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1st International Canine Valvular Disease Symposium

Sponsored by Boehringer Ingelheim Animal Health GmbH Binger Straße 173

Paris, October 30 th – 31st, 2004

55216 Ingelheim am Rhein Germany Tel.+49 (0) 61 32 77-0 Fax+49 (0) 61 32 77-82 22 [email protected]

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1st International Canine Valvular Disease Symposium

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1st International Canine Valvular Disease Symposium

Preface As Sponsor, the Boehringer Ingelheim Animal Health division is proud to present the proceedings of the 1st International Canine Valvular Disease Symposium (ICVS) held in Paris, France, October 2004. We would like to thank the distinguished group of speakers for their cooperation and collaboration. Without their valuable input, this symposium would not have been possible. Canine Mitral Valve Disease is by far the most common cardiovascular disease in dogs – reportedly responsible for an excess of 70 % of all cases. Despite ongoing research, relatively little is known about the real causes and prognosis of valvular degeneration in dogs. The presence of mitral regurgitation is relatively easy for the practitioner to diagnose, however, the monitoring of disease progression and the choice of optimal treatment options is still very much under research. The symposium and proceedings cover the three main areas of Mitral Valve Disease Research; pathophysiology, disease prognosis/progression and finally a review of both current and future treatment options. As human and veterinary Mitral Valve Research is closely related, all three sessions include contributions from leading researchers in human medicine. We hope that you will both enjoy and benefit from the research compiled herein.

Boehringer Ingelheim Animal Health Sponsored by Boehringer Ingelheim Animal Health GmbH Binger Straße 173 55216 Ingelheim am Rhein Germany Phone +49 (0) 61 32 77-0 Fax +49 (0) 61 32 77-82 22 [email protected] www.boehringer-ingelheim.com Design and layout Stern GmbH, Wiesbaden Foto imagesource The enclosed abstracts are the property of the individual authors. The comments and opinions expressed therein are those of the authors and do not necessarily reflect the position or beliefs of Boehringer Ingelheim or its employees. No abstract should be reproduced, transmitted or used for 3rd party purposes without the express written consent of the author.

Saturday October 30 th, 2004

Sunday October 31st, 2004

Content

Content

1. Pathophysiology

3. Treatment

Pathophysiology of Mitral Valve Disease

4

ACE Inhibition in Canine Mitral Valve Disease – Review of Clinical Data

60

Mark R. Starling

Robert L. Hamlin

Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration

Pimobendan in the Management of CHF due to Chronic Mitral Valve Insufficiency: The Veterinary Experience

6

Brendan M. Corcoran Endothelial and Platelet Function in Canine Mitral Valve Disease

12

Lisbeth H. Olsen Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs?

Veterinary Study for the Confirmation of Pimobendan in Canine Endocardiosis – Results of VetSCOPE

66

Christophe W. Lombard 16

Jens Häggström

What is on the Horizon? Chronic Valvular Disease – Pharmacotherapy Current & Future Directions

2. Prognosis/Progression Echocardiographic Overview of Mitral Valve Disease

62

Michael O'Grady

72

Sonya G. Gordon 22

Current Status of Human Mitral Valve Surgery

Virginia Luis Fuentes

E. W. Matthias Kirsch

M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 1st part: Overview

Mitral Valve Surgery: Current Veterinary Practice 26

78 82

E. Christopher Orton

John E. Rush M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 2nd part: Clinical Experience and Possible Use

30

Gérard LeBobinnec Echocardiographic Estimation of Mean Left Atrial Pressure in Canine Mitral Regurgitation

34

Mark A. Oyama Diagnostic Value of Pulmonary Transit Times in Mitral Regurgitation

38

Jens Häggström Quantification of Mitral Regurgitant Volume and Effective Orifice Area using the Proximal Isovelocity Surface Area (PISA) Method

42

Mark A. Oyama Cardiac Markers in Canine Mitral Valve Disease

48

D. David Sisson Remodeling Remodeling and the Role of RAAS

50

Mark R. Starling Cardiac Remodeling in Canine Mitral Valve Volume Overload

52

A. Ray Dillon 2

1st International Canine Valvular Disease Symposium

1st International Canine Valvular Disease Symposium

3

Pathophysiology of Mitral Valve Disease Mark R. Starling

Pathophysiology of Mitral Valve Disease

Mark R. Starling

Oral presentation only.

MD, PhD, BA

Medical Director Banner Baywood Heart Hospital, Mesa, Arizona, USA Clinical interests: Mitral Valve Disease, Treatment of Heart Failure, Cardiomyopathy Research interests: Pathophysiology of LVD, Mitral Valve Disease, Cardiomyopathy, Neurohumoral Mechanisms, Ventricular Performance Contact: [email protected]

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1st International Canine Valvular Disease Symposium

1st International Canine Valvular Disease Symposium

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Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration Brendan M. Corcoran

Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration

Many of the gross and histopathological features

are a few small nodular lesions at the site of

of Mitral Valve Endocardiosis (MVE) in the dog

valve apposition, to Grade 4, where there is

were described in detail in the 1970s, but the

severe valve edge thickening and involvement of

sources are limited to a few published papers.

the chordae tendineae, with or without chordal

The pioneering work of John Whitney provides

rupture. This system of classification is still used

Brendan M. Corcoran

most of our understanding of the pathological

widely today, and appears to be a reasonably

DVM, MVB, DipPharm, PhD, MRCVS

changes in affected valve leaflets, and along with

robust grading system.

Ariela Pomerance, he was one of the progenitors Senior Lecturer and Director of the Hospital for Small Animals

of the idea that there were important comparative

Division of Veterinary Clinical Studies

aspects relevant to the similar disease in

Royal (Dick) School of Veterinary Studies

humans. Subsequently, James Buchanan added

University of Edinburgh, Easter Bush Veterinary Centre, UK

to our understanding of the pathology and

Specialty: Cardiopulmonary Medicine

summarised the totality of our knowledge of this

Clinical/Research interests: Small Animal Cardiology and Respiratory Medicine

disease in 1977. Around the same time as John

Contact: [email protected]

Whitney was reporting on MVE, Ernst and Schneider were doing similar work in Germany, but published in German and, unfortunately, their observations did not reach a wider audience. By 1980 interest in the pathological descrip-

Figure 1. Gross pathological view of an abnormal valve

tion appeared to have declined apart from a paper by Kazuo Kogure in Japan, who erroneous-

How this translates to a histopathological classi-

ly referred to the disease as mitral valvular fibro-

fication is not clear, as by its very nature lower

sis. Prior to 1970 there were descriptions of the

grades of the disease will have regions of nor-

disease published, and after 1980 the main vet-

mality along the valve length interspersed with

erinary interest in myxomatous mitral valve dis-

diseased areas. However, there are good, and

ease has been in diagnosis, therapy and the

reasonably consistent, descriptions of the histo-

pathophysiological response.

pathological changes found at diseased sites of the valve. The normal mitral valve leaflets con-

More recently there has been increased interest

sist of two layers of endothelium sandwiching a

in looking at the pathology of this disease

tissue rich in collagen, acid mucopolysacchari-

afresh. This has been because of the advent of

des and elastin. On the atrial side the endothe-

available molecular biology tools. Groups inter-

lium has a crinkled appearance, while on the

ested in morphological, cellular and molecular

ventricular side it is flattened. The flattening can

pathology of this disease can now be found in

be so marked as to make it appear that the endo-

the UK, Scandinavia and the USA, giving great

thelial lining is missing. Beneath the endothe-

promise for advancing our understanding of the

lium is a collagen and elastin-rich matrix (fibrosa)

aetiopathogenesis of MVE.

that provides the structural rigidity of the valve. The collagen is highly organised and laid out in

6

1st International Canine Valvular Disease Symposium

However, we are still reliant on the early workers

compact parallel bundles. Beneath this layer is a

to describe the pathology of MVE. Whitney and

more loose connective tissue zone with a high

Pomerance (1970, 1974) ascribed a 5 grade clas-

concentration of acid mucopolysaccharides

sification system (with normal being 0) to the

(spongiosa). Moving from the base of the valve,

disease, which varied form Grade 1, where there

where it is attached to the myocardium, towards

1st International Canine Valvular Disease Symposium

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Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration Brendan M. Corcoran

Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration Brendan M. Corcoran

the valve leaflet edge, there are obvious differ-

to a more mixed myofibroblast or smooth muscle-

ture. Considering MVE predominantly affects the

ences in structural appearance. At the valve

like phenotype. This has been demonstrated on

valve leaflet edge (appositional edge), is highly

basal zone cardiac myocytes occupy the majority

EM in dogs and by immunohistochemistry in

age-dependent and probably is present to some

of the tissue, but the basic structure of endothe-

both dogs and humans. This cellular phenotypic

extent in all geriatric dogs, it is tempting to sup-

lium/fibrosa/spongiosa can be appreciated.

alteration may be a consequence of the disease

pose that damage to the endothelium is a trigger

Moving to the mid zone the classic structural

process rather than a cause, but the over-all

event to the development of the dyscollagenesis

make-up is more apparent, as it also is in the

effect would appear to be a reduction in matrix

so obvious in this disease. The fact that in some

distal (free-edge) zone. The major difference be-

production capability (collagen). Furthermore,

breeds the disease develops earlier in life and

tween the two latter zones is that the free-edge

there is evidence of an increase in matrix metal-

can be more severe compared to the general dog

lacks innervation.

loproteinases that target collagen, suggesting

population, is an additional confounding factor.

Figure 2. Abnormal valve under light microscopy

When the disease is present the valve morpho-

the matrix disorganisation is a combination of reduced capacity for producing collagen, derange-

For many years there has been little or no research

logy shows characteristic changes. These chan-

What can be stated with certainty is that there is

ment of post-cellular collagen organisation and

activity attempting to unravel the complexity of

ges are most noted at the free edge, but can

marked collagen disarray in affected areas, with

increased collagen catabolism.

the aetiopathogenesis of this disease. However,

extend to the mid-zone, but rarely impinge on

haphazard organisation. Furthermore, the colla-

the valve base. Areas of discontinuity of the

gen strands exhibit abnormal periodic banding

Concurrent with the cellular changes within the

applied which is giving new insights into the

endothelium can be seen, but not always, and

along their length. There is evidence for abnor-

valve leaflet are alterations to the valvular endo-

disease process. In the future more powerful

there are localised expansions of the spongiosa

mal post-cellular organisation of collagen in

thelial covering. Endothelial denuding in the dog

molecular biology techniques, particularly in the

with concurrent loss of the fibrosa. In many

canine MVE, and also evidence for collagen cat-

has been demonstrated on both transmission

area of canine genomics and proteomics, will

ways it would appear that the spongiosa has

abolism in both the canine and human forms of

and scanning electron microscopy, with evidence

accelerate the acquisition of knowledge about

expanded in size, but also invaded the fibrosa.

the disease.

of phenotypic alteration.

this disease. Whether or not such technologies

there is now active basic science research being

will actually allow identification of the cause of

Occasionally, it is noted that there is an increase

8

in the amount of elastin at diseased sites and

At the cellular level, the descriptions of the

MVE remains to be seen. In the interim, it is

the conventional thinking is that there is a loss

1970s are slightly suspect and somewhat at vari-

necessary for veterinary cardiology research to

of collagen and increase in acid mucopolysacca-

ance with each other. There is no evidence of a

properly describe the structural and cellular

rides. How true this is is difficult to state with

cellular inflammatory reaction, but there is evi-

alteration of the canine myxomatous mitral

complete certainty. At high power magnification,

dence of marked cellular changes involving the

valve leaflet in order to apply such powerful

and even more under electron microscopy (EM),

endothelium and cells located within the sub-

molecular biology tools wisely.

there is apparent collagen loss, although this

endothelial structures. Occasionally, reference

may be better described as collagen disarray.

has been made to fibrosis being present in

Evidence from human studies would suggest

affected valves, but this would not appear to be

there is minimal change in the overall collagen

the case, or at least this finding is inconsistent

content of diseased valves, and the evidence for

and insignificant. These may in fact be examples

definite increased acid-mucopolysaccharides is

of Lambl's excrescences. In the normal valve the

On SEM, increased numbers of surface plasma-

contradictory. This may not be so unexpected as,

majority of the cells within the valve substance

lemmal micro appendages are visible on cells

under EM, collagen rich areas are often found

are interstitial (valvular interstitial cells; VIC),

adjacent to denuded areas, suggesting altered

interspersed or adjacent to obvious collagen

with occasional macrophages and mast cells

cellular activity. Using immunohistochemical

sparse areas. This feature of the pathology might

being present. The VICs are the source of matrix

techniques, alteration in endothelial function

not be as easily appreciated under the low reso-

products that make up the bulk of the valve. The

has also been demonstrated in diseased canine

lution capability of light microscopy.

impression in the diseased canine and human

valves. It is recognised that the endothelium

valves is that there is an increase in the number

interacts with the sub-endothelial structures and

of such cells, but more interestingly an alteration

may have a role to play in the control of the con-

from a predominantly fibroblast-like phenotype

tinuous life-long remodeling of the valve struc-

1st International Canine Valvular Disease Symposium

Figure 3. Endothelial denuding under electron microscopy

1st International Canine Valvular Disease Symposium

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Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration Brendan M. Corcoran

Ultrastructural and Pathological Changes in Mitral Valves of Dogs with Myxomatous Degeneration Brendan M. Corcoran

References: 1. Black A, Corcoran BM, French AT & Dukes-McEwan J.

6. Mow T. & Pedersen H.D. (1999). Increased Endothelin receptor

Ultrastructural Morphological Evidence of Altered Valvular

density in myxomatous canine mitral valve leaflets. Journal of

Interstitial Cell Phenotype in Canine Mitral Valve Myxomatous

Cardiovascular Pharmacology 34, 254-260.

Degeneration (submitted).

7. Pomerance A & Whitney JC (1970). Heart valve changes com-

2. Buchanan, JW (1977). Chronic valvular disease (endocardio-

mon to man and dog: a comparative study. Cardiovascular

sis) in dogs. Advances in Veterinary Science and Comparative

Research 4, 61-66.

Medicine 21, 75-106.

8. Whitney JC (1974). Observations on the effect of age on the

3. Corcoran BM, Black A, Anderson H, Dukes-McEwan J, French

severity of heart valve lesions in the dog. Journal of Small

A, Smith P & Devine C (2004). Identification of surface morpho-

Animal Practice 15, 511-522.

logical changes in left atrioventricular valve of dogs with endo-

9. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P & Schoen

cardiosis by use of scanning electron microscopy. American

FJ (2001). Activated interstitial myofibroblasts express catabolic

Journal of Veterinary Research, 65, 198-206.

enzymes and mediate matrix remodeling in myxomatous heart

4. Ernst E, Schneider P & Trautwein G (1974). Die Endokardiose

valves. Circulation, 104, 2525-2532.

der Atrioventrikularklappen des Hundes IV.

10. Zimmerman SA & Orton EC (2004). Canine heart valve

Elektronenmikroskopische Untersuchungen. Zbl. Vet. Med A,

interstitial cells: phenotypic and functional properties of normal

21, 400-416.

and myxomatous valves. Proc 22nd ACVIM Forum Minneapolis,

5. Kogure K. (1980). Pathology of chronic mitral valve disease in

pp871.

the dog. Japanese Journal of Veterinary Science 42, 323-335.

10

1st International Canine Valvular Disease Symposium

1st International Canine Valvular Disease Symposium

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Endothelial and Platelet Function in Canine Mitral Valve Disease Lisbeth H. Olsen / Henrik D. Pedersen

Endothelial and Platelet Function in Canine Mitral Valve Disease

Endothelial damage seems to play a central role

exists. It has been shown that NO inhibits the

in the pathogenesis of canine mitral valve disease

synthesis and effects of Endothelin, however, it

(MVD). Altered valvular motion, abnormal closure

is still unclear whether NO is a “good guy” in the

and changed haemodynamic forces due to mitral

valve, which inhibits harmful effects of Endothelin

valve prolapse and mitral regurgitation likely

or whether NO in a high concentration is a “bad

Lisbeth H. Olsen

lead to repeated impact to the valve.

guy” which mediates tissue damage itself.

DVM

Damage/shear stress to endothelial cells in vitro

Systemically, decreased plasma concentrations

is known to influence the synthesis and release

of NO metabolites (nitrate and nitrite) have been

of mediators that can interact with the subendo-

found in Cavalier King Charles Spaniels (CKCS)

thelial tissue. However, little is known about

with mild to severe mitral regurgitation

vasoactive substances that mediate the subendo-

(Pedersen et al, 2003). This finding suggests that

thelial changes in the valve such as deposition of

CKCS have already early in the course of develop-

mucopolysaccharides and collagen degeneration.

ment of MVD a form of endothelial dysfunction.

Associate Professor, Department of Animal and Veterinary Basic Sciences Royal Veterinary and Agricultural University Frederiksberg, Denmark Specialty: Pathophysiological and Genetic Aspects of Canine Myxomatous Mitral Valve Disease Clinical/Research interests: Pathophysiological Aspects of Myxomatous Mitral Valve Disease, especially Platelet and Endothelial Function Contact: [email protected]

Endothelial dysfunction appears to be a part of A strong correlation has been found between

the complex pathophysiology of many heart

the degree of disease in the canine mitral valve

diseases in humans, apparently independent of

and Endothelin-receptor density by using auto-

etiology. Treatments which improve endothelial

radiography suggesting that Endothelin plays a

function, including antioxidant therapy, oral

role locally in the pathogenesis of MVD (Mow

L-Arginine supplement and Endothelin-receptor

Co-author:

and Pedersen 1999). Endothelin is a very potent

blockade, have shown promising results in

Henrik D. Pedersen

vasoconstrictor but is also an important paracrine

humans. Studies on the effect of these treatments

substance. Endothelin is known to play a major

in dogs would be interesting, especially with

DVM, DrVetSci

role in the pathogenesis of vascular restenosis –

regard to Endothelin-receptor blockers since

Department of Animal and Veterinary Basic Sciences

another condition in which endothelial damage

they are also expected to have local beneficial

Royal Veterinary and Agricultural University

leads to subendothelial changes. Interestingly,

effects in the diseased valve.

Frederiksberg, Denmark

Endothelin-receptor blockers are found to limit

Increased platelet aggregation response has

the development of restenosis after percutane-

been found in many CKCS (Olsen et al, 2001).

ous transluminal coronary angioplasty in rats.

Because CKCS is highly predisposed to MVD, it

Further studies are indicated to evaluate whether

is speculated that increased platelet reactivity

Endothelin-receptor blockers may have protective

could be associated with development of valvu-

effects in development of MVD in dogs.

lar changes. Furthermore, vascular changes resembling the pathological changes in the valve

12

1st International Canine Valvular Disease Symposium

Increased NADPH (the reduced form of nico-

are described in the femoral and pulmonary

tinamide-adenine dinucleotide phosphate)

arteries of CKCS, suggesting a systemic cardio-

diaphorase activity, suggesting an increased NOS

vascular disorder (Buchanan et al, 1997, Karlstam

(nitric oxide synthase) activity, is found in areas

et al, 2000). It could be speculated that platelets

of the mitral valve with myxomatous changes

and endothelium play a key role in determining

(Olsen et al, 2003). This indicates that nitric

onset and rate of development of the disease

oxide (NO) probably plays a role locally in the

and may be important future therapeutic targets

pathogenesis of MVD. Endothelin and NO are

in dogs with MVD. Further studies are indicated

both found to be important regulators of the

to elucidate the possible relationship between

production of extracellular matrix and a regulatory

MVD, vascular changes and endothelial and

balance between the two substances apparently

platelet function in dogs.

1st International Canine Valvular Disease Symposium

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Endothelial and Platelet Function in Canine Mitral Valve Disease Lisbeth H. Olsen / Henrik D. Pedersen

Endothelial and Platelet Function in Canine Mitral Valve Disease Lisbeth H. Olsen / Henrik D. Pedersen

References Buchanan JW, Beardow AW, Sammarco CD (1997). Femoral

Olsen LH, Mortensen K, Martinussen T, Larsson L-I, Baandrup U,

artery occlusion in Cavalier King Charles Spaniels. J Am Vet Med

Pedersen HD (2003). Increased NADPH-diaphorase activity in

Assoc 211: 872-874.

canine myxomatous mitral valve leaflets. J Comp Pathol 129:

Karlstam E, Häggström J, Kvart C, Jönsson L, Michaelsson M

120-130.

(2000). Pulmonary artery lesions in Cavalier King Charles

Pedersen HD, Schütt T, Søndergaard R, Qvortrup K, Olsen LH,

Spaniels. Vet Rec 147: 166-167.

Kristensen AT (2003). Decreased plasma concentration of nitric

Mow T, Pedersen HD (1999). Increased Endothelin-receptor den-

oxide metabolites in dogs with untreated mitral regurgitation.

sity in myxomatous canine mitral valve leaflets. J Cardiovasc

J Vet Intern Med 17: 178-184.

Pharmacol 34: 254-260. Olsen LH, Kristensen AT, Häggström J, Jensen AL, Klitgaard B, Hansson H, Pedersen HD (2001). Increased platelet aggregation response in Cavalier King Charles Spaniels with mitral valve prolapse. J Vet Intern Med 15: 209-216.

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1st International Canine Valvular Disease Symposium

1st International Canine Valvular Disease Symposium

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Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs? Jens Häggström

Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs?

Jens Häggström DVM, PhD, Diplomate ECVIM (Cardiology)

Cavalier King Charles Spaniel is a breed with

(females from 4-5 years), which is considerable

increasing popularity in the world. Its physical

younger than most other breeds where MR often

appearance and pleasant temper makes it a per-

is diagnosed from 6-7 years(5). Because of this,

fect family dog. This breed is descended from the

Cavaliers have time to progress from mild stages

small toy spaniels, which served as companion

of MR to severe life-threatening MR before they

dogs at European courts back in medieval

die from other serious illness (Figure 1).

(1)

times . Thus, its present appearance and mentality is the result from centuries of breeding during

Professor Internal Medicine Department of Clinical Sciences, Small Animals Faculty of Veterinary Medicine and Animal Science Swedish University of Agricultural Sciences, Uppsala, Sweden Speciality: Cardiology Clinical/Research interests: Mitral Valve Disease in Dogs, Pathophysiology of Heart Failure, Therapy of Heart Failure Contact: [email protected]

which many of the natural physical and mental traits of wolves have been altered. Indeed, the

% Mortality Cardiovascular disease 15

Cavaliers Males Females

Cavalier King Charles Spaniel is one of the Dachshunds Males Females

breeds with the fewest lupine aggressive and submissive behavioral patterns remaining(2).

10

However, with increasing popularity, an increasing number of Cavaliers are presented with mitral

M

5

F

regurgitation (MR) attributable to myxomatous

M F

mitral valve disease (MMVD) at veterinary clinics. Subsequent clinical studies in the breed confirmed this clinical observation(3-5). The facts that the breed is comparably common and that they

0 2

4

6 8 Age (years)

10

12

develop MMVD lead to that this population of

Figure 1. Actuarial data from Agria Insurance Ltd for the years

dogs is often included in clinical studies of MMVD

2001 and 2002. The graph shows percentage cardiovascular

and in trials aimed at studying treatment effects

mortality as a function of age. Cavaliers have an earlier onset of MMVD than Dachshunds, which leads to higher mortality

of certain cardiovascular drugs. However, because

rates 3 to 4 years later in life. Within each breed, the mortality

that Cavalier breed stands out as exceptionally

rate increases at a younger age in males than in females.

prone to develop MMVD, its relevance as a model for MMVD in general has been questioned.

Cavaliers are actually surprisingly healthy dogs apart from their problem with MMVD and this is

It is impossible to understand the difference

reflected in Swedish actuarial data in dogs < 10

between Cavaliers and other dogs concerning

years by a comparably low overall mortality, a

MMVD development if one does not consider

high cause specific mortality (number of deaths

the demographic risk variables. Cavaliers are not

due to a given cause in a given breed/average

different from other small to medium-sized

number of dogs at that breed at risk), and the

breeds in the sense that they develop MMVD,

highest proportional age mortality (number of

because this disease is described in practically

deaths due to a given cause in a given breed/

every canine breed. The two major risk factors

number of deaths due to that cause in all

for developing MMVD in a breed are age and

breeds) for all breeds for all types of disease(8).

(6, 7)

gender, in ranking order

16

1st International Canine Valvular Disease Symposium

. Cavaliers are dif-

Why do Cavaliers develop MMVD at a comparably

ferent from other breeds because they develop

young age? Because little is known with certainty

MMVD at a younger age than most other breeds.

about underlying etiology and pathogenesis of

Especially male Cavaliers are prone to develop

MMVD, it is not known why Cavaliers develop

MMVD (and MR). Typically, MR can be diagnosed

MMVD at young age. It has been shown that

in male Cavaliers from the age of 3-4 years

genetic factors play a major role for the

1st International Canine Valvular Disease Symposium

17

Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs? Jens Häggström

Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs? Jens Häggström

cells)(14, 15). Furthermore, collagen and other matrix

development of MMVD. In Cavaliers and

resistance to ventricular emptying) and to (23)

the general population (which requires a repre-

Dachshunds, the age at which MMVD develops

components may become exposed to the blood

increased sympathetic tonus . Why these large

sentative sample of the general population).

has been shown to be inherited as a polygenetic

in areas of diseased valves where the endothe-

dogs appear to tolerate the MR so much poorer

Therefore, any study restricting the inclusion cri-

threshold trait, i.e. more than one gene influences

lium appears to be missing. The progression of

than the typical small dog is currently an enigma.

teria will be questioned for its validity for the

the trait and that males and females have different

MR and clinical signs of decompensated heart

The fact that atrial fibrillation is a more common

general population. Myxomatous mitral valve

thresholds (age) at which MMVD develops(7, 9). As

failure may also be influenced by the response of

complication in large dogs, simply owing to larger

disease is not always an easy disease to study

not all dogs develop MMVD, probably one or

the left ventricular myocardium and the develop-

atrial size, does not explain this principal differ-

because many dogs develop the disease at old

more primary inciting factors increase the risk of

ment of mitral valve annulus dilatation (which

ence. Naturally, Cavaliers with MMVD constitute

age, which means that the risk for other concur-

disease in predisposed animals. The nature of

promotes secondary MR). Apparently, Cavaliers

a poor model for mitral valve disease in these

rent disease is great. Therefore, Cavaliers offer a

these primary initiating factors are currently not

differ from Dachshunds by the fact that, in case

large dogs.

unique possibility to study MMVD because,

known, although certain abnormalities of colla-

of MR, the left atrial to left ventricular-end-dias(16)

tolic ratio is lower in Cavaliers . Although this

gen and other extracellular matrix components (6, 10)

(17)

except for the MMVD, they are comparably In most types of clinical research there is a prob-

healthy and they develop the disease (and heart

ratio is similar in the breeds in normal dogs ,

lem to obtain a study population as similar as

failure) at a comparably young age. Furthermore,

Such associations have been shown in people

the MR causes a greater increase of the LVEDD in

possible to reduce the overall variation (and

the MMVD found in Cavaliers have not been

but little is known if this is true in dogs, too.

Cavaliers for a given degree of MR. The underlying

thereby increase the probability to obtain signifi-

shown to be different in nature from that is

However, recently a relationship between MVP

cause for this breed difference is currently not

cance) but at the same time maintain validity for

found in other small to medium sized dogs.

and a narrow chest in a population of

known.

have been suggested to predispose to MMVD

.

Dachshunds was reported(7). It was hypothesized in this paper and in one in humans(11) that a nar-

It should be pointed out that the above outlined

row chest may lead to entrapment of the heart

characteristics are valid for MR in small to

within the thorax, which could predispose to

medium sized dogs. We actually know little

MMVD.

about MR in large dogs. Because we have assumed that dogs of various breeds and shapes

Although it is our experience that the gross- and

have the same expression of disease and

histopathological and ultrastructural characteris-

respond to it in a similar way, we have, with a

tics of MMVD in Cavaliers and dogs of other

few exceptions, considered significant MMVD a

breeds are identical, it cannot be ruled out that

comparably rare condition in large dogs(4, 18). How-

MMVD not only develops at a younger age, but

ever, it has been the clinical impression that some

also progresses more rapidly in Cavaliers than in

large dogs may present with massive MR and

other dogs. Within breed, three factors have

myocardial failure in the presence of comparably

presently been identified to influence the pro-

subtle changes in mitral valve morphology, and

gression of MMVD and MR. These are age, gender

do not present the “classical” thickening and

and severity of valvular changes(12). It has been

prolapse of the mitral valve leaflets so common

suggested that MMVD leads to abnormal valve

in the small dog(19-22).

motion, i.e. prolapse of the leaflets, which in

It is currently not known why these large dogs

turn increase the shear stress imposed on them,

develop such massive MR in the absence of

both directly through the abnormal leaflet appo-

significant valve abnormalities. Myocardial failure

sition and indirectly through the increased regur-

in dogs is known to develop as a consequence

(12, 13)

gitant flow

18

. It is likely that the endothelial

of chronic volume overload(21). We know from

damage or loss plays an important role in the

studies in small dogs that, although decreased

progression of the disease because endothelial

overall cardiac pump function is impaired, overt

cells are known to communicate extensively

myocardial failure is often not obvious in cases

with subendothelial cells (e.g. valvular interstitial

of MR owing to pathophysiology of MR (decreased

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Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs? Jens Häggström

Is the Cavalier King Charles Spaniel a Useful Model for Myxomatous Mitral Valve Disease in Other Dogs? Jens Häggström

References: 1. Burgess S. The Cavalier King Charles Spaniel.

17. Cornell C, Kittleson M, Della Torre P, et al. Allometric scaling

Queensborough, England: K&R Books, Ltd; 1975.

of M-mode cardiac measurements in normal adult dogs. J Vet

2. Goodwin D, Bradshaw J, Wickens S. Paedomorphosis affects

Intern Med 2004;18:311-321.

agonistic visual signals of domestic dogs. Anim Beh

18. Buchanan J. Causes and prevalence of cardiovascular disease.

1997;53:297-304.

In: Kirk R, Bonagura J, Eds. Kirk´s Current Veterinary Therapy XI.

3. Darke PGG. Valvular incompetence in Cavalier King Charles

Philadelphia: WB Saunders; 1992. p. 647-655.

Spaniels. Vet Rec 1987;120:365-366.

19. De Madron E. Primary acquired mitral insufficiency in adult

4. Thrusfield MV, Aitken CGG, Darke PGG. Observations on breed

large breed dogs. Proceedings of the 10th Annual ACVIM Forum;

and sex in relation to canine heart valve incompetence. J Small

1992; San Diego, CA; 1992. p. 608-609.

Anim Pract 1985;26:709-717.

20. Amberger C, Glardon O, Lombard C. Validité des examens

5. Häggström J, Hansson K, Kvart C, et al. Chronic valvular dise-

complémentaires dans l’évaluation de l’insuffisance cardiaque

ase in the cavalier King Charles Spaniel in Sweden. Vet Rec

par endocardiose mitrale: étude à partir de 106 cas. Prat Méd

1992;131:549-553.

Chir Anim Comp 1995;30:659-670.

6. Häggström J. Chronic valvular disease in Cavalier King

21. Kittleson M, Kienle R. Myxomatous atrioventricular valvular

Charles Spaniels – epidemiology, inheritance and pathophysio-

degeneration. In: Small Animal Cardiovascular Medicine. St.

logy. Thesis, Swedish University of Agricultural Sciences,

Louis, MO: Mosby Inc.; 1998. p. 297-318.

Uppsala, 1996.

22. Borgarelli M, Zini E, D’Agnolo G, et al. Comparison of pri-

7. Olsen L, Fredholm M, Pedersen H. Epidemiology and inher-

mary mitral valve disease in german shepherd dogs and dogs

itance of mitral valve prolapse in Dachshunds. J Vet Intern Med

of small-sized breeds. J Vet Cardiol 2004 in press.

1999;13:448-456.

23. Lord P, Eriksson A, Häggström J, et al. Increased pulmonary

8. Bonnett B, Egenvall A, Olson P, Hedhammar A. Mortality in

transit times in asymptomatic dogs with mitral regurgitation.

insured Swedish dogs: rates and causes of death in various

J Vet Intern Med 2003;17:824-829.

breeds. Vet Rec 1997;141:40-44. 9. Swenson L, Häggström J, Kvart J, et al. Relationship between parental cardiac status in Cavalier King Charles Spaniels and prevalence and severity of chronic valvular disease in offspring. J Am Vet Med Assoc 1996;208:2009-2012. 10. Pedersen HD, Häggström J. Mitral valve prolapse in the dog: A model of mitral valve prolapse in man. J Cardiovasc Res 2000;47:234-243. 11. Raggi P, Callister T, Lippolis N, et al. Is mitral valve prolapse due to cardiac entrapment in the chest cavity? A CT view. Chest 2000;117:636-642. 12. Olsen L, Martinussen T, Pedersen H. Early echocardiographic predictors of myxomatous mitral valve disease in dachshunds. Vet Rec 2003;152:293-297 13. Pedersen H, Lorentzen K, Kristensen B. Echocardiographic mitral valve prolapse in Cavalier King Charles Spaniels: epidemiology and prognostic significance for regurgitation. Vet Rec 1999;144:315-320. 14. Stein P, Wang C, Riddle J, et al. Scanning electron microscopy of operatively excised severely regurgitant floppy mitral valves. Am J Cardiol 1989;64:392-394. 15. Corcoran B, Black A, Anderson H, Dukes McEvan J, French A. Investigation of mitral valve morphology in dogs with mitral valve endocardiosis using scanning electron microscopy. In: Congress Proceeding 12th ECVIM-CA/ESVIM Congress. Munich; Germany; 2002, p. 178. 16. Häggström J. New and Old treatment modalities of myxomatous mitral valve disease in dogs. Proceeding 21st Annual ACVIM Forum; Charlotte, NC; 2003.

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Echocardiographic Overview of Mitral Valve Disease Virginia Luis Fuentes

Echocardiographic Overview of Mitral Valve Disease Two-dimensional echocardiography (2D-echo) 2D-echo can be very helpful in the assessment of mitral valve disease, for both lesion identification and quantification of chamber dimensions.

Virginia Luis Fuentes MA, VetMB, PhD, CertVR, DVC, MRCVS, Diplomate ACVIM, Diplomate ECVIM (Cardiology)

Lesion identification The earliest change visible on 2D-echo is usually

RCVS Specialist in Veterinary Medicine

prolapse of the mitral valve leaflets, which bulge

Senior Lecturer in Internal Medicine

towards the left atrium, extending beyond a hypo-

Department of Veterinary Clinical Sciences

thetical line drawn across the mitral annulus3-7.

Royal Veterinary College, Hatfield, UK

Diffuse thickening of mitral valve leaflets with minimal

Clinical/Research interests: Echocardiography, Canine and Feline Myocardial Disease,

changes in chamber dimensions.

Vascular Ultrasound Contact: [email protected]

Right parasternal long axis view of normal mitral valve position at end-systole.

Severe ‘flail’ segment of anterior mitral valve leaflet, probably secondary to ruptured chord.

Right parasternal long axis view showing mitral valve prolapse.

Subjective thickening of the valve leaflets may be seen as the changes progress. With rupture of

Thickened mitral valve leaflet with remnant of ruptured chord

a chord, abnormal motion of the mitral valve

on left atrial side of mitral valve.

may be imaged (‘flail’ leaflet), or even remnants of the ruptured chord itself.

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Echocardiographic Overview of Mitral Valve Disease Virginia Luis Fuentes

Echocardiographic Overview of Mitral Valve Disease Virginia Luis Fuentes

Assessment of systolic function in mitral

Assessment of diastolic function in mitral regur-

regurgitation

gitation

It is particularly difficult to assess systolic func-

Diastolic function can also be difficult to assess

tion noninvasively in dogs with mitral regurgita-

in the setting of mitral regurgitation, as early

tion, as the loading conditions favour wall

rapid filling is increased in the setting of in-

motion even in the presence of intrinsic systolic

creased LA pressures or in mitral regurgitation.

dysfunction. Increased end-systolic dimensions

End-diastolic variables may be more helpful in

suggest a deterioration in systolic function, as

identifying increased filling pressures, and TDI

do fractional shortening values in the normal

may again prove useful9.

range2. Most small-breed dogs with more than moderate mitral regurgitation will have an apparently hyperdynamic LV. Tissue Doppler Imaging (TDI) may prove to be of value in the assessment of systolic function in this setting. The ‘sphericity’ of the left ventricle can be assessed when the ratio of the long axis dimension is compared with the short axis diameter.

References

Severe prolapse of both mitral and tricuspid valves with thick1. Häggström J, Hansson K, Karlberg BE, Kvart C, Olsson K:

6. Pedersen HD, Kristensen BO, Norby B, et al.

M-mode echocardiography

Plasma concentrations of atrial natriuretic peptide in relation

Echocardiographic Study of Mitral-Valve Prolapse in

M-mode echocardiography allows quantification

to severity of mitral regurgitation in Cavalier King Charles

Dachshunds. J Vet Med A Zbl Vet A Physiol 1996; 43: 103-110.

Quantitative 2D-echo

of LV size and wall motion, and increasing LV

Spaniels. Am J Vet Res 1994; 55: 698-703

7. Pedersen HD, Lorentzen KA, Kristensen BO,

M-mode echocardiography is generally used for

dilation can be documented with disease pro-

2. Kittleson MD, Eyster GE, Knowlen GG, Bari Olivier N,

Echocardiographic mitral valve prolapse in Cavalier King

Anderson LK. Myocardial function in small dogs with chronic

Charles Spaniels: epidemiology and prognostic significance for

quantification of chamber dimensions, but

gression. Wall thickeness generally remains

mitral regurgitation and severe congestive heart failure. J Am

regurgitation. Vet Record 1999; 144: 315-320

normal, indicating eccentric hypertrophy. In the

Vet Med Assoc 1984; 184: 455-459

8. Rishniw M, Erb HN. Evaluation of four 2-dimensional echo-

assessment of left atrial (LA) size and left ven-

initial stages, LV wall motion usually appears

3. Olsen LH, Fredholm M, Pedersen HD, Epidemiology and

cardiographic methods of assessing left atrial size in dogs. J Vet

tricular (LV) shape. As mitral valve disease in-

hyperdynamic.

inheritance of mitral valve prolapse in Dachshunds. J Vet Intern

Intern Med 2000; 14: 429-435

ened chordae and left heart volume overload.

2D-echo offers significant advantages in the 1,8

creases in severity, both LA and LV become more dilated, with a change in LV geometry that results in a more spherical chamber.

Doppler echocardiography Color Doppler echocardiography is useful for

Med 1999; 13: 448-456

9. Rossi A, Cicoira M, Golia G, Anselmi M, Zardioni P. Mitral

4. Pedersen HD, Häggström J, Mitral valve prolapse in the dog:

regurgitation and left ventricular diastolic dysfunction similarly

a model of mitral valve prolapse in man. Cardiovasc Res

affect mitral and pulmonary vein flow Doppler parameters: the

2000; 47: 234-243

advantage of end-diastolic markers. J Am Soc Echocardiogr

5. Pedersen HD, Kristensen BO, Lorentzen KA, Koch J, Jensen AL,

2001; 14: 562-568

documenting the jets of mitral and tricuspid

Flagstad A. Mitral valve prolapse in 3-year-old healthy Cavalier

insufficiency. Evaluation of the jet size relative to

King Charles Spaniels. An echocardiographic study. Can J Vet

atrial area gives a semi-quantitative estimate of

Res 1995; 59: 294-298

regurgitation severity. Other Doppler techniques (such as PISA) allow a more quantitative approach. Spectral Doppler is mainly of use for measurement of tricuspid regurgitation velocity, which allows estimation of pulmonary artery pressures. Pulmonary hypertension develops in some dogs with advanced mitral valve disease, and hastens the onset of right-sided congestive 2D-echo measurement of the left atrium may be more reliable

failure.

than M-mode.

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M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 1st part: Overview John E. Rush / Donald J. Brown

M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 1st part: Overview

Canine chronic valvular disease, the most com-

appreciate that the M-mode size of the left ven-

mon form of heart disease in dogs, leads to pro-

tricular internal dimension in diastole is 1.61

gressive cardiac enlargement and eventually

times the M-mode dimension of the aorta in a

congestive heart failure. Echocardiography has

normal dog. Another way to consider this is that

been used for many years to evaluate the size,

the ratio of the LVIDd/Ao will give you a number

John E. Rush

structure, and function of the heart. M-mode

of 1.61 in a normal dog, and that this number

DVM, MS, Diplomate ACVIM (Cardiology), Diplomate ACVECC

echocardiography was the first ultrasound

will increase in size if the diastolic size of the

modality to be popularized for cardiac mensura-

left ventricle increases and the aortic dimension

Professor and Associate Department Chair

tion, and it remains as the preferred method to

(measured or predicted) stays the same. Two

Department of Clinical Sciences

quantify left heart dimensions in most veterinary

aortic measurements can be used for comparison,

Tufts University School of Veterinary Medicine

clinical practices.

either the measured aorta from the M-mode

North Grafton, Massachusetts, USA

(aorta-based indices, noted as Aom) or the pre-

Specialty: Cardiology and Emergency/Critical Care

Dogs with heart disease can vary dramatically in

dicted size of the aorta for a dog of a certain

Clinical/Research interests: Chronic Valvular Disease, Dietary Manipulation of Heart Disease,

size, with some dogs weighing less than 2 kilo-

weight (weight-based indices, noted as Aow).

Drug Development for Heart Disease, Emergency Medicine and Critical Care

grams and others weighing nearly 100 kilograms.

Our studies and clinical experiences have lead to

To account for these within species differences

the conclusion that the weight-base indices are

in body and cardiac size, a number of methods

preferable for animals which approximate normal

have been used to create expected normal

body condition (BCS 3 to 7) and that animals

values for M-mode echocardiography. Equations

that are grossly obese or very thin are sometimes

to predict cardiac dimensions using linear

better evaluated using the aorta-based indices.

Co-author: Donald J. Brown DVM, PhD, SVM

Department of Clinical Sciences Tufts University School of Veterinary Medicine North Grafton, Massachusetts, USA

regression against body weight or body surface area have been used in many settings. However

In addition to the M-mode ERIs described above

this method can yield wide confidence intervals

for cardiac dimensions, several novel indices

leading to many dogs with clear cardiomegaly

were derived from short-axis area ratios. For

that are assessed as having normal cardiac

these measures, the short axis area of interest

dimensions. This is particularly true for very

was divided by the aortic root area, with both

small dogs.

numbers being derived from the M-mode echo study. Of these indices, w∆A has been identified

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1st International Canine Valvular Disease Symposium

M-mode echocardiographic ratio indices (ERIs)

to be a useful measure of left ventricular volume

have been developed as a method to better pre-

overload and has good ability to discriminate

dict normal cardiac dimensions for a particular

between normal dogs and dogs with chronic val-

individual and to more reliably evaluate for the

vular disease. The value for w∆A is obtained

presence of abnormal cardiac dimensions. The

using the formula w∆A = (LVIDd2 – LVIDs2)/Aow2.

basic tenant is that a measured M-mode value

To consider this measure another way, the area

(e.g., left ventricular internal dimension) is com-

(think volume) of blood pumped out of the left

pared to a relatively unchanging (or predicted)

ventricle relative to a 2-D plane alone (LVIDd2 –

structure (in this case, the aorta). This concept is

LVIDs2) is then divided by the cross sectional

quite similar to that used for the vertebral scale

area (again think volume) of the aorta and the

system, as reported by Buchanan and others, to

result is a ratio of these areas. As the left ventri-

evaluate cardiac enlargement by comparing car-

cle pumps more blood in response to a volume

diac size to the number of vertebral bodies.

overload, this ratio will increase. In addition,

Using the aorta as the dimension that all other

wLA may be useful to discriminate dogs with

measurements will be compared to, one can

congestive heart failure from dogs without con-

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M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 1st part: Overview John E. Rush / Donald J. Brown

M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 1st part: Overview John E. Rush / Donald J. Brown

gestive heart failure. wLA or other M-mode ERIs

asymptomatic dogs at risk of developing con-

LV =

left ventricle,

Aow = weight-based aortic root dimension cal-

may prove to be useful markers in clinical prac-

gestive heart failure.

IVS =

interventricular septum,

culated as k W1/3 where W is body mass (kg) and

tice or prospective clinical trials to identify

LVID = left ventricular internal dimension,

k is a species dependent constant equal to 0.795

LVW = left ventricular wall,

for dogs.

LVOD = left ventricular outer dimension,

Subscripts s and d refer to systolic and diastolic

LA =

determinations, respectively.

left atrial dimension,

ERI Calculation

Description

wRVd = RVd/Aow

Index of right ventricular internal dimension, diastole

wIVSd = IVSd/Aow

Index of interventricular septal thickness, diastole

wLVIDd = LVIDd/Aow

Index left ventricular internal dimension, diastole

wLVWd = LVWd/Aow

Index of left ventricular wall thickness, diastole

Buchanan JW, Bucheler J. Vertebral scale system to measure

Brown DJ, Rush JE, MacGregor JM, et al. M-mode echocardio-

wIVSs = IVSs/Aow

Index of interventricular septal thickness, systole

canine heart size on radiographs.

graphic ratio indices in normal dogs, cats, and horses: A novel

wLVIDs = LVIDs/Aow

Index of left ventricular internal dimension, systole

J Am Vet Med Assoc 1995: 206; 194.

quantitative method.

wLVWs = LVWs/Aow

Index of left ventricular wall thickness, systole

wAo = Aom/Aow

Index of aortic root dimension

wLA = LA/Aow

Index of left atrial dimension

References

J Vet Int Med 2003: 17; 653.

wLVODd = (IVSd+LVIDd+LVWd)/Aow Index of left ventricular outer dimension, diastole wLVODs = (IVSs+LVIDs+LVWs)/Aow

Index of left ventricular outer dimension, systole

wWTd = (IVSd+LVWd)/(k W1/3)

Index of combined septal and left ventricular wall thickness, diastole

wWTs = (IVSs+LVWs)/Aow

Index of combined septal and left ventricular wall thickness, systole

2

2

2

w∆A = (LVIDd – LVIDs )/Aow

Index of change in left ventricular internal area, i.e. short axis stroke area

wWAd = (LVODd2 – LVIDd2)/Aow2

Index of left ventricular short axis myocardial wall area, diastole

2

wWAs = (LVODs – LVIDs )/Aow

Index of left ventricular short axis myocardial wall area, systole

FS= (LVIDd – LVIDs)/LVIDd

Fractional shortening. Relative index of LV internal wall motion

FWTd = WTd/LVODd

Fractional LV myocardial wall thickness, diastole.

2

2

Relative index of LV wall thickness in diastole. FWTs = WTs/LVODs

Fractional LV myocardial wall thickness, systole. Relative index of LV wall thickness in systole.

2

2

2

F∆A = (LVIDd – LVIDs )/LVIDd

Fractional change in LV internal area. Relative index of LV wall motion.

2

2

2

FWAd = (LVODd – LVIDd )/(LVODd ) Fractional LV myocardial wall area (short axis), diastole. Relative index of LV wall thickness in diastole. 2

2

2

FWAs = (LVODs – LVIDs )/(LVODs )

Fractional LV myocardial wall area (short axis), systole.

F∆WA = (wWAs – wWAd) / wWAs

Fractional change in LV myocardial wall area (short axis).

Relative index of LV wall thickness in systole. Relative index of LV shortening in the longitudinal (long axis) direction. EF = (LVIDd3 – LVIDs3)/LVIDd3

Ejection fraction. Relative index of LV volume change.

Table 1: Description and calculation of M-mode echocardiographic ratio indices

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M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 2nd part: Clinical Experience and Possible Use Gérard LeBobinnec

M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 2nd part: Clinical Experience and Possible Use

Introduction: The starting point of treatment,

appear, and then can be modulated by treatment

“stumbling block” of MVD Therapy

in order to sometimes delay deleterious remodeling.

In spite of the application of ACE inhibitors and calcium sensitizer treatments in congestive

It is therefore tempting to use LA/AO modifica-

Gérard LeBobinnec

heart failure (CHF), there is a great question still

tions to initiate the treatment. But there is cur-

DVM, Diplomate ECVIM (Cardiology)

unsolved: when should the treatment be initiat-

rently no demonstration that this can delay the

ed? It has been demonstrated that ACEI and

onset of CHF.

Clinique Vétérinaire de l ’Alouette PESSAC, France

Pimobendan improve clinical status and prolong longevity in dogs with symptomatic CHF, whatever the aetiology is, DCM or MVD. About the

Interest of the new M-Mode echocardiographic

latter, the SVEP trial (strictly) demonstrated that

ratio indices:

Enalapril had unfortunately no preventive effect for developing CHF (KVART et al, JVIM, 2002). It

One of the main objection against the use of the

is then really difficult for the clinicians to define

(too) simple LA/AO index as a starting point for

a starting point of treatment, and many of them

treatment is that LA dilation is only one part of

go on ordering ACEI in asymptomatic MVD, not-

the disease. If left ventricle (LV) seems to be

withstanding this disappointing result.

implicated later, it is nevertheless probably a “master chessman” in the evolution of CHF.

However the enrolment criteria of the SVEP trial

That is the reason why a novel quantitative

were based on radiographic signs and on a

method is so interesting: based on the use of

modified NYHA scale. Yet, it is well known that

raw M-Mode measurements, the calculation of

radiography is not very reliable to evaluate the

“aorta based” indices is a way of evaluation of

entire left atrium (LA) and often overestimate it

LV modifications in MVI evolution.

(LOMBARD, Vet.Radiology, 1985). By now LA is essentially evaluated with the LA/Aorta ratio and

Left ventricular internal dimension in diastole

is one of the most simple criteria to estimate the

(LVIDd or more simply LVd) was preferred for the

severity of mitral regurgitation (MR) in MVD,

following reasons:

with a 2-D echo approach (right parasternal short axis transaortic view): in the now preferred

· Mitral regurgitation due to MVD leads to a

ISACHC classification, classes Ia and Ib of MVD

progressive volume overload of the LV. But in

can easily be distinguished with the limit of 1.6

volume overload, it was demonstrated that

(RISHNIW and ERB, JVIM, 2000). The main interest

systolic LV internal dimension (LVs), and there-

of using LA/AO ratio for classification of MVD is

fore the derived End Systolic Volume Index

first the simplicity of the method, and secondly

(ESVI) are not correlated with CHF evolution

the good correlation with other prognosis pa-

(AMBERGER and LOMBARD, ECVIM, 1996).

rameters: clinical parameters (murmur, heart rate variability); echo parameters (PISA, RJA);

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1st International Canine Valvular Disease Symposium

· Shortening Fraction is a poor indicator of

laboratory blood parameters (NT pro ANP, ANP,

volume overload, as for other aetiologies of

BNP, and NO). These laboratory parameters are

volume overload: the example of a surgically

important because, they prove in the present

reversible one (PDA) shows that only LVd is

cardio hormonal concept of CHF that endocrine

correctly correlated with CHF evolution (VAN

systems are already activated before symptoms

ISRAËL, 2003; VOLLMAR, 2003; GLAUS, 2003).

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M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 2nd part: Clinical Experience and Possible Use Gérard LeBobinnec

M-Mode Echocardiographic Ratio Indices in Canine Chronic Valvular Disease 2nd part: Clinical Experience and Possible Use Gérard LeBobinnec

· LV distension is the main factor of secretion of BNP which is another good indicator for the progression of MVD. A maximal limit value for the aorta based index for LV internal dimension in diastole (aLVIDd) was defined, based on the formula published by Brown et al (JVIM, 2003): aLVIDd = LVd /AO = 1.608 ± 0.202. No LV dilation: LVd/AO = 1.7

A maximal limit value of 1.8 was chosen with the aim to measure the time from LA/AO < 1.6 to LA/AO > 1.8, as well as the time between these 2 indices and ISACHC Class 2, with or without treatment.

Severe LV dilation: LVd/AO = 2.1

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Echocardiographic Estimation of Mean Left Atrial Pressure in Canine Mitral Regurgitation Mark A. Oyama

Echocardiographic Estimation of Mean Left Atrial Pressure in Canine Mitral Regurgitation

Elevated mean left atrial pressure (MLAP) second-

These properties become increasingly influential

ary to degenerative mitral valve disease (MVD) is

on MLAP as the amount of diastolic dysfunction

associated with clinically relevant morbidity and

within the LV increases. Accordingly, in diseases

mortality. The ability to non-invasively estimate

such as restrictive or hypertrophic cardiomyo-

MLAP would assist in the diagnosis and treatment

pathy, the potential effect on MLAP cannot be

Mark A. Oyama

of disease. In dogs with MVD, measurement of

ignored. In diseases that are primarily systolic or

DVM, Diplomate ACVIM (Cardiology)

MLAP is of considerable value in assessing the

valvular in nature (e.g. dilated cardiomyopathy

severity of cardiac dysfunction and monitoring

and MVD), the importance of diastolic dysfunc-

Assistant Professor

response to therapy. Currently, measurement of

tion has been increasingly recognized (Figure 2).

Department of Veterinary Clinical Medicine

MLAP (or its estimation from pulmonary capillary

College of Veterinary Medicine

wedge pressure) involves cardiac catheterization,

University of Illinois, Urbana, USA

an invasive procedure requiring specialized

Clinical/Research interests: Pathophysiology and Treatment of Canine Heart Disease,

equipment and technical ability. Doppler blood

Cellular Transplantation, Biomarkers of Cardiac Disease, Echocardiography

flow and tissue echocardiography permits the

Contact: [email protected]

measurement of early transmitral blood flow velocity (E) and the velocity of the mitral valve annulus (Ea). The ratio of these two values (E:Ea) correlates well with MLAP in human subjects. In this presentation, the theoretical basis of E:Ea and its ability to estimate MLAP in a canine

Figure 2. As the degree of diastolic function increases, so does

model of acute mitral regurgitation will be

the potential effect of left atrial pressure (LAP), and the need to

explored.

adjust measures of preload (i.e. max E) becomes necessary. In humans, the effect of diastolic function on LAP in cases of cardiomyopathy and myocardial infarction has been well descri-

Determinants of Mean Left Atrial Pressure

bed. Much less is known in cases of mitral regurgitation (MR),

Filling pressure in the left atrium and ventricle is

a disease not typically associated with a high degree of diasto-

predominantly a function of preload, however,

lic abnormalities.

MLAP is also dependent on the diastolic properties of the left ventricle (Figure 1).

Thus, accurate estimation of MLAP must incorporate measures of ventricular diastolic function as well as preload. Previous studies have reported a variety of diastolic alterations in subjects with severe MVD, including decreased elastic recoil and decreased ventricular stiffness. These changes highlight the potential importance of correcting measures of preload for changes in diastolic function in dogs with MVD.

Figure 1. Left atrial filling pressure (LAP) is the result of both preload (as measured by the maximum velocity of mitral inflow, E) and the diastolic properties of the receiving ventricle (as measured by the early mitral valve annulus motion, Ea ).

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Echocardiographic Estimation of Mean Left Atrial Pressure in Canine Mitral Regurgitation Mark A. Oyama

Echocardiographic Estimation of Mean Left Atrial Pressure in Canine Mitral Regurgitation Mark A. Oyama

Use of the E:Ea Ratio for Estimating MLAP

but the coefficient of determination (R2) for the

Max E is influenced by both MLAP and diastolic

linear regression equation using E:Ea was greater

function. Ea, as measured by Doppler tissue imag-

(0.83) vs. the linear regression equation using E

5.0

3.6

-6.4 to 13.6

ing (DTI) is relatively preload independent, and

(0.73). The relationship between E:Ea and MLAP

6.0

10.0

0.0 to 20.0

chronic MVD needs to be evaluated as does its

is therefore regarded as an index of ventricular

was described by the following regression equa-

7.0

16.4

6.4 to 26.4

application to other species and forms of heart

diastolic function. By combining the two measure-

tion (Figure 4):

8.0

22.8

12.8 to 32.8

disease (i.e. feline hypertrophic cardiomyopathy).

9.0

29.2

19.2 to 39.8

The relationship between E:Ea and other indirect

ments into a unitless ratio, E:Ea, the effects of

E/Ea

Predicted MLAP 95% CI for prediction (mm Hg)

(mm Hg)

Future Studies, Clinical Application, and Limitations The utility of E:Ea in dogs with naturally occurring

10.0

35.6

25.6 to 45.6

markers of MLAP (i.e. left atrial dimension,

in its place a value purely reflective of MLAP

11.0

41.9

31.9 to 51.9

NT-proANP) should be evaluated. If useful, E:Ea

(Figure 3).

12.0

48.3

38.3 to 58.3

could be used to help differentiate cases of

diastolic function can be removed from E, leaving

1) MLAPpredicted = 6.38 x (E:Ea) – 28.3

Table 1. Guidelines for predicting mean left atrial pressure (MLAP) from an echocardiographic measurement of E:Ea.

heart failure from respiratory disease, to monitor response to therapy, and to assess the effectiveness of new pharmaceuticals. Limitations of the method include the need for specialized ultra-

Our study revealed that in dogs with acute mitral

sound equipment capable of tissue Doppler

regurgitation, E:Ea >9.1 predicts MLAP

imaging, and the relative wide confidence inter-

>20mmHg, whereas E:Ea 15mmHg. Figure 4. Scatterplot of the relationship between E:Ea and Figure 3. Mitral inflow velocity (E) is obtained from Doppler

mean left atrial pressure (MLAP) for 7 dogs under isoflurane

blood flow interrogation and is influenced by the left atrial

anesthesia. Values for each dog were obtained after varying

pressure and diastolic function of the left ventricle. Early mitral

degrees of acute experimentally-induced mitral regurgitation

annular velocity (Ea) is obtained from Doppler tissue imaging

and after administration of nitroprusside or hydralazine to

and is influenced by diastolic function. By combining the two

change loading conditions. E:Ea is the ratio of E (early diastolic

Kim YJ et al. Mitral annulus velocity in the estimation of left ven-

Tibayan FA et al. Torsion dynamics in the evolution from acute to

values into a ratio, the effect of diastolic function is theoreti-

mitral inflow velocity) to Ea (the early mitral annulus velocity)

tricular filling pressure: prospective study in 200 patients. J Am

chronic mitral regurgitation. J Heart Valve Dis 2002 11(1):39-46.

cally removed and the left atrial pressure determined.

and is dimensionless. The linear regression line (solid) and

Soc Echocardiogr 2000 13(11):980-985.

Zile MR et al. Effects of left ventricular volume overload produ-

95% confidence interval for prediction (dashed) of MLAP from

Nagueh SF et al. Doppler tissue imaging: a noninvasive techni-

ced by mitral regurgitation on diastolic function. Am J Physiol

E:Ea also are depicted.

que for evaluation of left ventricular relaxation and estimation

1991 261(5 Pt 2):H1471-H1480.

Suggested Reading

of filling pressures. J Am Coll Cardiol 1997 30(6):1527-1533.

Zile MR et al. Changes in diastolic function during develop-

Estimation of MLAP in Canine Mitral

Based on the regression equation and standard

Ommen SR et al. Clinical utility of Doppler echocardiography

ment and correction of chronic LV volume overload produced by

Regurgitation

error of the estimates, guidelines for predicting

and tissue Doppler imaging in the estimation of left ventricular

mitral regurgitation. Circ 1993 87(4):1378-1388.

The ability of E:Ea to estimate MLAP was investi-

MLAP (and the 95% confidence interval for the

filling pressures: A comparative simultaneous Doppler-cathet-

gated in 7 anesthetized dogs with experimentally

predicted value) from an echocardiographic

created acute mitral valve regurgitation.

measurement of E:Ea were developed (Table 1).

Sequential mitral chordae tendineae rupture and

erization study. Circ 2000 102(15):1788-1794. Oyama MA et al. Echocardiographic estimation of mean left atrial pressure in a canine model of acute mitral valve insufficiency. J Vet Int Med. 2004 18(5): In press for Sept/Oct 2004.

IV vasodilator therapy (nitroprusside or hydralazine) was used to produce 40 different MLAP measurements. Percutaneous atrial septostomy was used to introduce a balloon-tipped catheter into the left atrial chamber and directly measure MLAP. Results of this study demonstrated that both E and E:Ea were linearly related with MLAP,

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Diagnostic Value of Pulmonary Transit Times in Mitral Regurgitation Jens Häggström

Diagnostic Value of Pulmonary Transit Times in Mitral Regurgitation

The assessment of myocardial and pump func-

failure is present and the sympathetic nervous

tion in dogs with mitral regurgitation (MR) due

system is activated to increase apparent con-

to myxomatous mitral valve (MMVD) disease

tractility, even these measurements overestimate

would be useful in grading severity for both clin-

intrinsic myocardial contractility(4). Thus, there is

ical and research purposes. The presence of

a need for a physiologically-based index of over-

Jens Häggström

myocardial or pump dysfunction in compensat-

all cardiac function in MR.

DVM, PhD, Diplomate ECVIM (Cardiology)

ed MR and mild failure still is uncertain. It has been suggested that myocardial systolic function

The transit time of blood (t) through an organ is

Professor Internal Medicine

is comparably (to other types of heart disease)

determined by the flow (F) and the blood volume

Department of Clinical Sciences, Small Animals

well preserved because the ejection into the left

(V) of the organ: t=V/F. Pulmonary transit times

Faculty of Veterinary Medicine and Animal Science

atrium at low pressure require relatively little

(PTT) have been studied since the early days of

Swedish University of Agricultural Sciences, Uppsala, Sweden

work by the left ventricle

Speciality: Cardiology

may tolerate even severe MR for years(3). Neverthe-

gamma camera has been used. The latter

Clinical/Research interests: Mitral Valve Disease in Dogs, Pathophysiology of Heart Failure,

less, because of chronic volume overload and the

method enables sampling, by use of regions of

Therapy of Heart Failure

fact that the hypertrophy, while necessary, is a

interest (ROI), from the pulmonary artery and

Contact: [email protected]

pathologic remodeling, myocardial contractility

left atrium to exclude the prolonging effect on

is believed to decrease slowly, even in clinically

the transit time of the cardiac volumes(8). When

compensated dogs, but progressively and

the transit times were expressed in terms of

inexorably(2, 4).

mean R-R interval (mRR), nPTT (PTT/mRR =

(1, 2)

. Canine patients

cardiac catheterization(7), but more recently the

nPTT) instead of time, these and other studies

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1st International Canine Valvular Disease Symposium

Myocardial function is routinely assessed using

found that the normal value was a constant of

echocardiography in veterinary practice.

5-7 in normal humans and in mammals of vastly

However, in MR the myocardial function is not

different sizes(9-11). Even exercise in normal

easily assessed using this method. There is a

humans did not affect nPTT(12). In heart failure

problem with wide reference ranges for normal

caused by a wide variety of natural and induced

cardiac chamber dimensions, which often have

diseases in the species mentioned above, the

to be related to the body weight(5). An increase in

nPTT and cardiopulmonary flow index were

left ventricular end-diastolic dimension in the

increased(8). The nPTT may be regarded as the

presence of normal or minimally increased left

number of stroke volumes (SV) that the pulmo-

ventricular end-systolic dimension is usually the

nary vascular bed holds at any given moment,

consequence of increased preload and rapid left

by the relationship: nPTT = PTT/mRR, =

ventricular emptying into the low-pressure left

(PBV/CO)/mRR, = (PBV/SV x HR)/mRR, = PBV/SV.

atrium(3, 6). Values of ejection phase indices (e.g.,

Where, HR = heart rate, CO = cardiac output,

left ventricular fractional shortening, ejection

and pulmonary blood volume (PBV) = PTT x CO.

fraction, and mean velocity of circumferential

NPTT is a dimensionless unit and the relationship

shortening) are often normal (mild MR) or grea-

between nPTT, PBV and SV can be described by

ter than normal (moderate to severe MR). End-

this example: a red blood cell is pushed from the

systolic volume indices (e.g. left ventricular end-

pulmonary trunk through the lung to the left

systolic short axis dimension or end-systolic

atrium, moving with each heart beat a certain

volume index) are suggested to more accurately

distance which is determined by the blood volume

estimate myocardial contractility in MR(3, 6). By

in each of the parts of the central circulation

this parameter, myocardial failure occurs only

(pulmonary arteries, vascular bed and veins) and

late, in severe cases of MR. However, when heart

the SV behind it. With increased nPTT, it takes

1st International Canine Valvular Disease Symposium

39

Diagnostic Value of Pulmonary Transit Times in Mitral Regurgitation Jens Häggström

Diagnostic Value of Pulmonary Transit Times in Mitral Regurgitation Jens Häggström

References

more heart beats than normal to pump any

tone of the pulmonary vascular bed(15, 16). This

given unit of blood through the pulmonary

finding and the fact that the compensated dogs

1. Braunwald E. Valvular Heart Disease. In: Braunwald E, Ed.

11. Gotoh K, Hirano A, Hirakawa S. Non-invasive estimation of

vascular bed. The pulmonary vascular bed holds

were free of clinical or radiographical signs of

Heart disease. 5 ed. Philadeplphia: WB Saunders Co; 1997.

the human pulmonary blood volume with gamma camera and

more SV than normal. Either forward SV is

congestion make it less likely that they had

p. 1019-1020.

RI-angiocardiography. Jpn Circ J 1981;42:113-119.

decreased, PBV is increased, or both changes occur.

2. Sisson D, Kvart C, Darke P. Aquired valvular heart disease in

12. Iskandrian A, Hakki A, Kane S, et al. Changes in pulmonary

increased PBV, and more likely they had decreased

dogs and cats. In: Fox P, Sisson D, Moise N, Eds. Textbook of

blood volume during upright exercise. Clinical implications.

SV. If this is the case, the HR must be increased

canine and feline cardiology. 2nd ed. Philadelphia: WB

Chest 1982;82:54-58.

to maintain normal cardiac output. However,

Saunders Co; 1999. p. 536-565.

13. Lord P, Eriksson A, Häggström J, et al. Increased pulmonary

3. Kvart C, Häggström J. Acquired Valvular Heart Disease. In:

transit times in dogs with mitral regurgitation indicate decrea-

Inspired by the problems involved with estimat-

although we have previously reported a trend

Ettinger S, Feldman E, Eds. Textbook of Veterinary Internal

sed pump function before failure. Accepted J Vet Intern Med.

ing overall cardiac pump function in MR with

towards decreased heart rate variability in clini-

Medicine. Diseases of Dogs and Cats. 5th ed. Philadelphia:

2003.

cally compensated MR dogs, the heart rates

WB Saunders Co; 2000. p. 787-800.

14. Milne E. Some new concepts of pulmonary blood flow and

4. Urabe Y, Mann DL, Kent RL, et al. Cellular and ventricular

volume. Radiol Clin North Am 1978;16:515-536.

non-invasive methods, we have recently completed a study concerning pulmonary transit

were not different in these dogs compared to

times in dogs with MR attributable to MMVD in

normal controls(17), and atrial natriuretic peptide

Cavaliers(13). We measured PTT and nPTT by first pass radionuclide angiocardiography (FPRNA)

contractile dysfunction in experimental canine mitral regurgita-

15. Hirakawa S, Suzuki T, Gotoh K, et al. Human pulmonary

tion. Circ Res 1992;70:131-47.

vascular and venous compliances are reduced before and

(ANP) concentrations were minimally increased(18).

5. Cornell C, Kittleson M, Della Torre P, et al. Allometric scaling

during left-sided heart failure. J Appl Physiol 1995;78:323-333.

This indicated a comparably small impact of the

of M-mode cardiac measurements in normal adult dogs. J Vet

16. Moraes D, Colucci W, Givertz M. Secondary pulmonary

Intern Med 2004;18:311-321.

hypertension in chronic heart failure: the role of the endothe-

performed concurrently with ECG recordings.

MR on overall circulation, i.e. forward SV (as

6. Kittleson M, Knowlen GG, Bari Olivier N, et al. Myocardial

lium in pathophysiology and management. Circulation

The FPRNA was acquired as a dynamic study and

indicated by the heart rate) and pulmonary

function in small dogs with chronic mitral regurgitation and

2000;102:1718-1723.

was analyzed using a computer program written

venous pressure (as indicated by ANP levels).

severe congestive heart failure. J Am Vet Med Assoc. 1984

17. Häggström J, Hamlin RL, Hansson K, et al. Heart-rate varia-

for use with standard nuclear medicine software.

Thus, either the dogs classified as compensated

15;184:455-459.

bility in relation to severity of mitral regurgitation in the

We found that, in normal control dogs, the asso-

were not truly compensated (they may have had

7. Zierler K. Indicator dilution methods for measuring blood

Cavalier King Charles Spaniel. J Small Anim Pract 1996;37:69-75.

ciation between PTT and mRR was constant, but

decreased cardiac output without clinical signs),

there was no correlation between nPTT and mRR. These results show that the ratio nPTT = PTT/mRR is a constant for normal dogs. Age,

flow, volume, and other properties of biological systems: a brief

18. Häggström J, Hansson K, Kvart C, et al. Secretion patterns of

history and memoir. Ann Biol Eng 2000;28:836-848.

the natriuretic peptides in naturally acquired mitral regurgita-

or, more likely, they have a small increase in

8. Hannan W, Vojacek J, Connell H, et al. Radionuclide determi-

tion attributable to chronic valvular disease in dogs. J Vet

heart rate that is difficult to detect owing to the

ned pulmonary blood volume in ischaemic heart disease. Thorax

Cardiol 2000;2:7-16.

great overall variation in heart rate.

gender, and weight did not affect the associa-

1981;36:922-927.

19. Bilotta F, Fiorani L, Lendaro E, et al. Pulmonary transit of

9. Giuntini C, Lewis M, Sales Luis A, et al. A study of the pulmo-

sonicated albumin microbubbles during controlled mechanical

nary blood volume in man by quantitative radiocardiography.

ventilation: a transthoracic echocardiographic study. Anesth

Is measurement of pulmonary transit times a

J Clin Invest 1963;42:1589-1605.

Analg. 1999 Aug;89:273-277.

dogs with MR, instead of increasing propor-

future method for evaluating overall pump func-

10. Lewis M, Gnoj J, Fisher V, et al. Determinants of pulmonary

tionately with increasing mRRs, increased more,

tion in routine veterinary practice? In our study

lying above the line of identity of the normal

we used a radionuclear method and a gamma-

dogs. In dogs with compensated MR, nPTT

camera to obtain the transit times. Naturally,

ranged from 4.0 to 9.7, mean 6.3 ± 1.6, and

this type of method and equipment is not readily

those with decompensated MR from 8.0 to 18.8,

applied in routine practice for several reasons.

mean 11.8 ± 3.4.

However, transit times may in the future be

tion. Normal nPTT was 4.4 ± 0.6. The PTTs in

blood volume. J Clin Invest 1970;49:170-182.

obtained from other methods. For instance, As mentioned above, these results with increased

transit times may be obtained from the echocar-

nPPT indicate that SV or PBV, or both, are in-

diogram using an intravenous contrast agent

creased already in clinically compensated MR

and a high-end echocardiographic equipment(19).

dogs. Although the pulmonary vascular bed may

It is likely that the transit times correlate with

be distended, i.e. congested, due to high pulmo-

some other, more easily obtained variable.

nary venous capillary pressures in left ventricular

Future research may indicate that the transit

(8)

failure , or increased flow may occur in left to

times may even be substituted for such a variable.

right shunt or fluid overload(14), studies have reported that PBV was not increased in failure, as a result of reduced compliance or increased

40

1st International Canine Valvular Disease Symposium

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Quantification of Mitral Regurgitant Volume and Effective Orifice Area using the Proximal Isovelocity Surface Area (PISA) Method Mark A. Oyama

Quantification of Mitral Regurgitant Volume and Effective Orifice Area using the Proximal Isovelocity Surface Area (PISA) Method

Myxomatous mitral valve disease (MVD) is the most common cardiac affliction of older smallbreed dogs, and in the most severe cases, is characterized by progressive mitral regurgitation, cardiac hypertrophy, activation of neurohormonal

Mark A. Oyama

responses, fluid retention, and congestive heart

DVM, Diplomate ACVIM (Cardiology)

failure. Typically, evaluation of MVD is accomplished using radiography, electrocardiography

Assistant Professor

and echocardiography. The information collected

Department of Veterinary Clinical Medicine

during the echocardiographic exam is both

College of Veterinary Medicine

quantitative and qualitative in nature. While

University of Illinois, Urbana, USA

many aspects of cardiac function have estab-

city (Va). The velocity of elements and the radius of the hemis-

Clinical/Research interests: Pathophysiology and Treatment of Canine Heart Disease,

lished quantitative indices of performance (e.g.

phere they form are inversely proportional. Thus, at distances

Cellular Transplantation, Biomarkers of Cardiac Disease, Echocardiography

quantification of contractility via fractional short-

closest to the orifice, elements are moving at a higher and hig-

Contact: [email protected]

ening), the assessment of other parameters,

Figure 1. Blood elements accelerate as they approach the mitral regurgitant orifice. At any given distance from the orifice, blood elements form a hemisphere defined by a specific velo-

her velocities and form ever smaller hemispheres.

including severity of MVD, is more subjective.

By measuring the radius of the shell at a known

Often, MVD is qualified as mild, moderate or

velocity (Va), the maximal rate of flow (Qmax)

severe based on the size of the left atrium and

through the regurgitant area can be calculated as

extent of the color flow Doppler signal, rather

the product of hemisphere surface area and

than by direct quantification of the regurgitant

velocity (Figure 2).

volume or orifice area. The ability to non-invasively measure regurgitant volume would permit an examiner to better assess disease progression, drug efficacy and response to therapy. This presentation will review the potential of the proximal isovelocity surface area (PISA) method in quantifying mitral regurgitant volume in dogs with experimental MVD. PISA Method and Experimental Results In 1991, Recusani et al. and Utsunomiya et al.

Figure 2.

reported on a novel echocardiographic technique to quantify mitral regurgitant volume and

1) Qmax = (2 π r2) x Va

orifice area in humans with valvular disease, the PISA method. PISA utilizes the regurgitant

Spectral Doppler tracings of the mitral regurgitant

Doppler color flow signal across the defective

jet yield the duration of regurgitation (t) as well

valve. This hemispherical signal represents an

as the peak velocity of regurgitant flow (VMRmax).

isovelocity shell, whose surface area marks

From these values, the regurgitant volume (RV)

blood elements that are moving towards the

and regurgitant orifice area (ROA) can be derived.

valve at an identical velocity (Figure 1). The radius of the hemispherical signal is measured

2) RV = Qmax x t

as it converges towards the regurgitant orifice. 3) ROA = Qmax / VMRmax

42

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1st International Canine Valvular Disease Symposium

43

Quantification of Mitral Regurgitant Volume and Effective Orifice Area using the Proximal Isovelocity Surface Area (PISA) Method Mark A. Oyama

Quantification of Mitral Regurgitant Volume and Effective Orifice Area using the Proximal Isovelocity Surface Area (PISA) Method Mark A. Oyama

To validate and assess the utility of the modified The validity of the PISA technique is highly

PISA technique, the PISA-derived regurgitant

dependent on which particular color flow hemi-

volume was compared to the value calculated

sphere is selected for measurement. Often, it is

from single-plane angiography in 8 dogs with

difficult to determine the velocity that forms the

experimentally created mitral regurgitation.

most accurate isovelocity shell. This difficulty is

Using a combination of sequential chordae ten-

compounded by deformation of the hemispheri-

dineae rupture and vasodilatory therapy (IV

cal Doppler signal by the lateral walls of the left

hydralazine or nitroprusside), 25 different levels

ventricle and by the geometry of the regurgitant

of mitral regurgitation were produced in the 8

orifice. Qmax is overestimated due to lateral

dogs. Regurgitant volume calculated by the

compression of a Doppler signal that measured

modified PISA method correlated well with results calculated from single plane angiography

far from the regurgitant orifice, while radial comFigure 4. A color M-mode image (right-hand frame) is construc-

pression of the isovelocity shell will underestimate Qmax in areas near the regurgitant orifice.

ted from the 2D color flow image along a line extending from Figure 3. A) In the idealized situation, blood elements form

These variables can dramatically alter the calcu-

perfectly symmetrical hemispheres as they approach the mitral

lated regurgitant volume. In order to circumvent

valve orifice and the operator is free to choose any velocity (V)

these difficulties, a modified PISA technique that

at which to measure the flow rate through the valve (Q).

simultaneously measures multiple isovelocity

B) In reality, as blood approaches the valve orifice, the hemispheres are radially compressed, resulting in the underestima-

shells can be employed. By doing so, the regions

tion of their surface area and resultant flow (hemisphere 3).

of over and underestimation can be clearly identi-

C) In addition, at distance from the valve orifice, the lateral

fied and the true Qmax can be calculated (Figure

the mitral valve orifice into the LV chamber. Using electronic

superior to those derived from the traditional

calipers, the operator can derive multiple sets of velocities and

PISA method in which the operator attempted to

hemisphere radii ([V1, R2], [V2, R2], etc.) along the M-mode axis. These sets of data represent hemispheres that both over

ment (P=0.018, R=0.51 vs. angiography). With

contains the “ideal” hemisphere that reflects the true flow rate

respect to the ability to longitudinally track

(See Figure 5).

changes in the regurgitant volume after chordae rupture or vasodilatory therapy, the modified PISA method demonstrated close agreement

ting in the overestimation of surface area and flow rates (hemisphere 1). The ideal hemisphere (#2) lies between the

by Schwammenthal et al., we have demonstrated

two extremes and can be derived mathematically.

visually select the ideal hemisphere for measure-

and underestimate the true regurgitant flow rate as well as

walls of the LV constrain the formation of hemispheres, resul-

3). Using a modified PISA method first proposed

and thermodilution (PLVEDD/wall thickness) response

CHF, typically from pressure overloads or ischemic

that initially fosters an adaptive enlargement of

cardiomyopathies, to dogs with volume overload

the LV. In contrast, pressure overload creates an

is of limited relevance to our understanding of

increase in systolic wall stress that result in a

mitral valve disease of dogs. The distinction is

greater increase in wall thickness and more con-

particularly important early in remodeling, before

centric hypertrophy pattern (< LVEDD/wt). In this

the onset of severe clinical signs.

process, a complex sequence of compensatory events results in a continual state of remodeling

NIH funding for MR research using the dog

of the extra cellular matrix (EMC) that oppose

model has greatly benefited our understanding

excess collagen deposition in volume overload

of mitral valve disease in both dogs and humans.

and favor excess collagen deposition in pressure

The finding that the cardiac RAS systems in

overload. Nevertheless, left untreated, both

humans is different from that of rats, mice, and

result in a progressive dilation and hypertrophy

rabbits but close to that of the dog is useful.

characterized by a disproportionate increase in

Human patients with chronic degenerative MR

the LVEDD/wt ration, increased myocardial wall

are challenged with the decision as to when to

stress, and development of congestive heart

have valve replacement. (Many humans with MR

failure.

also have co-morbidity factors of ischemic dis-

52

1st International Canine Valvular Disease Symposium

ease and/or aortic regurgitation.) However, in

The integrity of the EMC has profound effects on

myxomatous disease, there continues to be

the contractile properties of the heart. The dynam-

uncertainty in humans about the ability of vaso-

ic plasticity of the ECM is maintained not only

dilator therapy to obviate or delay the need for

by changes in collagen structure and accumula-

1st International Canine Valvular Disease Symposium

53

Cardiac Remodeling in Canine Mitral Valve Volume Overload A. Ray Dillon

Cardiac Remodeling in Canine Mitral Valve Volume Overload A. Ray Dillon

tion, but also by two functional classes of mole-

We have demonstrated that before dogs develop

Chymase in the dog, but not in many other

demonstrated to be markedly higher than any

cules matrix metalloproteinases (MMPs) that

clinical disease from MR (experimental MR and

mammals, is similar to humans.

concentration in plasma, kidneys, or coronary

degrade the fibers and proteins that inhibit MMP

spontaneous MR), these above mechanisms

We examined the contributions of ACE vs chy-

arteries. Blocking experiments demonstrated a

(TIMPs). We have demonstrated in dogs with

have resulted in almost complete loss of the

mase to ANG II generation in membrane prepa-

different mechanism of conversion in the arte-

volume overload that an influx of mast cells,

EMC, increased myocardial stretch, initiation of

rations from LVs of human, dog, rabbit, rat and

ries than cardiac interstitium, confirming a para-

increase in MMPs, and decrease in TIMPs results

global remodeling and LV hypertrophy, increased

mouse. Figure 1 shows that > 90 % ANG II for-

crine effect of the renin-ANG system. LV chymase

in a rapid loss of EMC, increased LV compliance,

myocardial integrins, decreasing forward SV, and

mation was from chymase in human and dog

and ANG expression is up-regulated in dogs

myofiber slippage, myocyte hypertrophy, and

increased regurgitant fraction; all in the face of

hearts, while > 90 % was from ACE in rat, mouse

with MR.

decreased total LV contraction. Evident supports

normal myocyte contractility based on isolated

and rabbit hearts.

local paracrine activation of many of these

myocyte studies. The progression of the LV

mechanisms independent of hemodynamic

remodeling increases the regurgitant orifice, increases the regurgitant fraction, increases Paw,

uli set in motion a sequence of biochemical and

and with significant loss of the ECM, results in

inflammatory events in the interstitium that

“unconnected” myocytes with decompensated

dictate the changes that occur in the EMC.

heart failure. Attenuation by successful treatments

Norepinephrine, bradykinin, and reactive

of cardiac remodeling in human and animal

inflammatory species increase expression of

models of pressure overload and in ischemic

MMP 1, 2 and 9, while mechanical stretch of

cardiomyopathies have not been found to be

cardiac fibroblasts stimulates membrane MMP.

significant factors in volume overloads, and may

The activation of pro-MMP involves proteolytic

be in some classes of drugs detrimental. Based

cleavage, particularly by other MMPs and mast

on comparison of sine cardiac MRI and hemo-

cell chymase. TIMP 4 expression is differentially

dynamic studies, to the molecular mechanisms

regulated by hemodynamic stress of pressure

involved in volume overload cardiac remodeling,

fected by ACE inhibitor therapy in the dog. 18 adult dogs were sacrificed after 5 months of

80 % ANG II formation

relief from local wall stress. Hemodynamic stim-

Volume overload cardiac hypertrophy is unaf100

MR: 11 untreated (MR), 7 treated with the ACE inhibitor ramipril (MR+R), 11 shams. Serial cine-

60

magnetic resonance imaging demonstrated a similar 30 % increase in LV mass in the MR+R

40

and MR dogs. LV mass/volume ratio decreased significantly in both MR and MR+R groups in

20

spite of significant decreases in mean pulmonary artery (PA) pressure (13±1 vs 21±3 mmHg,

0 Mouse

Rabbit

Rat

Dog

Human

p