Cardiac MRI in integrative cardiovascular physiology research Per - - PowerPoint PPT Presentation

Cardiac MRI in integrative cardiovascular physiology research

Per Lav Madsen MD DMSc Consultant in Cardiology Associate Research Professor ESC CMR and SCMRI level III

• Dept. Cardiology, Copenhagen University Hospital, Herlev-Gentofte, Copenhagen

MRI is an imaging “platform”

• Crisp images with “soft tissue” characterisation

(edema and localized and diffuse fibrosis)

• Precise cardiac chamber volumes
• Precise flow in large arteries
• Myocardial tissue perfusion

Myocardial perfusion in T2DM

Myocardial fibrosis in T2DM

Strengths and limitations of CMR for integrative physiology

• Artificial pacemaker, ICD, or cochlear

implant

• Gadolinium contrast for e-GFR>30 only
• Weight-limit of patient ca. 130 kg
• Arrhythmia including atrial fibrillation

Contra-indications

• Crisp cine images with easy conversion to 3D
• Reference standard for cardiac chamber volumes + flow in large thoracic

vessels

• Precise chamber systolic (established) and diastolic (evolving) function
• Organ perfusion: myocardium, skeletal muscle, spleen, liver, etc.
• Temporal resolution 20-45 ms (echo better)
• Spatial resolution 1.5 x 1.5 x 8-15 mm (CT better)

Strengths and limitations of MRI

• Do my subjects have steady heart rates;

tachycardia is NOT a problem

• Will the subject lie still
• Is e-GFR>30 (for tissue perfusion)

So for cardiovascular studies consider:

Can I use it for dynamic exercise studies yet: Not really, but coming

Stedig-Ehrenborg et al., 2013

M E T H O D S

Variability of rating and implications for statistical power analysis

• Intra- and inter-observer variability for LV end-

diastolic volume is within 5-6 mL

• With power of 0.80 and alpha 0.05 you detect a

difference of

• 10% in LV ejection fraction with only 12

subjects in each group

• 10% RV ejection fraction with only 16

subjects in each group

Flow/cardiac output

Within 3 yrs, 85% of patients with regurgitant fraction >33% progress to surgery in comparison with 8% of patients with regurgitant fraction ≤33% (Myerson et al., 2012)

Tie Herlev-Gentpftf Valve

12% regurgitation fraction

SAP DAP

Maternal cardiac output in normal pregnancy

14 18 22 26 30 34 38 43 52 2 4 6 8 10

Ascending aorta

14 18 22 26 30 34 38 43 52 2 4 6 8 10

Gestational week Blood Flow (L min-1) Descending aorta

Pulmonary hyperinflation

Left ventricle Right ventricle

The decrease of cardiac chamber volumes and output during positive-pressure ventilation. Kyhl K, Ahtarovski KA, Iversen K, Thomsen C, Vejlstrup N, Engstrøm T, Madsen PL . Am J Physiol Heart Circ Physiol. 2013 Oct 1;305(7):H1004-9.

positive pressure ventilation

Distortion of cardiac synchrony during pulmonary hyperinflation. Frestad D, Kyl K, Drvis I, Barak O, Mijacika T, Secher NH, Dujic Z, Buca A, Lav Madsen P. Submitted, 2016

Rest Packing

Elite breath-hold divers “packing”

Rest GI HR, min-1 67 ± 10 86 ± 20* MAP, mmHg 91 ± 7 97 ± 8 Left lung volume, L 1.5 ± 0.6 4.0 ± 1.3** Right lung volume, L 1.8 ± 0.6 4.3 ± 1.3** Total lung volume, L 3.4 ± 1.1 8.3 ± 2.6** RVEDV, mL 190 ± 28 114 ± 32** RVEF, % 54 ± 5 47 ± 5* RVPER, mL s-1 546 ± 376 245 ± 85* RVPER/RVEDV, s-1 2.9 ± 2.0 2.1 ± 0.7** RVPFR, mL s-1 441 ± 172 180 ± 66** RVPFR/RVEDV, s-1 2.3 ± 0.9 1.5 ± 0.6** LVEDV, mL 166 ± 31 91 ± 29** LVEF, % 65 ± 4 59 ± 6* LVPER, mL s-1 560 ± 152 322 ± 104** LVPER/LVEDV, s-1 3.4 ± 0.9 3.5 ± 1.1 LVPFR, mL s-1 553 ± 145 207 ± 62** LVPFR/LVEDV, s-1 3.3 ± 0.9 2.3 ± 0.7**

Rest Packing

Gadolinium contrast

Gadolinium contrast

Stewart-Hamilton technique: Pulmonary blood volume = transit time x cardiac output

• No change in transit time (5.7 (SD1.8) sec) with

packing

• Cardiac output decreased from 6724 (SD1589)

mL/min to 3778 (SD831) mL/min (P<0.01)

• Pulmonary blood volume decreased from 629

(SD188) mL to 357 (SD173) mL (P<0.01)

Myocardial perfusion

Semi-quantitative analysis

• Up-slope + time to peak
• Indexed to maximal

hyperaemic response (during adenosine)

Quantitative analysis

• Myocardial blood flow (in

mL/100 mg of myocardium) based on analysis of SI up- stroke with input function based on LV S.I.

• Mathematical deconvolution

based on Fermi function

Change ¡(%) Rest Packing Myocardium ¡(n=9)

• Max. ¡up-­‑slope, ¡s-­‑1

2.53±1.29 1.02±1.01

• ­‑1.52±0.15† ¡(-­‑60%)
• perf. ¡index

0.12±0.03 0.10±0.03

• ­‑0.02±0.01* ¡(-­‑17%)

Epicardium ¡(n=9)

• Max. ¡up-­‑slope, ¡

s-­‑1 2.58±1.18 1.25±0.96

• ­‑1.33±0.14* ¡(-­‑52%)

Perfusion ¡index 0.12±0.02 0.08±0.08

• ­‑0.04±0.01* ¡(-­‑33%)

Endocardium ¡ (n=9)

• Max. ¡up-­‑slope, ¡

s-­‑1 2.85±1.07 1.06±0.89

• ­‑1.79±0.12* ¡(-­‑63%)

Perfusion ¡index 0.13±0.02 0.12±0.10

• ­‑0.01±0.01 ¡(-­‑8%)

Liver ¡(n=8)

• Max. ¡up-­‑slope, ¡s-­‑1

1.24±0.27 0.96±0.21

• ­‑0.27±0.14 ¡(-­‑23%)
• perf. ¡index

0.06±0.03 0.07±0.02 0.01±0.01 ¡(17%) Skeletal ¡muscle ¡(n=9)

• Max. ¡up-­‑slope, ¡s-­‑1

1.20±0.86 0.32±0.17

• ­‑0.87±0.31* ¡(-­‑73%)
• Perf. ¡index

0.05±0.04 0.04±0.03

• ­‑0.02±0.01 ¡(-­‑20%)

Pulmonary

• Max. ¡up-­‑slope, ¡s-­‑1

1.62±1.08 0.41±0.29

• ­‑1.21±1.11* ¡(-­‑75%)
• Perf. ¡index

0.12±0.11 0.06±0.07

• ­‑0.05±0.14* ¡(-­‑42%)

Kidney ¡(n=6)

• Max. ¡up-­‑slope, ¡s-­‑1

9.5±4.1 4.2±1.9

• ­‑5.3±3.1* ¡(-­‑56%)
• Perf. ¡index

0.39±0.07 0.22±0.09

• ­‑0.18±0.11* ¡(-­‑46%)

Spleen ¡(n=1)

• Max. ¡up-­‑slope, ¡s-­‑1

7.3 3.9

• ­‑3.4 ¡(-­‑47%)
• Perf. ¡index

0.35 0.19

• ­‑0.16 ¡(-­‑46%)

Organ perfusion during pulmonary hyperinflation in humans; a magnetic resonance imaging study. Kyhl K, Drvis I, Barak O, Mijacika T, Enstrøm T, Secher NH, Dujic Z, Lav Madsen P. Am J Physiol Heart Circ Physiol. 2016 Feb 1;310(3):H444-51.

Cardiac output: -43% Myocardium: -60% Hepar: 0% Skeletal muscle: -23% Lungs: -74% Kidney: -56% Spleen: -47%

Can you learn more about the fundamentals of the failing heart if you are now able to measure volume-related variables?

For example: Can you use CMR to diagnose “diastolic dysfunction” (instead of “HFpEF”)

Arterio-ventriculo-atrial coupling in healthy young and elderly

Arterio-ventriculo-atrial coupling

300# 320# 340# 360# 380# 400# 420# 440# 1# 2# 3# 4# 5# 6# 7# 8# 9# 10# 11# 12# 13# 14# 15# 16# 17# 18# 19# 20# 21# 22# 23# 24# 25# mL#s%1## 25#Phases#of#Cardiac#Cycle##

ERp$ FRp$

Wigger´s diagram (1915)

1 2 3 4 5 6 10 20 30 40 50

Peak-filling rate/LVEDV, s-1 % of stroke volume

1 2 3 4 5

• 2
• 1

1 2

Mean of ERp(i) and FRp(i), s-1 ERp(i) - FRp(i), s-1

Mean (SD)

1 2 3 4 100 200 300

Peak-filling rate/LVEDV, s-1 Maximal atrial volume, mL

Yes, CMR can be used to determined diastolic dysfunction

(- and perhaps even help get rid of the ridiculous term “HFpEF”)

And can you use CMR to tease out the fundamentals

• f Starlings law of the heart?

“Ascending leg” “Descending leg”

0 mmHg

• 30 mmHg, 10 min

In NORMAL subjects, both LVEDV and RVEDV decrease together with their outputs

154 mL 85 mL/beat 141 mL 82 mL/beat

• 50 mL (-32%)
• 31 mL/beat (-36%)
• 28 mL (-20%)
• 12 mL/beat (-12%)

Rest

• 30 mmHg, 5 min

In patients with HFrEF, lowered venous return causes RVEDV/RVSV to decrease, but the LVEDV and LVSV to increase

EDV 145 mL SV 60 mL/beat EDV 189 mL SV 63 mL/beat

• 27 mL (-16%)
• 20 mL/beat (-31%)

+6 mL (+3%) +14 mL/beat (+37%) 44% 37%

LVEF > 37% LVEF < 37%

The cut-off point is at an LVEF < 37%

• 28 mL
• 28 mL/beat
• 7 mL
• 3 mL/beat
• 29 mL
• 14 mL/beat

+18 mL +30 mL/beat

Conclusion: The decreasing leg of Starling is explained by diastolic-interventricular interaction

• These days, cardiology conferences are all

about myocardial structure/function/fibrosis

• I hope this talk has inspired you to consider

CMR for your cardiovascular physiology studies

Thank you, enjoy your stay in CpH

starlings law of the heart revisited

• Activation of the venous pump
• An decrease in systolic

venous compliance centralizes the blood volume

magnetic resonance spectroscopy

R E S U L T S

Magnetic resonance spectroscopy

hyperpolarized magnetic resonance spectroscopy

20 40 60 80 100

Volume curves

Cardiac phase Right ventricular volume (mL/m2)

• 1

5 10 15 20 25

• Rest

Glycopyrrolate Dobutamine

Right heart function during parasympathetic blockade and beta-adrenergic stimulation in humans. Kyhl K, Ahtarovski KK, Iversen K, Lønborg J, Engstrøm T, Vejlstrup NG, Lav Madsen P

• 30 mmHg, 5 min
• 30 mmHg, 10 min

LV filling is upheld by the lung blood pool

• 35 mL (-22%)
• 26 mL/slag (-30%)*
• 22 mL (-15%)
• 6 mL/slag (-5%)
• 15 mL (-13%)
• 5 mL/slag (-6%)^
• 6 mL (-4%)
• 6 mL/slag (-6%)

Microwave irradiation Solvent , e.g. 50 mL water heated to 130 °C Cryostat, e.g. 1 K and 5 T

CH3 CO

13C

OO-

Pyruvic acid enriched with 13C in C-1 position

e-

Electron Paramagnetic Agent, dissolves in pyruvic acid

+

1 10 100 1.000 10.000 100.000 1.000.000 0,1 1 10 100 Polarisation (ppm) Temperature (K)

13C 1H e

DNP Dissolution Relaxation (detection) Cooling

FIG 1

A C B

Hyperpolarized magnetic resonance spectroscopy

FIG 3

Hauge Lauritzen et al., 2014

M E T H O D S

Myocardial and Renal Glucose Metabolism in Type 2 Diabetic Rats: Effect of Liraglutide. Lauritzen MH, Magnusson P, Hove JD, Madsbad S, Laustsen C, Ardenkjaer-Larsen JH, Tyler D, Lav Madsen P.

V e h ic le L ig u ra tid e V e h ic le L ig u ra tid e 0 .0 0 .2 0 .4 0 .6 0 .8 1 .0

L a c ta te m u s c le

L a c ta te /p y ru v a te ra tio D ia b e tic C o n tro l

*

V e h ic le L ig u ra tid e V e h ic le L ig u ra tid e 0 .0 0 .5 1 .0 1 .5

A la n in e m u s c le

C o n tro l D ia b e tic

*

Myocardial and Renal Glucose Metabolism in Type 2 Diabetic Rats: Effect of Liraglutide. Lauritzen MH, Magnusson P, Hove JD, Madsbad S, Laustsen C, Ardenkjaer-Larsen JH, Tyler D, Lav Madsen P.

V e h i c l e L i g u r a t i d e V e h i c l e L i g u r a t i d e 0 .0 0 .1 0 .2 0 .3

A la n in e H e a rt A la n in e /P y ru v a te ra tio

C o n tro l D ia b e tic

* ***

V e h i c l e L i g u r a t i d e V e h i c l e L i g u r a t i d e 0 .1 5 0 .2 0 0 .2 5 0 .3 0 0 .3 5

L a c ta te H e a rt L a c ta te /P y ru v a te ra tio

C o n tro l D ia b e tic

Myocardial and Renal Glucose Metabolism in Type 2 Diabetic Rats: Effect of Liraglutide. Lauritzen MH, Magnusson P, Hove JD, Madsbad S, Laustsen C, Ardenkjaer-Larsen JH, Tyler D, Lav Madsen P.

Per Lav Madsen MD DMSc

The heart in shock

Right ventricle Left ventricle Circulatory transit times Pulmonary transit time Systemic transit time

The heart in shock

Per Lav Madsen

Consultant in Cardiology ESC and SCMRI level III, MD DMSc

Central hypovolaemia

• Activation of the venous pump
• An decrease in systolic

venous compliance centralizes the blood volume

Non-ischamic cardiomyopathy

Gadolinium contrast

Evaluation of Primary Mitral Valve Insufficiency by Magnetic Resonance Imaging

Mark Aplin, Kasper Kyhl, Jenny Bjerre, Nikolaj Ihlemann, John P. Greenwood, Sven Plein, Akhlaque Uddin, Niels Tønder, Nis Baun Høst, Malin Glindvad Ahlström, Jens Hove, Christian Hassager, Kasper Iversen, Niels G. Vejlstrup, and Per Lav Madsen Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds University, UK, and Depts. Cardiology, Copenhagen University Hospitals of Rigshospitalet, Hillerød, Bispebjerg, Hvidovre and Herlev, Copenhagen, Denmark

C A R D I A C M R I

R E S U L T S

Severe primary

• LVEDV(i) > 108 mL m-2
• LAmax(i) > 73 mL m-2
• Total left heart volume(i) > 188 mL m-2
• Pulmonary vein diameter > 2 cm
• LVSV > 70 mL m-2 + low aortic outflow
• LVEDV/RVEDV ratio > 1.2 (often >1.6)
• MI regurgitation fraction > 0.30
• MI regurgitation volume > 40 mL

C O N C L U S I O N S

LVEF > 37% LVEF < 37% RVEDV 143 mL LVEDV 168 mL RVEDV 158 mL LVEDV 209 mL

The difference is seen with LVEF < 37%

you + happy birthday Niels

!40,0% !30,0% !20,0% !10,0% 0,0% 10,0% 20,0% 30,0% 40,0% 0% 10% 20% 30% 40% 50% 60% 70% 80% END!DIASTOLIC%VOLUME%CHANGE,%%%

, right ventricle , left ventricle

ype 2 Diabetic Rats: Effect of Liraglutide. Lauritzen n C, Ardenkjaer-Larsen JH, Tyler D, Lav Madsen P.

LAD LM LcX

Kyhl Kristensen et al. Am J Physiol 2013;305:1004-9

Dorte Ørsøe

110563-1114

• Flow in all thoracic vessels
• Cardiac volumes
• Myocardial, pulmonary, and organ perfusion
• Spectroscopy of energy-rich phosphate levels
• Hyperpolarized magnetic resonance

spectroscopy

Pyr

FIG 5

V 181 mL (100 mL/m2) VEDV 138 mL (75 mL/m2) VSV 127 mL, RVSV 78 mL 116/42 mL (36%), net 74 mL

• Circulation. 2012 Sep 18;126(12):1452-60. doi: 10.1161/

CIRCULATIONAHA.111.083600. Epub 2012 Aug 9. Aortic regurgitation quantification using cardiovascular magnetic resonance: association with clinical outcome. Myerson SG1, d'Arcy J, Mohiaddin R, Greenwood JP, Karamitsos TD, Francis JM, Banning AP, Christiansen JP, Neubauer S. 113 patients with echocardiographic moderate or severe AR were monitored for up to 9 years (mean 2.6 ± 2.1 years) following a CMR scan, and the progression to symptoms or other indications for surgery was monitored. AR quantification identified outcome with high accuracy: 85% of the 39 subjects with regurgitant fraction >33% progressed to surgery (mostly within 3 years) in comparison with 8% of 74 subjects with regurgitant fraction ≤ 33% (P<0.0001). CMR-derived left ventricular end-diastolic volume >246 mL had good, although lower, discriminatory ability (area under the curve 0.88), but the combination of this measure with regurgitant fraction provided the best discriminatory power.

Stedig-Ehrenborg et al., 2013

gadolinium dTPA

• For perfusion studies (rest + adenosine stress), gadolinium

is infused as bolus (0.05-0.10 mmol/kg) in large peripheral vein (4-6, scanning 8 seconds later

• For stress studies, adenosine (140 micro-g/kg/min) is

infused for 2-4 min before + during scan

• For the “late gad” study an accumulated dose of at least

0.1 mmol/kg is needed

• Cyclical gadolinium contrast agents are extremely safe,

but must not be used in patients with a e-GFR < 30 (“nephrogenic systemic fibrosis”)

the short axis stack (double-oblique)

M E T H O D S

diffuse fibrosis

Iles et al. J Am Coll Cardiol 2008; 52: 1574-80

Diastolic dysfunction in diabetic patients

Ng et al. Circ Cardiovasc Imaging 2012;5:51-9

Myocardial blood flow during cold-pressure test

Fairbairn et al. Radiology, 2014;270:82-90

Myocardial blood flow during cold-pressure test

Fairbairn et al. Radiology, 2014;270:82-90

Ng et al. Circ Cardiovasc Imaging 2012;5:51-9

Diastolic dysfunction in diabetic patients

Qualitative analysis

• Visual inspection
• Comparison is between

normal and hypoperfused tissue

• Based on changes during

adenosine stress

• Groups can be compared with

respect to yes/no answers

Ng et al. Circ Cardiovasc Imaging 2012;5:51-9 Ng et al. Circ Cardiovasc Imaging 2012;5:51-9

Diastolic dysfunction in diabetic patients

Kyhl Kristensen et al. Am J Physiol 2013;305:1004-9

• MRI is gold standard for non-invasive flows,

including determination of regurgitation fractions/ Qp:Qs-ratios

• Echo-Doppler should be applied for estimation of

pressure gradients

Figure 3. Cardiac high-energy phosphate levels, expressed as the PCr to ATP ratio (PCr/ATP), correlated negatively with the plasma free fatty acid (FFA) concentrations (r20.32, P0.01) for all subjects and correlated positively with the plasma glu- cose concentrations (r20.55, P0.05) for the patients with type 2 diabetes, but there was no correlation for control subjects. Trendlines are shown to guide the eye.

Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Scheuermann-Freestone, Lav Madsen, Manners, Blamire, Buckingham, Styles, Radda, Neubauer,

• Clarke. Circulation (2003) 107, 3040-3046

__________________________________________________________________________

the transversal stack

Mild Severe Receiver operating characteristics analysis

R E S U L T S

Non-ischamic cardiomyopathy

Gadolinium contrast

Non-ischamic cardiomyopathy

Gadolinium contrast