Physiology note - Ventricular Filling Pressures and their markers

 

Dr Priyanka 

MD, DM

Continental Hospitals, Hyderabad

                              VENTRICULAR FILLING PRESSURES  AND BIOMARKERS

 Cardiac cycle of the heart has 2 basic phases the systole (contraction) and  the diastole (relaxation/filling) phases. LV filling pressure indicates the pressure in the ventricles during diastole.

 

SIGNIFICANCE AND TERMS

The elevated LVFP( left ventricular filling pressures) can lead to diastolic heart failure or heart failure with preserved ejection fraction.

In general, in adults LVFP above 15 mm Hg considered as elevated

1.     LVEDP – LV end diastolic pressure

2.     LAP – left atrial pressure

These terms are used to estimate LV filling pressures based on the mode of measurement

 

UNDERSTANDING LV FILLING PRESSURE IN CARDIAC CYCLE

The changes in the volume and pressure in the left ventricle are better plotted against time to understand the changes in a cardiac cycle in the PV loops

 

 

 

Figure 1: PV loop

 

Each phase denotes (FROM ABOVE DIAGRAM)

Phase a – DIASTOLE / “ VENTRICULAR FILLING”

( LV fills with blood and after which the  mitral valve starts closing)

Phase b-  ISOVOLUMETRIC CONTRACTION

(where both aortic and mitral valve closes with no change in LV volume)

Phase c-  EJECTION

(blood is ejected to aorta after which aortic valve starts closing)

Phase d – ISOVOLUMETRIC RELAXATION

(both valves close)

Point 1-  pressures and volume at end of diastole or phase a – EDV (end diastolic volume) & ESV (end systolic volume)

Point 2 – During phase b - ISOVOLUMETRIC RELAXATION where all valves close and LVP increase more than aortic diastolic pressure to causing the opening of aortic valve denoted as 2

Point 3 - As left ventricular volume declines, left ventricular pressure rises until it reaches peak systolic levels, then drops as the ventricle starts to relax. This process is followed by the closure of the aortic valve.

Point 4—During isovolumetric relaxation, left ventricular pressure (LVP) drops while volume stays constant at end-systolic volume (ESV). When LVP falls below left atrial pressure, the mitral valve opens and ventricular filling starts. Early filling sees further LVP decline due to ongoing relaxation; once relaxation completes, LVP rises as the ventricle fills.

 

Stroke Volume  = EDV -ESV

Stroke work is the area under the loop

FACTORS DETRMINING LV FILLING PRESSURES

             1.     PRELOAD

2.     AFTERLOAD

3.     CONTRACTILITY

4.     LEFT ATRIAL PRESSURE

5.     VENTRICULAR RELAXATION

6.     LV CHAMBER COMPLIANCE

 

1.     PRELOAD

Increased Preload: In a healthy, compliant left ventricle (LV), an increase in venous return (which augments preload) causes the LV to fill to a greater end-diastolic volume with only a small or transient increase in pressure.

 

Decreased Preload: A decrease in preload results in a smaller end-diastolic volume and a lower LVFP assuming afterload and contractility are constant. 

 

This can be correlated with frank starling law

 

 

FRANK STARLING LAW

The Frank-Starling law of the heart posits that stroke volume rises proportionally with increases in ventricular end-diastolic volume, up to a defined physiological threshold.

 

 

                                                 Figure 2: Frank Starling law

 

2.     AFTERLOAD

 

               Increased filling pressure: 

    To compensate for the reduced stroke volume, the ventricle must increase its end-diastolic volume (the volume of blood at the start of the next contraction). This is often achieved through the Frank–Starling mechanism, which states that a greater stretch of the muscle fibres (due to the increased volume) leads to a more forceful contraction. 

     This increased stretch and volume directly contributes to a higher left ventricular end-diastolic pressure (LVEDP), which is a key component of LVFP. 

                                                     Figure 3: Afterload affects CO

 

3.     CONTRACTILITY

Increased Contractility: When the heart's contractility rises, it pumps more effectively, reducing LVEDP by emptying the ventricle more fully and allowing for efficient diastolic filling at lower pressures.

Decreased Contractility: Reduced contractility, as in heart failure, means less effective ventricular emptying and slower relaxation. To sustain output, the heart depends on a higher preload, increasing LVEDP and left atrial pressure, potentially causing pulmonary oedema.

 

 

                                                     Figure 4: Contractility on SV

 

4.     LAP

 Pressure gradient: Blood moves from the left atrium to the left ventricle when there’s a difference in pressure between them. The mitral valve opens once left atrial pressure (LAP) exceeds left ventricular filling pressure (LVFP), allowing blood to enter the ventricle.

 Impaired relaxation: When the left ventricle doesn’t relax as it should, its minimum filling pressure rises. Even if the left atrium manages the extra blood volume, this higher pressure can still elevate LAP

 Gradually leading to LV remodelling, LA enlargement causes diastolic failure, pulmonary congestion and atrial fibrillation.

 

5.     LUSIOTROPY/ VENTRICULAR RELAXATION

Ventricular relaxation is an active, energy-dependent process involving calcium reuptake by the sarcoplasmic reticulum, leading to actin–myosin detachment.

After aortic valve closure, the ventricle relaxes isovolumetrically as pressure rapidly falls until it drops below left atrial pressure, prompting mitral valve opening and early rapid filling driven by ventricular suction.

When relaxation is impaired, the decline in left ventricular pressure slows, delaying mitral valve opening and reducing early diastolic filling.

Consequently, more filling relies on atrial contraction, and if relaxation remains markedly delayed, left ventricular end-diastolic pressure rises, elevating left atrial and pulmonary pressures and contributing to heart failure symptoms.

This  condition can be worsened with increased heart rates which can directly reduce the IVRT

 

6.     LV COMPLIANCE

Reduced compliance:

A stiff LV cannot stretch well; small volume increases cause large pressure rises and elevate LVFP.

Normal/increased compliance:

A compliant LV stretches to accommodate volume, keeping filling pressures low.

 

  MEASUREMENT OF LVFP

1.     INVASIVE – left sided catheterisation, pulmonary art catheter/ right heart catheterisation

 

2.     NON INVASIVE – 2D ECHO, cardiac MRI,

 

1.     INVASIVE

LVFP is measured as LVEDP during left heart catheterization or as LV pre-A pressure, which reflects LA mean pressure. In right heart catheterization, LVFP is gauged by PCWP, an indirect marker of LA mean pressure. Typically, LVEDP exceeds both PCWP and LV pre-A pressure during sinus rhythm. LVFP is considered elevated if LVEDP ≥16 mmHg and PCWP or LV pre-A pressure ≥15 mmHg.

 

2.     NON INVASIVE :

2D ECHO   PARAMETERS:

1.     MITRAL E/A - Mitral E/A is the ratio of the peak early diastolic flow velocity (E-wave) to the peak late diastolic flow velocity (A-wave) across the mitral valve

2.     E.E’ RATIO:  ratio between early diastolic flow velocity vs e' (e-prime) refers to the early diastolic mitral annular velocity measured using Tissue Doppler Imaging (TDI)

3.     IVRT – iso volumetric relaxation time

4.     LA volume index

5.     TR velocity

6.     PV (AR-A) – pulmonary vein anterograde and mitral valve A wave duration

 

 

 

 

 

Figure 5 : Algorithm of 2DECHO for diastolic dysfunction

 

 

 

                                     Figure 6 : Classification of Diastolic dysfunction in ECHO

 

                            BIOMARKERS  in diastolic dysfunction

 

HF with preserved ejection fraction can be assessed  using the biomarkers of multiple pathological pathways

 

 

 

 

 Figure 7 : Various mechanism and Biomarkers in HFpEF

 

1.Natriuretic peptides :

BNP is mainly produced and released by the cardiac ventricles as a pro-hormone in response to myocardial stretch. It is subsequently cleaved into two fragments: vasoactive BNP and the inactive NT-proBNP.

As BNP and NT-proBNP have relatively long half-lives—22 minutes and 70 minutes, respectively—they serve as reliable markers for diagnosis, severity assessment, and therapeutic monitoring.

In patients with chronic kidney disease or acute kidney injury, NT-proBNP levels are often elevated due to reduced renal clearance, but trends and relative changes remain useful for evaluating cardiac stress

Interpretation should consider renal function, age, and obesity.

Normal values:

BNP - < 100/ pgml,  

NT pro BNP: <125 pg/mL for under 75 years; <450 pg/mL for over 75 years.

 

2.HS-Troponin

HFpEF patients were found to have significantly higher troponin levels at rest, with the degree of elevation directly correlated to higher pulmonary capillary wedge pressure and worse systolic and diastolic tissue Doppler velocities.

Troponin levels were also correlated with reductions in oxygen supply and a corresponding greater degree of supply–demand mismatch.

3.Soluble Neprilysin

Neprilysin cleaves numerous vasoactive peptides. Some of these peptides have vasodilating effects (including NPs, adrenomedullin and bradykinin), and others have vasoconstrictor effects (angiotensin I and II and endothelin [ET]-1

Neprilysin serum levels (sNEP) exhibited significant prognostic value in both chronic and acutely decompensated HF.

sNEP was catalytically active, more research is required to recommended this biomarker

 

4.other BIOMARKERS

 

Table 1: Biomarkers of Inflammation and Extracellular Matrix in Heart Failure with Preserved Ejection Fraction

Biomarker	Mechanism of Action	Clinical Significance
CRP	Activates complement and stimulates cytokines	Inflammatory marker; correlated with diastolic dysfunction in HFpEF
IL-1B	Mediator of inflammatory response; cell proliferation, differentiation	IL-1 blockade may improve fitness and prevent hospitalisations
ST2	Blocks effects of IL-33	Higher levels linked to fibrosis, adverse remodelling, worse outcomes
GDF15	Highly expressed in inflammatory stress	Increased levels linked to higher HF risk and adverse outcomes
Pro-collagen propeptides	Markers of myocardial collagen turnover and fibrosis	PIIINP levels predict death and hospitalisation in HF
MMPs	Degrades extracellular matrix	MMP2 and MMP9 activity is enhanced in HFpEF
TIMPs	Inhibitor of MMPs	Higher TIMP1 levels associated with worse outcomes
Galectin-3	Involved in fibrogenesis, inflammation, ventricular remodelling	Used for HFpEF phenotyping, risk stratification, and targeting

 

Table 2: Biomarkers of Vascular Derangements and Senescence in Heart Failure with Preserved Ejection Fraction

 

 

 

Biomarker	Mechanism of Action	Clinical Significance
NO	Vasodilation, anti-thrombotic, anti-inflammatory	Reduced NO linked to inflammatory pathogenesis in HFpEF
ADM	Vasodilator, immunomodulating, anti-proliferative	High ADM linked to pulmonary issues, reduced cardiac output, and impaired exercise
Endothelin	Most potent vasoconstrictor peptide	ET-1 levels predict hospitalisation and mortality in HFpEF
PAI-1	Inhibits plasminogen activators and fibrinolysis	PAI-1 complex predicts all-cause and cardiovascular mortality
IGFBP7	Regulates IGFs; linked to inflammation, senescence	Elevated levels associated with diastolic dysfunction, HF severity, and prognosis

  

 Table 3:  Biomarkers of Obesity, Renal Dysfunction and Iron Metabolism in Heart Failure with Preserved Ejection Fraction

 

Biomarker	Mechanism of Action	Clinical Significance
FABP4	Linked to obesity, insulin resistance, atherosclerosis	Associated with death or HF admission
Leptin	Regulates appetite; resistance is common in obesity	Resistance linked to diastolic dysfunction and sodium retention
Adiponectin	Increases insulin sensitivity and b-oxidation	Not associated with death or HF admission
Resistin	Increases insulin resistance and inflammation	Not associated with prognosis
NGAL	Marker of renal injury	Associated with prognosis in univariate analysis
Cystatin C	Marker of renal injury; increases collagen degradation	Predicts new-onset HFpEF; associated with prognosis
Albuminuria	Marker of kidney damage and inflammation	Associated with incident HF hospitalisation
KIM-1	Marker of renal injury	Independently associated with death and HF hospitalisation
Haemoglobin	Anaemia decreases oxygen; increases cardiac mass	Independently associated with death and HF hospitalisation
Iron deficiency	Decreases energy production in mitochondria	Associated with all-cause mortality, not HF hospitalisation

NOVEL BIOMARKERS

1)    Micro RNA -  epigenetic potential in biomarkers, can differentiate HPrEF vs HFpEF , more research is required.

2)    Proteomics – various proteins secrete in different pathological states, HFpEF patients exhibited higher circulating biomarkers of volume expansion (adrenomedullin), myocardial fibrosis (thrombospondin-2) and systemic inflammation (galectin-9, CD4) compared to obese non-HFpEF or lean HFpEF patients.

Soma scan technology used to diagnose

Future for individual phenotype related heart failures detection , research in progress.

 

3)    Metabolomics – Inflammation, oxidative stress, impaired cell signalling, mitochondrial dysfunction causes alters in protein metabolites serine, cystine etc could be useful in early detection of HFpEF, research ongoing

 

 

CONCLUSION

HFpEF can be a diagnosed by  clinical, invasive and non-invasive methods,  various biomarkers help in prognosis and  early diagnosis aiding in better management.

 

Recommended reading

1.      Fukuta H, Little WC. The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin. 2008;4(1):1-11. doi:10.1016/j.hfc.2007.10.004

2.      Morrissey C. Echo for diastology. Ann Card Anaesth. 2016;19(Supplement):S12-S18. doi:10.4103/0971-9784.192585

3. Bayes-Genis A, Cediel G, Domingo M, Codina P, Santiago E, Lupón J. Biomarkers in Heart Failure with Preserved Ejection Fraction. Card Fail Rev. 2022;8:e20. Published 2022 Jun 23. doi:10.154