76 (0.40, 1.46)
0.85 (0.45, 1.61)
1.00 (0.53, 1.88)
1.23 (0.70, 2.15)
0.77 (0.43, 1.37)
1.20 (0.66, 2.18)
0.88 (0.50, 1.56)
0.74 (0.41, 1.32)
0.96 (0.55, 1.67)
0.96 (0.53, 1.72)
0.79 (0.45, 1.37)
0.64 (0.30, 1.37)
OR (95% CI)
1.28 (0.73, 2.24)
0.90 (0.48, 1.69)
0.92 (0.52, 1.63)
100.00
3.65
4.79
4.54
4.84
3.87
4.32
4.58
4.46
4.18
4.79
5.74
4.31
5.48
5.77
5.52
4.95
6.11
3.60
Weight
4.70
4.51
5.29
%
0.95 (0.83, 1.08)
1.24 (0.65, 2.35)
1.23 (0.70, 2.15)
0.95 (0.52, 1.76)
1.18 (0.67, 2.07)
0.49 (0.22, 1.10)
1.05 (0.57, 1.94)
0.76 (0.40, 1.46)
0.85 (0.45, 1.61)
1.00 (0.53, 1.88)
1.23 (0.70, 2.15)
0.77 (0.43, 1.37)
1.20 (0.66, 2.18)
0.88 (0.50, 1.56)
0.74 (0.41, 1.32)
0.96 (0.55, 1.67)
0.96 (0.53, 1.72)
0.79 (0.45, 1.37)
0.64 (0.30, 1.37)
OR (95% CI)
1.28 (0.73, 2.24)
0.90 (0.48, 1.69)
0.92 (0.52, 1.63)
100.00
3.65
4.79
4.54
4.84
3.87
4.32
4.58
4.46
4.18
4.79
5.74
4.31
5.48
5.77
5.52
4.95
6.11
3.60
Weight
4.70
4.51
5.29
%
1.1 1 10
DIABETES MELLITUS
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.540)
Study
Worchester
Veterans
ADHERE
GWTG
EFFECT
DIAMOND-CHF
CHARM
Olmstead
EURO HF
DIG
0.93 (0.76, 1.14)
OR (95% CI)
0.84 (0.48, 1.49)
0.89 (0.51, 1.54)
1.00 (0.53, 1.88)
1.17 (0.67, 2.04)
1.20 (0.60, 2.39)
0.45 (0.24, 0.83)
0.92 (0.51, 1.63)
1.25 (0.49, 3.16)
0.82 (0.24, 2.79)
1.17 (0.67, 2.05)
100.00
Weight
12.75
%
13.21
9.59
11.48
7.38
15.34
11.98
3.99
2.84
11.43
0.93 (0.76, 1.14)
OR (95% CI)
0.84 (0.48, 1.49)
0.89 (0.51, 1.54)
1.00 (0.53, 1.88)
1.17 (0.67, 2.04)
1.20 (0.60, 2.39)
0.45 (0.24, 0.83)
0.92 (0.51, 1.63)
1.25 (0.49, 3.16)
0.82 (0.24, 2.79)
1.17 (0.67, 2.05)
100.00
Weight
12.75
%
13.21
9.59
11.48
7.38
15.34
11.98
3.99
2.84
11.43
1.1 1 10
CKD
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.639)
GWTG
Study
SENIORS
CHARM
Olmstead
EFFECT
Veterans
1.34 (1.03, 1.76)
1.73 (0.83, 3.62)
OR (95% CI)
1.00 (0.49, 2.03)
1.24 (0.65, 2.35)
1.17 (0.67, 2.04)
2.39 (1.06, 5.39)
1.27 (0.69, 2.32)
100.00
11.77
Weight
16.59
18.09
24.82
8.51
20.22
%
1.34 (1.03, 1.76)
1.73 (0.83, 3.62)
OR (95% CI)
1.00 (0.49, 2.03)
1.24 (0.65, 2.35)
1.17 (0.67, 2.04)
2.39 (1.06, 5.39)
1.27 (0.69, 2.32)
100.00
11.77
Weight
16.59
18.09
24.82
8.51
20.22
%
1.1 1 10
ANAEMIA
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Overall (I-squared = 0.0%, p = 0.750)
EFFECT
GWTG
Worchester
RELAX-AHF
DIAMOND-CHF
Veterans
Tribouilloy
ADHERE
Study
MEDICARE
Olmstead
1.19 (0.97, 1.46)
0.43 (0.16, 1.17)
1.33 (0.73, 2.44)
1.28 (0.69, 2.37)
1.00 (0.47, 2.13)
1.50 (0.77, 2.93)
1.39 (0.76, 2.55)
0.94 (0.47, 1.87)
1.21 (0.66, 2.24)
OR (95% CI)
1.15 (0.63, 2.07)
1.43 (0.79, 2.58)
100.00
7.27
10.76
10.67
8.00
8.37
10.60
10.00
11.09
Weight
12.17
11.07
%
1.19 (0.97, 1.46)
0.43 (0.16, 1.17)
1.33 (0.73, 2.44)
1.28 (0.69, 2.37)
1.00 (0.47, 2.13)
1.50 (0.77, 2.93)
1.39 (0.76, 2.55)
0.94 (0.47, 1.87)
1.21 (0.66, 2.24)
OR (95% CI)
1.15 (0.63, 2.07)
1.43 (0.79, 2.58)
100.00
7.27
10.76
10.67
8.00
8.37
10.60
10.00
11.09
Weight
12.17
11.07
%
1.1 1 10
COPD/ASTHMA
Comorbidities in HFpEF vs. HFrEF
Tryposkiadis K, Triposkiadis F, 2015
Clinical Significance ofComorbidities
Clinical Course and Available Therapiesin Heart Failure
Allen LA, et al. Circulation 2012;125:1928-1952
Co-Morbidities in Patients with Heart Failure:the European Heart Failure Pilot Survey
van Deursen, et al. European Journal of Heart Failure 2014; 16: 103–111
0 comorbidities
1-3 comorbidities
> 3 comorbidities
Free
of h
ospi
taliz
atio
n
Follow up time (days)
Follow up time (days)
0 comorbidities
1-3 comorbidities
> 3 comorbidities
0 100 200 300
1.0
0.8
0.6Cum
ulat
ive
surv
ival
0.0
0 100 200 300
1.0
0.8
0.6
0.0
Endothelium
Cardiomyocytes
ONOO- NO
VCAM E-selectinROS
TGF-β
Fibroblasts Myofibroblasts
Leukocytes
Collagen
• IL-6• TNF-α• sST2• Pentraxin 3
Fpassive PKG
cGMP
sGC
Hypertrophy
Myocardial Remodeling in HFPEFImportance of Comorbidities
Paulus WJ, Tschoepe C. JACC 2013; 62:263-71
• Hypertension• Overweight/Obesity• Diabetes Mellitus• Kidney disease• Iron deficiency• COPD
Endothelium
Cardiomyocytes
Myocardial Remodeling in HFREF
Paulus WJ, Tschoepe C. JACC 2013; 62:263-71
Autophagy Apoptosis Necrosis
Collagen
ROS
• Ischemia• Infection• Toxicity
Inflammation Links Heart Failurewith Coexisting Morbidities
Triposkiadis F, et al. Heart Fail Rev 2012;17:355-66
Management of NoncardiacComorbidities in Heart Failure
The CARRESS-HF Trial: Ultrafiltration inDecompensated HF with Cardiorenal Syndrome
188 patients with ADHF, worsened renal function, and persistent congestion were randomly assigned to astrategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients).
Bart BA, et al.N Engl J Med 2012;367:2296-304
Iron Supplementation in PatientsWith Heart Failure and Iron Deficiency
Qian C, et al. Can J Cardiol 2015, in press
More vs. Less Intensive Glycaemic Controlon Myocardial Infarction and Heart Failure
Turnbull FM, et al. Diabetologia 2009; 52: 2288–98
To Lose Weight or Not to Lose Weight,That Is the Big Question—in
Obesity-Related Heart Failure
Peterson LR. Diabetes 2015;64:1509–1510
COPD in Heart Failure: AccurateDiagnosis and Treatment
In conclusion: bronchodilators may improve symptoms in HF in the short term, even in the absence of COPD, but negative cardiovascularside effects may prevail during long- or even short-term therapy. When patients need bronchodilation for pulmonary symptomimprovement and reduction of the risk of exacerbations, long-acting anticholinergics seem to be preferred over beta-2-agonists inpatients with concurrent HF, although both drugs were related to severe side effects especially in patients with underlying cardiovasculardiseases. In any case, after initiation of bronchodilators, physicians should carefully monitor symptom improvements and side effectsin patients with HF, and eventually consider drug discontinuation.
Güder G, et al. European Journal of Heart Failure 2014;16: 1273–82
Adaptive Servo-Ventilation for CentralSleep Apnea in Systolic Heart Failure
1325 patients with a left ventricular ejection fraction of 45% or less, an apnea–hypopnea index (AHI) of 15 or more events(occurrences of apnea or hypopnea) per hour, and a predominance of central events were randomly assigned to receiveguideline-based medical treatment with adaptive servo-ventilation or guideline based medical treatment alone (control).
Cowie MR, et al. N Engl J Med 2015;373:1095-105
Conclusions
• Multimorbidity is common in HF, with more than 80% of HF patientshaving 2 or more additional chronic conditions in a recent communitycohort.
• HFpEF is associated with more additional conditions compared withHFrEF. However, the patterns of co-occurring conditions are similarbetween HFpEF and HFrEF.
• Although noncardiac comorbidities adversely affect prognosis, there isno evidence that specific comorbidity treatments are associated with alower incidence of major cardiovascular events in HF.
• The lack of effect of several comorbidity treatments on HF outcomemay be due to the fact that interventions have more likely been appliedin those with more severe HF, drug adverse effects or HF deteriorationby the treatment effect per se.
Several definitions have been suggested for comorbidity based on different conceptualizations ofa single core concept: the presence of more than 1 distinct condition in an individual. Althoughalways used as a person-level construct, 4 major types of distinctions are made:• the nature of the health condition• the relative importance of the co-occurring conditions• the chronology of presentation of the conditions• the expanded conceptualizations
Time span
Sequence
Point of time
Period of time
Valderas JM, et al.Ann Fam Med 2009;7:357-363
Definition of Comorbidity
Chamberlain AM, et al. The American Journal of Medicine 2015; 128: 38-45
Ratio of Observed to Expected Co-Occurrence ofChronic Conditions in HF Patients
Prevalence of HF and Proportionwith Preserved LVEF
McMurray and Pfeffer. Lancet 2005; 365:1877-89
Secular Trends in thePrevalence of HFpLVEF
Owan, et al. N Engl J Med 2006;355:251-9
All consecutive patients hospitalized with decompensated HF at Mayo Clinic Hospitals, from 1987 through 2001 were studied. Atotal of 6076 patients with HF were discharged over the 15-year period; data on LVEF were available for 4596 of these patients(76%). Of these, 53 % had a reduced LVEF and 47 %t had a preserved LVEF. Secular trends in type of HF, associated CV disease,and survival were defined.
Survival in HFpEF vs. HFrEF
Owan, et al. N Engl J Med 2006;355:251-9
European Heart Journal2012;33: 750–1757
Distribution of Deaths inStudies of HFpEF
Chan MMY, Lam CSP. European Journal of Heart Failure 2013; 5:604–613
Myocardial Dysfunction and Remodeling inHFrEF and Advanced HFrEF
Paulus WJ, Tschoepe C. JACC 2013; 62:263-71
Distribution of Deaths inHFpEF vs. HFrEF
Chan MMY, Lam CSP. European Journal of Heart Failure 2013; 5:604–613
Multimorbidity in Heart Failure:A Community Perspective
Chamberlain AM, et al. The American Journal of Medicine 2015; 128: 38-45
Men Women
Distribution of Mode of Death in HFpEF
I-PRESERVEZile MR, et al.Circulation 2010;121:1393–1405
CHARM-PreservedSolomon SD, et al.Circulation 2004; 110:2180–2183
TIME-CHF Study: Classification by Causesvs. Modes of Death in HFpEF
Rickenbacher P, et al. Eur J Heart Fail 2012;14:1218–1229
Causes of Death Modes of Death
Prevalence of CAD and Percentageof Non-cardiovascular Deaths
Henkel DM, et al. Circ Heart Fail 2008;1:91–97Rickenbacher P, et al. Eur J Heart Fail 2012;14:1218–1229.
HF with LVEF > 50%:HFpEF or Diastolic Heart Failure?
McMurray JJV, et al. European Heart Journal 2012; 33: 1787–1847
HFpEF
48%
28%12%
12%
Patterns of Left Ventricular Hypertrophy inHFpEF
Katz DH, et al. Am J Cardiol 2013; 112: 1158–64
Yancy CW, et al. JACC 2013; 62:e147–239
Generation of EFs 60% from Fibers thatShorten 15%
Circumferentialfiber Spiral
fiber
Longitudinalfiber
EF=15 %
EF=30 % EF=60 %
Sallin EA. Biophys J 1969; 9: 954-64
Shortening and Thickening of a Single Circumferentially LayeredCylindrical Model
de Simone G, Devereux RB. Eur J Echocardiography 2002; 3: 192–198
Alignment of the Myofibers within theVentricular Wall
Anderson, et al. Eur J Cardiothorac Surg 2005; 28:517–25
Myofiber Architecture of LV and Models forUnderstanding LV Function
Sengupta, et al. J Am Coll Cardiol 2008; 1:366–76
“Wringing” Motion of the Left VentricleDuring Systole
Technology and Health Care 1997; 5:45-52
Syst
olic
Rota
tion
Angl
e (d
egre
es)
LV Twist and Strain in HFpEF vs. HFrEF
Control HFpEF HFrEF
LV twist(degrees)
CircumferentialStrain (%)
LongitudinalStrain (%)
RadialStrain (%)
Wang, et al. Eur Heart J 2008;29:1283–9
Speckle Strain Echocardiography PredictsOutcome in Patients with HFrEF and HFpEF
420 pts with HF by Framingham criteria and either LV EF <50% (n=320), or elevated LV filling pressure by Doppler in thesetting of LVEF ≥50% (n=100), were enrolled. Speckle tracking was used to measure strain and strain rate in multiple vectors.The primary endpoint was HF hospitalization or cardiovascular death.
Stampehl MR, et al. Echocardiography 2015;32:71–78
Cox Survival Curves
Aortic Stenosis with Preserved LVEF
Prediction of Mortality
Kusunose K, et al.Circ Cardiovasc Imaging 2014;7:938-945
HFpEF: Transitory Stage to HFrEFor Distinct Phenotype ?
Komajda M, Lam CSP. European Heart Journal 2014; 35: 1022–1032
Longitudinal Changes in LVEF in HFpEF and HFrEFAmong a community cohort of incident HF patients diagnosed from 1984 to 2009 in Olmsted County, Minnesota, all EFs assessed(echocardiography) were obtained from initial HF diagnosis until death or last follow-up (March 2010). Mixed effects models fit a unique linearregression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis.
Prognostic Value of Change in EF over Time
Dunlay SM, et al. Circ Heart Fail 2012;5:720-726
The Natural History of Left VentricularGeometry in the Community
Evaluation of 4,492 observations (2,604 unique Framingham Heart Study participants attending consecutive examinations) to categorizeLV geometry at baseline and after 4 years. Four groups were defined on the basis of the sex-specific distributions of LVM and RWT(normal: LVM and RWT <80th percentile; concentric remodeling: LVM <80th percentile but RWT 80th percentile; eccentrichypertrophy: LVM 80th percentile but RWT < 80th percentile; and concentric hypertrophy: LVM and RWT 80th percentile).
Lieb W, et al. J Am Coll Cardiol Img 2014;7:870–8
Transition Rates of LV Geometric PatternDuring a Mean Follow-Up of 4 Years
Lieb W, et al. J Am Coll Cardiol Img 2014;7:870–8
HFpEF: Heterogeneity andComorbidities
Heterogeneity of HFpEF
Senni M, et al. European Heart Journal 2014; 35 :2797–2811
Patient Characteristics andComorbidities in HFpEF
Age, years 75Female sex,% 60Hypertension,% 55-86Coronary arterydisease, %
28-59
COPD or asthma,% 31-38Renal insufficiency,% 26-52Anemia,% 22-53Diabetes,% 36-45Obesity,% 33-51
Edelmann F, et al. Clin Res Cardiol 2011;100:755-64Mentz RJ, et al. J Am Coll Cardiol 2014; 64:2281–93
Etiological Models of Comorbid Disease
Valderas JM, et al. Ann Fam Med 2009;7:357-363
Mechanisms of PulmonaryHypertension in HFpEF
Guazzi M. Circ Heart Fail 2014;7:367-377
Definition and Classification of Group 2Pulmonary Hypertension
Guazzi M, et al. J Heart Lung Transplant 2015, in press
Right Ventricular Function in Heart FailureWith Preserved Ejection Fraction
HFpEF (Framingham HF criteria, LVEF ≥50%) pts (n=562) from Olmsted County, Minnesota, underwent echocardiography at HFdiagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of TAPSE and bysemiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment.
Mohammed S, et al. Circulation. 2014;130:2310-2320
Kaplan–Meier Survival Curves in HFpEFAccording to the Level of RV function or TR
Mohammed S, et al. Circulation. 2014;130:2310-2320
Treatment
Trial Therapy Inclusion criteria N Follow-up
Primary endpoint Trial result
CHARM-preservedLancet 2003;362(9386):777-81
Candesartan NYHA II-IVLVEF>40%Prior cardiachospitalization
3023 3years
CV death or HFhospitalization
Negative (22% vs.24%;P=0.118)
PEP-CHFEur Heart J 2006;27:2338-45
Perindopril Age>70Diastolic dysfunctionLV wall motion index> 1.4Prior HF hospitalization
850 2.1years
All-cause death andHF hospitalization
Negative (25.1% vs.23.6%; P=0.545)
I-PRESERVENEJM 2008;359:2456-67
Irbesartan NYHA II-IVLVEF>45%Prior HF hospitalization
4128 4.1years
All cause death or CVhospitalization
Negative (36% vs.37%; P=0.35)
ALDO-DHFJAMA 2013;309:781-791
Spironolactone NYHA II-IIILVEF>50%Diastolic dysfunction
422 1year
Change in E/E’Change in peak VO2
Mixed results:E/E’: -0.6 vs. +0.8(P<0.001)VO2: +0.5 vs. +0.5ml/kg/min (P=0.81)
TOPCATNEJM 2014;370:1383-1392
Spironolactone NYHA II-IVLVEF>45%Prior HF hospitalization orelevated BNP
3445 3.25years
CV death, abortedcardiac arrest, or HFhospitalization
Negative (18.6% vs.20%;P=0.14)
Trials Targeting RAAS in HFpEF
Therapy Trial Name Design Inclusion Criteria N Primary outcomemeasure
Results/Status
PDE-5 inhibitor RELAXRedfield MM, etal. JAMA 2013;309:1268–1277
Sildenafil vs.placebo
LVEF>50% 216 Change in peak VO2 at 6months
No difference
I f channelinhibitor
Kosmala, et al.J Am Coll Cardiol2013; 62:1330–1338.
Ivabradine vs.placebo
LVEF>50%Diastolic dysfunction
61 Change in peak VO2 Increase in peak VO2with ivabradine (3.0 vs.0.4 ml/kg/min; P=0.003)
Angiotensinreceptorneprilisyninhibitor
PARAMOUNTSolomon SD, et al.Lancet 2012;380:1387–1395.
PARAGON
LCZ696 vs.valsartan
LVEF>45%NT-proBNP> 400 pg/ml
LVEF>45%Elevated NT-proBNP orHF hospitalization
308
4300
Change in NT-proBNP at3 months
Cumulative number ofCV death and HFhospitalization
Ratio of change inproBNP forLCZ696/valsartan 0.77(p=0.005)
Enrolling
sGC inhibitor SOCRATES-PRESEVED
Vericiguat vs.placebo
LVEF>45%Worsening HF
470 Change in NT-proBNPand LAVI
Enrolling
Renaldenervation
DIASTOLE
RESPECT-HF
Renaldenervation vs.OMT
LVEF>50%Diastolic dysfunctionSBP > 140/90 mmHg
ADHF with LVEF> 50%E/E’ > 15 or NT-proBNP> 220 pg/ml
60
144
CV death, abortedcardiac arrest, or HFhospitalization
Change in LAVI or LVMIon cMRI at 6 moths.
Enrollinh
Enrolling
Interatrialseptal shuntdevice
REDUCE LAP-HF Single arm trialof IASD system(DC Devices)
Age > 40 yearsLVEF>40%Elevated PCWP/LVEDPthat is greater than CVP
100 Incidence of death,stroke, MI or systemicembolic event at 6months
Enrolling
Recently Completed or CurrentInvestigations of Novel Therapies In HFpEF
Current Treatment of HFpEF
Abbate A, et al. Int J Cardiol 2015;179:430-40
Senni M, et al. European Heart Journal 2014; 35 :2797–2811
Matching Key HFpEF Phenotypes toSelect Therapeutic Interventions
Novel Biomarkers in Congestive Heart Failureand Potential Roles in Management
Shah KS, Maisel AS. Heart Failure Clin 2014; 10: 471–479
Conclusions
HFpEF is a common disease characterized by significant morbidity and mortality.
HFpEF is not solely a diastolic disease but is also characterized by disturbances ofmyocardial systolic deformation.
Whether HFpEF and HFrEF are two distinct entities or two ends of a commonspectrum remains a matter of debate.
Comorbidities such as anemia and pulmonary disease tend to be more prevalent inHFpEF, but diabetes and renal disease and burdens are similar in HFpEF and HFrEF .Comorbidities similarly increase morbidity and mortality in HFpEF and HFrEF.
RV dysfunction is common in HFpEF patients, is associated with clinical andechocardiographic evidence of more advanced HF, and are predictive of pooreroutcomes.
An urgent unmet need remains to improve our understanding of the mechanisms ofHFpEF and to develop better diagnostic and therapeutic strategies for this condition.