Included are well explained physiology of diastole and echocardiographic features of distolic dysfunction along with recent advances in HFpEF

1. DR. VIJAY YADAV
DM CARDIOLOGY-1ST YEAR
MCVTC, IOM
11th Feb 2020
DIASTOLOGY AND THE HEART
FAILURE WITH PRESERVED
EJECTION FRACTION (HFPEF)

3. CICR is a positive feedback response, but switches off
once [SR]ca drops by 50%.
Ca/CaM dependent inactivation of L-type Ca++ current
Phosphorylation of Phospholamban (B-adrenergic
stimulation – PKA; Calmodulin kinase II) stimulates
SERCA Ca++ uptake.
SERCA2a: the most dominant form
1 ATP hydrolysed & 2 Ca taken inside SR

4. Protein Change in Heart failure Result
L-type Ca++
channels
Decreased ↓ Ionotropy & Lusitropy
Titin Hypophosphorylated ↑ Myocardial stiffness
SERCA2a Decreased Abnormal relaxation
Phospholamban Hypophosphorylated Inhibits SERCA → Abnormal relaxation
BRIDGING BASICS TO CLINICAL HF
Physiology of the Heart. Philadelphia: Lippincott Williams & Wilkins;
2001.

5. Cardiac function is critically dependent upon diastolic physiologic
mechanisms to provide adequate LV filling in parallel with LV
ejection.
LV diastolic pressure is determined by:
• Volume of blood in the ventricle
• Compliance of the ventricle
• Degree of external pressure applied on the LV by the pericardium and right
heart chambers
During diastole, the LV, LA, and pulmonary veins form a "common
chamber," which is continuous with the pulmonary capillary bed.

6. Early rapid filling: 70-80%
Diastasis: < 5%
Atrial systole: 15-25%

7. LV diastolic function can be assessed in each of the four phases by studying
The mitral inflow doppler pattern.

8. Peak negative dP/dt is the peak instantaneous rate of LV pressure decline.
Measures of isovolumic relaxation: Micromanometer tipped catheter
When the natural log of LV diastolic pressure is plotted versus time, Tau is the slope of this linear
relationship.
Tau is the time required for LV pressure to fall by approximately two-thirds of its initial value. Normal
value is < 40 msec.
Impaired relaxation:
IVRT: Increased
dP/dT: Decreased
Tau: Increased
IVRT: Time between aortic
valve closure to the
opening of mitral valve
Normal: 50-100 msec
Increased IVRT: ↑Aortic pressure
Decreased IVRT: ↑LA pressure

9. PROLONGED IVRT: WHAT
DOES IT MEAN??
Increase in duration between aortic valve closure & mitral
valve opening.
Delay in mitral valve opening.
Lower pressure gradient between LA-LV.
LA pressure is not elevated.

10. Auxotonic relaxation
Early filling phase
Diastasis
Atria systole

11. Rapid filling phase occurs due to pressure gradient between LA-
LV.
LV filling depends both on active relaxation and on the
recoil/suction that results from the release of potential energy
stored during systole by contraction.
LV relaxation is rapid for the first 30-40 msec after MV opening,
causes decline of LV pressure, creates an early diastolic gradient
between LA-LV apex.
The blood is thus “PULLED” into the LV.
RAPID FILLING PHASE

12. Rapid filling phase is denoted by
early diastolic (E) mitral flow wave
and antegrade diastolic (D) flow
wave of the pulmonary vein.
Accounts for 70-80% of LV filling.
Deceleration time (DT) is the duration between the peak of early filling wave
and where its linear descending slope reaches zero.
DT denotes chamber stiffness regardless of HR, afterload, & contractility.
Normal DT is 150 – 200 msec.
Prolonged in impaired relaxation & shortened in restrictive filling states.

14. Diastolic Pressure Volume Relationship (DPVR)
Patients with HFpEF have abnormal DPVR with elevated β & abnormal distensibilty.
NEJM 2004;350:1953

15. LV STIFFNESS CONSTANT
DPVR is shifted upward & to the left.
For any LV volume, pressure is higher
Indicates increased stiffness & decreased
distensibility.
The stiffness constant was increased in all the
patients with diastolic heart failure.
NEJM 2004;350:1953

16. NEJM 2004;350:1953

19. TITIN – The largest protein yet described
Connects myosin & M - line to Z-line
Giant multi-functional sarcomeric filament that provides passive
stiffness to cardiac myocytes.
Can stretch upto 0.6 – 1.2 micrometer in length.
1. Stabilize sarcomere structure
2. Generates restoring force to
relengthen the sarcomere & aid in
early diastolic filling
3. Prevents overstretching of
sarcomeres and EDV and returns
potential energy to shorten
sarcomere during systole

20. In cardiac muscle, 3 classes of titin isoforms are present: adult N2BA, adult N2B, and the fetal
cardiac titin (FCT) isoforms.

21. Blood continues to flow into the LV but slows as LV pressure
rises.
Diastasis begins as the LA-LV pressure equilibrate in mid-disatole
resulting in minimal to no flow across mitral valve.
Contributes < 5% to LV filling.
The length of diastasis is heart-rate dependent, i.e. long with
bradycardia, and short with tachycardia.
DIASTASIS

22. In subjects with impaired relaxation and longer cardiac cycle,
residual
effects of LV relaxation may persist and positive filling wave
during diastasis (L-wave) may be observed
 Physiologic L wave:
 Less than 20 cm/sec
 Bradycardic patients
 Pathologic L wave:
 More than 20 cm/sec
 Seen in patients with
delayed relaxation with
increased LV stiffness.
 Clinical HF, LVH, LVSD
 Predictive of future
hospitalizations for HF.

23. Atrial systole/Kick
 At the end of diastole, the LA contracts & LA pressure rises.
 Empties the remaining LA volume into the LV.
 LV pressure >> LA pressure ……the mitral valve closes & diastole
ends.
 Contributes 15-25% of LV filling.
 Represented by late diastolic (A) mitral flow wave & atrial flow
reversal (Ar) in pulmonary veins.
 Absent in atrial fibrillation.
 Fragmented in atrial flutter.

24. Atrial systole/Kick
 In markedly elevated LV
diastolic pressure, atrial
contraction may not
produce any antegrade flow
wave and may be seen to
send flow retrogradely in
pulmonary veins due to
resistance gradient

25. 2016 ESC definition
2013 ACC/AHA definition

26. Proportion of hospitalized HFpEF patients increased from 33% to 39% over a 5-year period
Proportion of hospitalized HFrEF patients decreased from 52% to 47% over a 5-year period
By 2020, upto 65% of patients hospitalized with HF will have EF > 40%

27. Observational studies: Rate of hospitalization – HFpEF = HFrEF
Outcomes following hospitalization for decompensated HFpEF are quite poor, with
more than one-third of patients dead or rehospitalized within 60–90 days of discharge
J Am Coll Cardiol. 2007;50(8):768-77.
Mortality:
Some epidemiologic studies have found that all-cause mortality for HFpEF is similar to
that for HFrEF; other epidemiologic studies and RCTs suggest that all-cause mortality
is somewhat lower in HFpEF than in HFrEF.
The annual mortality is approximately 10% in epidemiologic studies.
The annual mortality is about 5% in RCT’s.
Long-term mortality trends in HFpEF is similar to HFrEF, with 5-year survival less than
50% in HFpEF cohorts.
N Engl J Med. 2006;355(3):251-9.
Mode of death:
Cardiovascular (50-70%): Sudden death (35%) & Heart failure (20%)
Non-cardiovascular death incidence is high (30-40%) vs (15%) in HFrEF

29. Restrictive CMP
HOCM
VHD – Stenotic/Regurgitant
Right heart failure:
Pulmonary HTN
RVI
ARVD
Atrial myxoma
DIFFERENTIAL DIAGNOSIS

30. Etiology
1) Age > 65 years
2) Hypertension: 80-90%
3) Female: 60-70%
4) Obesity: 30-50%
5) CAD: 20-40%
6) Diabetes: 20-30%
7) Current AF: 20-30%
8) History of AF: 50%
9) Chronic kidney disease
10) Pulmonary HTN (PASP > 40 mmHg)
11) Sleep apnea
12) HOCM, RCMP, CCP : Rare causes

31. 1. Comorbidities induce systemic pro-
inflammatory state with increased
biomarkers.
2. Endothelial dysfunction releases
ROS
3. ↓NO and ↑peroxynitrite (ONOO-)
4. ↓sGC, cGMP, & PKG in
cardiomyocyte
5. Low PKG activity increases passive
tension in cardiomyocyte due to
hypophosphorylation of titin.
6. VCAM & E-selectin favors migration
of hematopoietic cells to
subendothelium or monocytes.
7. Release TGF-β that converts
fibroblast to myofibroblast.
8. Myocardial fibrosis and increased
stiffening with decreased
compliance.

32. Shah SJ.J Cardiovasc Transl Res. 2017;10: 233-244

33. HFpEF has evolved from being a small LV, concentric LVH, normal EF & diastolic dysfunction to
being a multiorgan system disease.

34. Shah SJ.J Cardiovasc Transl Res. 2017;10: 233-244

35. Shah SJ.J Cardiovasc Transl Res. 2017;10: 233-244

36. HFpEF pheno-group #1: Natriuretic peptide deficiency syndrome
Characterized by low BNP, Younger, Least cardiac structural & functional abnormalities, &
has best outcomes
BNP is below the range typically considered diagnostic of HF (e.g., BNP < 100 pg/ml) in
approximately 30% of patients with HFpEF
Obesity is a major cause of low BNP levels due to increased BNP clearance and reduced BNP
production. Increased plasma volume and greater central adiposity (including epicardial fat)
create ventricular interdependence and pericardial restraint, which gives rise to the HFpEF
syndrome.
Inability to generate NPs results in sodium retention and elevated blood pressure, both of
which are major contributors to HFpEF
Other causes:
Genetic polymorphisms in the NPPA and NPPB genes
African ancestry
Insulin resistance
Increased Androgens
Increased activity of neprilysin results in low NP level
The diagnosis is often missed owing to low NP

37. HFpEF pheno-group #2: Obesity-cardiometabolic phenotype
Encompasses systemic hypertension, obesity, type 2 diabetes, and the metabolic syndrome
Higher BNP levels, worse LV relaxation (lowest e’ velocity), highest prevalence of DM &
obesity
T-tubule disruption which results in abnormal calcium handling within cardiomyocytes
Respond best to drugs that target microvascular dysfunction or the cardiometabolic phenotype
(e.g., SGLT-2 inhibitors )
HFpEF pheno-group #3: Right ventricular failure, cardiorenal
phenotype
Highest prevalence of RV dysfunction, Pulmonary HTN, Renal dysfunction (CKD)
Respond poorly to drugs
Has the worst outcomes

39. Symptoms and signs in patients with
HFpEF enrolled in PARAGON-HF
0%
20%
40%
60%
80%
100%
120%
DOE Fatigue Edema Orthopnoea JVD Rales PND Dyspnoea at
rest
Circ Heart Fail 2018; 11:e004962 PARAGON-HF trial

40. DIAGNOSTIC CRITERIA
Eur Heart J 2016;37:2129-200.

41. 2 major or 1 major + 2 minor

42. BOSTON CRITERIA
Definite HF: 8-12
Possible HF: 5-7
No HF: < 4 points

43. H2FPEF Score for Diagnosis
Circulation. 2018;138:861–870
H2PEF score HFpEF probability
0 – 1 < 25%
2 – 5 40-80%
≥6 90%

44. LV Structure: Normal LV volume, Increase LV mass, and RWT

45. J Am Soc Echocardiogr 2016;29:277

46. J Am Soc Echocardiogr. 2016;29[4]:277–314

47. Diastolic dysfunction
Prevalence Prognosis
• Normal filling pattern: Excellent
prognosis
• Abnormal filling pattern (Grade I –
III): progressively increased risk of
mortality
• Stage of diastolic dysfunction is a
stronger predictor of mortality than
EF.
• Grade II-III LVDD: 4 x increase risk
of death in HF patients with CAD
• Short DT & Increased E/e’: Poor
prognosis
CHARM & I-PRESERVE Trials
N LVEDV,
95%
Conc LVH,
60%
LVDD, 70% LA
enlargement,
65%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
N LVEDV Conc LVH LVDD LA enlargement

48. JAMA 2003;289:194

49. 1. Galectin-3
2. ST-2
3. Tissue inhibitor of metalloproteinases (TIMP’s)
4. Amini-terminal Type III procollagen
5. Homocysteine
6. Resistin

50. Clinical trials in HFpEF have produced largely neutral results to date and most management
is directed toward associated conditions (eg, hypertension) and symptoms (eg, edema).
Goal directed medical therapy for associated comorbid conditions.
General measures:
1. Salt restriction < 2 gm/day
2. Fluid restriction
3. Moderation in alcohol consumption
4. Pneumococcal & Influenza vaccination

51. Drug class Drug name Trial name
ACEi Perindopril PEP-CHF
ARB Candesratan CHARM PRESERVE
Irbesartan I-PRESERVE
Beta Blocker Nevibolol SENIORS
MRA Spironolactone TOPACT, ALDO-DHF
Eplerenone RAAM-PEF
Na/K ATPase - Digoxin DIG
ARNI Sacubitril/Valsartan PARAMOUNT
PARAGON-HF
Funny channel (If) - Ivabradine EDIFY
Late Na (I Na) - Ranolazine RAZE
RALI-DHF
PDE-5 inhibitor Sildenafil RELAX
Vasodilator Isosorbide mononitrate NEAT-HFpEF
Oral Soluble GC
stimulators
Riociguat
Vericiguat
DILATE-1
SOCRATES-
PRESERVED

52. Study cohorts: 3445 patients
Inclusion: Symptomatic HF with EF > 45%
Spironolactone vs Placebo
Primary outcome: Death from CV disease, cardiac arrest, hospitalization for HF
Follow up: 3.3 years

54. Indications of spironolactone
• Recently (within 60 days) elevated natriuretic peptide (either
[BNP] ≥100 pg per mL or [NT-proBNP] ≥360 pg per mL).
• Careful monitoring for hyperkalemia and renal function
possible
• To initiate MRA, the patient's serum potassium should be ≤4.7
mEq/L and eGFR must be ≥30 mL/min per 1.73 m2.
• To uptitrate the MRA dose, the patient's serum potassium
should be ≤4.5 mEq/L.
• The initial dose is 12.5 mg once daily, which is titrated as
tolerated every four weeks to the maximum tolerated dose.
• The goal dose is 25 to 50 mg.

55. 1. Change in peak VO2 at 12 months
2. Change in E/e´ at 12 months
Primary endpoint E/e was significantly
reduced in the spironolactone group.
However, peak volume of oxygen (VO2)
was not affected by spironolactone.

56. Randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF
Eplerenone vs. Placebo
Primary end-point: 6MWT
Secondary end-points: Diastolic dysfunction and Biomarkers of collagen
turnover(procollagen type I aminoterminal peptide)
Follow up: 6 months
Results:
1. No improvement in 6MWT
2. Significant reduction in serum markers of collagen turnover with eplerenone

60. Sildenafil (n=113) or placebo (n = 103) was administered orally at 20 mg, 3 times daily for
12 weeks, followed by 60 mg, 3 times daily for 12 weeks.
Sildenafil, compared with placebo, did not result in significant improvement in exercise
capacity or clinical status in patients with HFpEF.

61. Multicenter, double-blind, crossover study
Subject cohorts: 110
Randomized to: 6-week dose-escalation
regimen of isosorbide mononitrate (from 30 mg
to 60 mg to 120 mg once daily)
Primary end-point: Daily activity level
quantified by patient worn accelerometer
Result: Patients with heart failure and a
preserved ejection fraction who received
isosorbide mononitrate were less active and did
not have better quality of life or submaximal
exercise capacity than did patients who
received placebo possibly because of excess
hypotension.

62. Randomised, parallel-group, double-blind multicenter trial
NYHA class II–III heart failure, LVEF > 45%, NT-Pro BNP > 400 pg/mL
Randomized to: LCZ696 200 mg BD (n = 149) or valsartan 160 mg BD (n=152) x 36 weeks
Primary endpoint: Change in NTproBNP from baseline to 12 weeks

63. Sacubitril–valsartan 97/103 mg BD
or valsartan 160 mg BD

65. HF patients with a LVEF > 50%
Mean pulmonary artery pressure (mPAP) > 25 mm Hg
Pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest
Randomized to single oral doses of placebo or RIOCIGUAT (0.5, 1, or 2 mg)
Primary end-point: Peak decrease in mPAP from baseline upto 6 hours
Secondary end-point: hemodynamic and echocardiographic parameters, safety, and
pharmacokinetics

66. 1.Vericiguat was well tolerated
2.Associated with improvements in
QoL
3.No change in NT-proBNP @ 12
weeks

68. Implantable hemodynamic monitoring
CHAMPION TRIAL
CardioMEMS pulmonary artery monitoring device
US FDA approved
The treatment group had a 37% reduction in
heart-failure-related hospitalisation compared
with the control group (158 vs 254, HR 0·63, 95%
CI 0·52–0·77; p<0·0001)

70. Ongoing Researches for HFpEF
Transcatheter Intracardiac Shunt Device
REDUCE LAP – HF
REDUCE LAP – HF 1
Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure
during exercise, and could be a new strategy for the management of HFPEF.

71. Future Perspectives
Development of novel & effective
management strategies:
 Rx that restore calcium homeostatsis
 Change the phosphorylation state of titin
 Reduce ECM fibrosis
 Normalize NP’s levels

72. Take home messages
 HFpEF is a heterogenous syndrome which is more than just a
diastolic dysfunction.
 It continues to rise in prevalence.
 A normal level of BNP doesn’t rule out HFpEF.
 An Echo with doppler is critical in evaluation.
 There is no evidence that any of the current pharmacological
interventions can reduce mortality.
 Treatable conditions must be ruled out.
 The present treatment includes decongestion with diuretics and
careful management of co-morbidities.

73. Thank you