1. This document summarizes research on reversing cardiac remodeling through heart failure treatment. It discusses what remodeling is, the history of the term in medical literature, and types of remodeling (pathological vs physiological). 2. Studies show treatments that lead to "reverse remodeling" like sacubitril/valsartan improve outcomes for heart failure patients. Trials like PARADIGM-HF and PROVE-HF found sacubitril/valsartan reduced biomarkers and improved ejection fraction, indicating reverse remodeling. 3. Subgroup analyses in PROVE-HF found consistent reverse remodeling effects in newly diagnosed and ACE-ARB naive patients as well as those not reaching target sacubitril/vals

1. Reversing Cardiac Remodeling with
HF treatment
Dr. Nagula Praveen, MD,DM
drpraveennagula@gmail.com
@kizashipraveen

2. What is remodeling ?
• “…..change the structure or form of”

3. Remodeling…
• The term "remodeling" was used for the first time in 1982 by
Hockman and Buckey, in a myocardial infarction (MI) model.
• This term was aimed to characterize the replacement of infarcted
tissue with scar tissue.
Hockman JS, Bulkley BH. Expansion of acute myocardial infarction: an experimental study. Circulation. 1982;65(7):1446–1450.

4. • Janice Pfeffer was the first researcher to use the term remodeling in
the current context, to describe the progressive increase of the left
ventricular cavity in experimental model of MI in rats.
• The term was then used in some scientific articles on morphological
changes following acute MI.
• In 1990, Pfeffer and Braunwald published a review on cardiac
remodeling following MI, and the term was adopted to characterize
morphological changes after infarction, particularly increase in the
left ventricle.
2.Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res. 1985;57(1):84–95.
3. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81(4):1161–
1172.

5. • In 2000, a consensus from an international forum on cardiac remodeling was
published, which defined cardiac remodeling as a group of molecular,
cellular and interstitial changes that clinically manifest as changes in size,
shape and function of the heart resulting from cardiac injury.
• Two types of cardiac remodeling were recognized
– physiological (adaptive) remodeling and
– pathological remodeling
4.Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac
remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35(3):569–582.
5. Anand IS, Florea VG, Solomon SD, Konstam MA, Udelson JE. Noninvasive assessment of left ventricular remodeling: concepts, techniques and
implications for clinical trials. J Card Fail. 2002;8(6 ) Suppl:S452–S464.

6. HEART FAILURE

7. Heart failure a world-wide burden
Worldwide
prevalence1
>37.7
%
By 2030 the
number of HF
patients will
rise 1
By
2030
25%
rise
Lifetime risk of
HF is 33 % for
men and 28.5
% for women1
At 55
years
of age
Deaths occur
within one
year of
diagnosis 2
17-
45 %
One year
death rates
in India 2
23%
1. Mishra, S et al, Indian Heart Journal, (2018) 70, (1) : 105-127 2. Ferreira, JP et al Global Heart (2019) : 14(3) : 197-214

9. How are Indian HF patients different?
• The overall incidence is likely to
increase (in India) in the future owing
to the following factors:
– Aging population
– Rising coronary artery disease (CAD)
prevalence
– Epidemic rise of key risk factors such as
hypertension and DM
– Persistence of diseases such as RHD and
untreated congenital heart disease
• How are Indian HF patients different?
– Indian patients present with HF at a
younger age
– Male to female ratio is also different in
India (70:30)
– RHD is also a major contributor
– DM is much more prevalent among
Indians
– Prognosis of HF in Indian patients
appears to be worse than those in the
West
– Strikes patients in the prime of their lives
Kidambi BR et al. J Pract Cardiovasc Sci 2019;5:2-11

10. 1. Januzzi et al, JAMA 2019;322:1085-1095, 2.Aimo et al J am Coll Cardiol HF 2019 ; 7 : 782-794 3. Januzzi et al J Am Coll Cardiol 2019;74:1205-1217 4.
Kramer DG et al J AM Coll Cardiol 2010 ; 56: 392-406 5. Saraon T et al Cardiol Rev 2015;23-173-181 6. Kim GH et al Nat Rev Cardiol 2018;15:83-96

12. After an acute event.. MI

18. Main Predictors of Reverse & Forward
Remodeling in HF

23. Reverse remodeling and outcomes
Heart failure therapies
that lead to “reverse”
remodeling also foster
significant improvement
in prognosis
Kramer et al, J Am Coll Cardiol. 2010 Jul 27; 56(5): 392–406.

24. Change in LV structure and function at 1 year by
NT-proBNP reduction
Daubert MA et al,JACC Heart Fail 2019 Feb ; 7 : 158-1EF: Ejection Fraction, EDVi: End Diastolic Volume index, ESVi: End Systolic Volume index

26. Variables predictive of reverse cardiac
remodeling
Aimo et al J am Coll Cardiol HF 2019 ; 7 : 782-794

27. How can we reverse remodeling ?

31. Core therapy plus other drugs for the
management of HFrEF
. Mishra, S et al, Indian Heart Journal, (2018) 70, (1) : 105-127
HFrEF = heart failure with reduced ejection fraction; ARNI = angiotensin receptor neprilysin inhibitor; ACE = angiotensin converting
enzyme; ARB = angiotensin II receptor blocker; MRA = mineralocorticoid receptor antagonist; IV = intravenous; AF = atrial
fibrillation; CAD = coronary artery disease; HF = heart failure

32. Am J Cardiovasc Dis 2017;7(6):108-113 Januzzi JL, Butler J, Fombu E, et al; Am Heart J, 2018;199:130-136.

33. PARADIGM-HF: summary of efficacy results
Primary outcome
20% reduction in CV death or HF
hospitalization with ARNI compared
with enalapril
Secondary outcome
20% reduction in CV mortality
21% reduction in HF hospitalization
16% reduction in all-cause mortality
with ARNI vs enalapril
ARNI superior to enalapril in
reducing symptoms and physical
limitations of HF (indicated by KCCQ
score)
No significant difference in incidence
of new onset atrial fibrillation
between treatment groups
No significant difference in protocol-
defined decline in renal function
between treatment groups

34. Sacubitril/valsartan Doubles Effect on CV Death of
Current Inhibitors of the Renin-Angiotensin System –
PARDIGM HF Results
Presented at ESC HFA 2017, Paris by Prof. Dr. Adriaan Voors, Cardiologist University Medical Center
Groningen The Netherlands

35. Reverse Cardiac Remodeling
• Remodeling of the myocardium is central to the progression of HF
with reduced ejection fraction (HFrEF) and is associated with risk for
cardiovascular events.
• Reverse cardiac remodeling defined as improvement in ejection
fraction(EF) remains an important primary therapeutic target in
patients with heart failure (HF).
Kramer DG, Trikalinos TA, Kent DM et al, J Am Coll Cardiol. 2010 Jul 27;56(5):392-406

36. PROVE-HF Study design
• Adult patients with symptomatic HFrEF
(LVEF ≤40%) eligible for on-label
treatment with S/V were enrolled
• Following discontinuation of ACEI/ARB,
S/V was initiated and titrated
• Blood samples (x) were obtained at each
study visit for NT-proBNP measurement
• An echocardiogram was performed at
baseline, 6- and 12-months, and
interpreted by a core lab in a clinically
and temporally blinded fashion
Januzzi JL, Butler J, Fombu E, et al; Am Heart J, 2018;199:130-136.

37. NT-proBNP concentrations
Time point N Median NT-proBNP
(25th, 75th percentile), pg/mL
Baseline 760 816 (332, 1822)
Day 14 754 528 (226, 1378)
Day 30 740 546 (211, 1321)
Day 45 734 514 (192, 1297)
Month 2 721 535 (210, 1299)
Month 3 719 488 (211, 1315)
Month 6 699 473 (179, 1163)
Month 9 659 444 (170, 1153)
Month 12 638 455 (153, 1090)
Rapid and significant reduction of NT-proBNP was observed, with
majority of reduction within the first 2 weeks

38. Primary endpoint
• From baseline to 12 months, significant correlations were observed between the
change in NT-proBNP concentration and cardiac remodeling parameters.
• Parallel latent growth curve analyses demonstrated strong association between
early NT-proBNP change and subsequent reverse cardiac remodeling.
Parameter Pearson r (IQR) P value
NT-proBNP (pg/mL) / LVEF (%) -0.381 (-0.448, -0.310) <.0001
NT-proBNP (pg/mL) / LVEDVi (mL/m2) 0.320 (0.246, 0.391) <.0001
NT-proBNP (pg/mL) / LVESVi (mL/m2) 0.405 (0.335, 0.470) <.0001
NT-proBNP (pg/mL) / LAVi (mL/m2) 0.263 (0.186, 0.338) <.0001
NT-proBNP (pg/mL) / E/E’ 0.269 (0.182, 0.353) <.0001
IQR, interquartile range; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; mL, milliliter; LAVi,
left atrial volume index; E/E’, ratio of early diastolic filling velocity and early diastolic mitral annular velocity

39. Reverse cardiac remodeling
0
5
10
15
20
25
30
35
40
45
LVEF
0
10
20
30
40
50
60
70
80
90
100
LVEDVi LVESVi
BL 6M 12M
LVEF(%)
LVvolume(mL/m2)
+5.2%
+9.4%
-6.65
-12.25
-8.67
-15.29
BL 6M 12M BL 6M 12M
Baseline to 12 months: all P <.001
28.2
86.93
61.68
25% of subjects
experienced an
LVEF increase of
≥13% at 12 months
BL, baseline; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; LVESVi, left ventricular end-systolic
volume index

40. 0
5
10
15
20
25
30
35
40
LAVi
Reverse cardiac remodeling
0
2
4
6
8
10
12
14
E/e’
BL 6M 12M BL 6M 12M
-4.36
-7.57 -1.23 -1.30
LAvolume(mL/m2)
E/e’ratio
37.76
11.70
BL, baseline; mL, milliliter; LA, left atrial; LAVi, left atrial volume index; E/e’, ratio of early diastolic filling velocity and early diastolic mitral annular
velocity; LVMi, left ventricular mass index.
LVMi fell from
124.77 to 107.82 g/m2
(mean -16.00 g/m2; P <.001)
Baseline to 12 months: all P <.001

41. Subgroups of interest
• Reverse cardiac remodeling was comparable in each subgroup of interest
New-onset HF/ACEI-ARB naïve (N=118)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +12.8 (+11.05, +14.5)
LVEDVi (mL/m2) -13.81 (-15.78, -11.83)
LVESVi (mL/m2) -17.88 (-20.07, -15.68)
LAVi (mL/m2) -8.44 (-9.73, -7.15)
E/e’ -2.60 (-3.83, -1.37)
NP < PARADIGM incl criteria* (N=292)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +9.4 (+8.6, +10.3)
LVEDVi (mL/m2) -11.32 (-12.24, -10.40)
LVESVi (mL/m2) -14.15 (-15.15, -13.15)
LAVi (mL/m2) -7.06 (-7.54, -6.58)
E/e’ -0.93 (-1.43, -0.43)
Not reaching target dose (N=278)
Parameter
LS Mean change,
BL to 12 months (95% CI)
LVEF (%) +9.4 (+8.4, +10.3)
LVEDVi (mL/m2) -10.99 (-12.21, -9.77)
LVESVi (mL/m2) -14.32 (-15.67, -12.97)
LAVi (mL/m2) -7.23 (-7.97, -6.50)
E/e’ -0.46 (-1.32, +0.40); P =NS
All P <0.001 except where noted
*NT-proBNP < 600 pg/mL if not hospitalized or < 400 pg/mL if hospitalized within the past 12 months; BNP < 150 pg/mL if not hospitalized or < 100 pg/mL if hospitalized for HF within the past 12 months; BL,
baseline; LS, least-square; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; mL, milliliter; LAVi, left atrial volume index; E/E’, ratio of early diastolic filling velocity and
early diastolic mitral annular velocity; NP, natriuretic peptide.

42. Death or HF hospitalization by 12 months
Patients with largest reduction in NT-proBNP and LVESVi by 6 months
had lowest rates of subsequent death or HF hospitalization by 12 months

43. Conclusion: PROVE- HF Trial
• In this study of patients with HFrEF treated with sacubitril/valsartan, reduction
in NT-proBNP was significantly associated with reverse cardiac remodeling
• The degree of reverse remodeling demonstrated may help to explain how
sacubitril/valsartan reduces morbidity and mortality in patients with HFrEF
• Study outcomes were consistent in subgroups – Newly Diagnosed HF as well
as ACE-I / ARB naïve patients
• Analyses examining impact of sacubitril/valsartan on quality of life, symptoms,
and a broad range of mechanistic biomarkers are underway

44. EVALUATE: HF Study Design
Sac/Val
24/26 mg bid
Enalapril
2.5 mg bid
Day 1 Week 2 Week 12Week 4
Sac/val
49/51 mg bid
Enalapril
5 mg bid
Sacubitril/valsartan
97/103 mg bid
Enalapril 10 mg bid
Double-blind, double-dummy
treatment period
12 weeks
Screening period
n=465
Randomization
1:1
Week 1 Week 24
12 weeks
Open-label
treatment period
Week 14
Sac/val
49/51 mg bid
Sac/val
97/103 mg bid
Week -6
Hemodynamic Assessment
Echocardiography
Cardiac Biomarkers
KCCQ-12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Eligibility:
Age ≥ 50 yrs
Chronic HF with EF≤40%
NYHA I-III
History of hypertension
Stable doses of GDMT
SBP > 105 mm Hg
No AF at baseline

45. Primary Endpoint: Change in Zc from Baseline to
Week 12
223.8 213.2218.9 214.3
0
50
100
150
200
250
300
Sacubitril/Valsartan Enalapril
Baseline 12 Weeks Baseline 12 Weeks
Zc(dynes-sec/cm5)
-0.7 (-11.6, +10.1)- 2.9 (-13.8, +8.0)
-2.2 (-17.6, +13.2) p = 0.78

46. Secondary Endpoints:
Change in Cardiac Structure from Baseline to 12 weeks, by Treatment
-5.2 -4.9
-2.2
-3.2 -3.3
+0.6
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
LVEDVI LVESVI LAVI
Sacubitril/Valsartan Enalapril
Changefrombaselineto
12Weeks(mL/m2)
p=0.02 p=0.045 p=<0.001

47. Exploratory Endpoint: Change in KCCQ-12 Overall
Summary Score at Week 12
64.7 67.7
73.8 71.2
0
10
20
30
40
50
60
70
80
90
100
Sacubitril/Valsartan Enalapril
Baseline 12 Weeks Baseline 12 Weeks
4.2 (2.2, 6.2)8.7 (6.7, 10.7)
4.5 (1.7, 7.3), p = 0.002
KCCQOverallSummaryScore
Desai AS, et al. JAMA 2019

48. Proportion with Clinically Important Change in KCCQ-OS from
Baseline to 12 Weeks
Sacubitril/Valsartan Enalapril Odds Ratio (95% CI) p
Improvement
>= 5 points 58% 43% 1.84 (1.26, 2.68) 0.002
>= 10 points 38% 30% 1.42 (0.95, 2.11) 0.086
Worsening
>= 5 points 12% 26% 0.38 (0.23, 0.63) <0.001
>=10 points 6% 16% 0.37 (0.19, 0.71) 0.003
Desai AS, et al. JAMA 2019
Desai AS, et al. HFSA Scientific Sessions 2019

49. Change in KCCQ Scores from Baseline to 12 Weeks
Desai AS, et al. JAMA 2019
Desai AS, et al. HFSA Scientific Sessions 2019

50. J Am Heart Assoc. 2019;8:e012272.
• A meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers on CRR indices.
• Databases were searched for studies published between 2010 and 2019 that reported cardiac
reverse remodeling (CRR) indices following ARNI administration.

51. Forest plots for (A) effect of ARNI on LVEF
The pooled data from 10
studies showed increases
in LVEF (MD 4.64%, 95%
CI 3.93, 5.35;).

52. Forest plots for (B) other CRR indices of HFrEF patients
ARNI distinctly improved left
ventricular size and hypertrophy
compared with angiotensin-
converting enzyme inhibitors/
angiotensin receptor blockers in HF
with reduced EF patients, even
after short-term follow-up.
Patients appeared to benefit more
in terms of CRR treated with ARNI
as early as possible and for at least
3 months.
J Am Heart Assoc. 2019;8:e012272.

53. Summary
• Reverse cardiac remodeling remains an important primary therapeutic target in
patients with heart failure.
• Sacubitril/Valsartan can improve functional capacity and cardiac reverse remodeling in
heart failure patients with reduced ejection fraction versus angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers, with more prominent changes
occurring over time.
• The degree of reverse remodeling demonstrated may help to explain how
sacubitril/valsartan reduces morbidity and mortality in patients with HFrEF
• Patients with heart failure may receive greater cardiac reverse remodeling benefit if
they are treated with an angiotensin-receptor neprilysin inhibitor as early as possible.

54. Thank you