Assessment of Diastolic Function by Doppler Echocardiography in Normal Doberman Pinschers and Doberman Pinschers with Dilated Cardiomyopathy

O'Sullivan, M. L., O'Grady, M. R. and Minors, S. L. (2007), Assessment of Diastolic Function by Doppler Echocardiography in Normal Doberman Pinschers and Doberman Pinschers with Dilated Cardiomyopathy.

                                                                                                              Journal of Veterinary Internal Medicine, 21: 81–91.

                                                                                                             doi: 10.1111/j.1939-1676.2007.tb02932.x

Assessment  of  diastolic  function  in  patients  with  dilated  cardiomyopathy  (DCM)  has  the  potential  to  add
valuable information regarding hemodynamics, disease severity, and prognosis. The purpose of this study was to determine transmitral flow (TMF), isovolumic relaxation time (IVRT), pulmonary venous flow (PVF), flow propagation velocity (Vp), and mitral annular velocities by tissue Doppler in Doberman Pinschers with and without DCM. Hypothesis:
It was anticipated that normal and DCM Dobermans would differ with respect to these parameters, and that
associations with time to congestive heart failure (CHF) or death would be found.
Thirty client-owned Doberman Pinschers (10 each of normal, occult DCM, and overt DCM) were studied.
Each dog underwent echocardiography with or without thoracic radiography (to confirm CHF) for classification as normal or DCM-affected, followed by collection of echocardiographic diastolic parameters.
The group with occult DCM exhibited features of pseudonormal TMF, reduced systolic to diastolic PVF ratio, and
reduced Vp. Shorter early TMF deceleration time (DTE) was associated with shorter time to CHF or sudden death. The group with  overt  DCM  exhibited  restrictive  TMF,  blunted  systolic  PVF,  and  reduced  early  and  late  diastolic  mitral  annular velocities.
Conclusions and Clinical Importance:
Doberman Pinschers showed evidence of moderate and severe diastolic dysf unction in occult and overt DCM, respectively. Short DTE may be a useful predictor of onset of CHF or sudden death.
Key words:
Canine; Flow propagation velocity; Pulmonary venous flow; Tissue Doppler imaging; Transmitral flow.


Idiopathic dilated cardiomyopathy (DCM) is a primary   myocardial   disease   characterized   by   systolic dysfunction  and  secondary  eccentric  hypertrophy  of  1 or  both  ventricles  in  the  absence  of  a  definable  cause, likely representing a common expression of myocardial damage  produced  by  a  variety  of  unestablished  myo-cardial   insults   or   genetic   derangements.1 Doberman Pinschers present a unique opportunity for investigation of  this  disease  due  to  the  high  incidence  (up  to  50%) experienced by this breed.2 The natural history of DCM is characterized by an occult phase during which there is echocardiographic  or  electrocardiographic  (eg,  ventric-
ular tachyarrhythmias) evidence of cardiomyopathy but no  clinical  signs  of  disease.  Progression  of  the  disease
leads  ultimately  to  the  overt  phase  during  which  dogs experience  signs  of  congestive  heart  failure  (CHF)  or
sudden  death  (SD).  Diastolic  dysfunction,  defined  as increased  resistance  to  filling  of  1  or  both  ventricles,
likely plays an important role in the transition between occult and overt disease, promoting pulmonary congestion  and  exacerbating  arrhythmias.3 Diastolic  dysfunction also may become manifest very early in the disease process,  even  before  clinically  detectable  systolic  dysfunction can be identified by standard echocardiographic measures.4
Characterization of diastolic function thus may  be  useful  in  the  assessment  of  DCM  patients, potentially  yielding  valuable  information  about  hemodynamics,  disease  severity,  therapeutic  response,  and prognosis.

Doppler   echocardiography   combining   transmitral flow  (TMF),  isovolumic  relaxation  time  (IVRT),  and pulmonary venous flow (PVF) is accepted as a reliable, reproducible, and practical means of assessing diastolic function  in  humans.5–9 Many  of  these  indices  correlate closely   with   symptom   status   and   have   utility   in predicting   prognosis   and   therapeutic   response.5,10–14 Noninvasive  assessment  of  diastolic  function  may  be enhanced, however, by the measurement of left ventricular (LV) flow propagation velocity (Vp) with color M-mode  echocardiography  and  mitral  annular  motion  by tissue Doppler imaging (TDI), because these indices are cited    as    being    preload    independent    unlike    those above.7,15–17 A  small  number  of  veterinary  studies  have
described TMF and PVF, 18,19 and myocardial motion by TDI 20 in normal dogs. Limited studies involving canine
DCM patients have evaluated TMF or PVF, 21–23 and the utility   of   TDI   has   been   demonstrated   in   the   early
diagnosis  of  puppies  affected  with  Golden  Retriever Muscular Dystrophy (GRMD).4 To the authors’ knowledge,  a  comprehensive  noninvasive  assessment  of  diastolic function incorporating all of the aforementioned modalities  in  naturally  occurring  canine  DCM  has  not been reported.

The  purpose  of  this  study  was  to  describe  diastolic function  by  means  of  a  combination  of  echocardio-graphic  indices  (TMF,  IVRT,  PVF,  Vp,  and  TDI)  in Doberman Pinschers with occult DCM and overt DCM in comparison with normal Doberman Pinschers, and to investigate  the  presence  of  any  associations  between
these indices and prognosis.


Materials and Methods

The   study   protocol   was   approved   by   the   Animal   Care Committee  of  the  University  of  Guelph,  and  informed  consent was obtained from all owners.


All   patients   were   client-owned   Doberman   Pinschers 20 months  of  age  examined  between  March  2001  and  May  2002  at the  Small  Animal  Teaching  Hospital  of  the  Ontario  Veterinary College,  University  of  Guelph.  Each  dog  underwent  a  physical examination, 9-lead ECG, and echocardiography. Echocardiography for  screening  was  performed  by  an  experienced  echocardiographer   (MRO)   on   dogs   manually   restrained   in   right   lateral
recumbency   with   an   echocardiographic   system   equipped   with either a 2–4 or 3–5 MHz transducer. a A2 - dimensional guided M-mode  examination  from  the  right  parasternal  long-axis  view  was used to measure LV internal dimension in diastole (LVIDd) and in systole  (LVIDs),  and  fractional  shortening  (FS)  was  calculated.
The average of 3 measurements, with reacquisition of the image for each, was used.  Dogs were  included  in  the  normal group  (NL) if they were free of clinical signs of cardiac disease and if all of the following   criteria   were   met:   LVIDd,42.7 mm   for   males   or ,40.9 mm for females; LVIDs,34.7 mm for males or,33.1 mm for  females;  and  no  ventricular  premature  beats  during  the  ECG and  echocardiogram. b,c Dogs  were  included  in  the  occult  DCM group  (OccDCM)  if  they  were  free  of  clinical  signs  of  cardiac disease and if the following criteria for LV enlargement were met: LVIDd .49 mm or LVIDs.42 mm.d Dogs were included in the overt  DCM  group  (OvDCM)  if  all  of  the  following  criteria  were met:  LV  enlargement  as  above  for  the  occult  DCM  group;  FS#16%;  respiratory  clinical  signs  (any  of  cough,  wheeze,  dyspnea, orthopnea);   and   radiographic   evidence   of  pulmonary   edema. Exclusion  criteria  included  evidence  of  mitral  valve  disease  (ie, marked  mitral  regurgitation,  abnormal  mitral  valve  morphology, and  exuberant  septal  motion),  any  cardiac  disease  other  than
DCM,   or   the   presence   of   atrial   fibrillation.   The   medications received by and the diets fed to the dogs were not standardized. All OccDCM   dogs   were   receiving   angiotensin-converting   enzyme inhibitors (ACEI), and 2 were receiving beta-blockers at the time of   examination.   All   OvDCM   dogs   were   receiving   ACEI   and furosemide;   and   3   were   also   on   sotalol;   1   was   also   on spironolactone; and 1 had received a dobutamine infusion within
the previous 48 hours.


Echocardiographic Measurements of Diastolic Function

All  echocardiographic  examinations  of  diastolic  function  were performed  by  1  experienced  echocardio-grapher  (MLO).  Patients were restrained manually in left lateral recumbency and the same echocardiographic  system  equipped  with  a  2–4 MHz  transducer was  used.a All  indices  were  acquired  from  the  apical  4-chamber
view, except IVRT, which was obtained from the apical 5-chamber view. Continuous wave (CW) and pulsed wave (PW) Doppler and color M-mode recordings were made at a sweep speed of 100 mm/s. Three observations, with reacquisition of the image, were obtained for each parameter, and the average was used in data analysis. R-wave to R-wave intervals, both preceding and including the cycles used  for  measurement,  were  recorded  to  calculate  instantaneous heart  rate.  All  measurements  were  performed  at  end-expiration with the aid of a respiratory monitor. All TMF, IVRT, and PVF measurements were performed as described by Rakowski et al 6 and with  the  aid   of  a  technical  guide. 24 Color  M-mode  LV  flow propagation and TDI measurements were performed according to
Garcia et al.15



In brief, TMF was recorded with PW spectral Doppler with a 2-mm-long  sample  volume  placed  at  the  tips  of  the  open  mitral valve  leaflets.  Color  Doppler  was  used  to  help  align  the  cursor parallel   to   mitral   inflow.   Measurements   included   peak   early (E)  and  late  (A)  diastolic  filling  velocities,  the  duration  of  the late-filling wave (A dur), and deceleration time of the early-filling wave  (DTE)  (Fig 1).  The  ratio  E : A  was  calculated.  IVRT  was
measured  with  CW  spectral  Doppler  as  the  time  from  the  aortic valve closure artifact to the mitral valve opening artifact or to the onset of mitral inflow if the mitral valve opening artifact was not obtained.

PVF was recorded by PW spectral Doppler interrogation of the left   caudal   lobar   pulmonary   vein   (PV).   Color   Doppler   was optimized  for  low  velocity  flow.  The  PW  sample  volume  was placed about 1 cm into the PV. Sample volume length initially was set at 1–2 mm but was changed to 3–4 mm if the spectral Doppler signal was poor. Measurements included peak systolic (S), diastolic (D), and atrial reversal (AR) flow velocities (Fig 2), and duration
of the AR wave (AR dur). The ratio S : D and the ratio of TMF A duration to PVF AR duration were calculated.

Vp was  determined  from  a  color  M-mode  recording  of  LV inflow.   The  color   velocity  scale  was  adjusted  by   shifting  the baseline  to  optimize  color  aliasing  of  the  mitral  inflow  signal (between 35 and 55 cm/s). Vp was measured as the slope of the first aliasing isovelocity line of early diastolic flow, starting at the level of the mitral annulus and extending as far as possible toward the LV apex (at least 2.5 cm) (Fig 3).

Mitral annular motion was measured from the lateral (free wall) side with PW TDI. Color TDI was used to aid in sample volume placement, and the cursor was aligned as parallel as possible to the longitudinal  axis  of  LV  wall  motion.  A  sample  volume  length  of 5 mm was used, and Doppler gain was minimized. Measurements included peak early diastolic (Em), late diastolic (Am), and systolic (Sm)  mitral annular velocities  (Fig 4),  with calculation of  Em:Am



For the OccDCM group, time to CHF or SD was recorded as the number of days from enrollment (day of data collection) to the onset  of  respiratory  signs  and  need  for  diuretics,  or  to  SD.  Dogs experiencing noncardiac death before one of the above endpoints or those still occult at the end of the study follow-up period (March 2003) were right censored. For the OvDCM group, survival time was calculated as the number of days from enrollment to CHF death, SD, or euthanasia because of CHF. Dogs experiencing noncardiac death before one of the above endpoints were right censored.


Statistical Analysis
Statistical analyses were performed by computer-based statistical software.e Tests of normality (Shapiro-Wilk and Kolmogorov-Smirnov tests, significance level P. .1) were applied and verified by examining residual plots. Log transformations were performed if  residuals  were  not  normally  distributed.  Differences  among groups  in  baseline  characteristics  were  assessed  by  analysis  of variance (ANOVA) and the Least squares difference (LSD) test for multiple   comparisons.   Differences   among   groups   in   diastolic indices  were  evaluated  by  analysis  of  covariance  (ANOVA  of values adjusted for regression on an independent variable),25 with the following potential covariates included: sex, age, body weight (BW),   and   heart   rate   (HR).   Interactions   between   covariates,
between  covariates and the  group  effect, and  quadratic terms  for age and BW also were included. Least squares means (LS means), which  incorporate  and  thus  account  for  the  effects  of  significant covariates   (essentially   adjusting   the    means   to   account   for differences  between  groups  in  significant  covariates),  were  calculated   for   each   variable   based   on   the   respective   model.25 For example,  if  age  was  a  significant  covariate  for  E : A  ratio,  then differences between groups in E : A ratio may have been the result of differences in age, therefore E : A ratio must be adjusted for age to   make   the   group   means   comparable.   Tests   of   multiple comparisons  then  were  applied  (LSD  test  for  comparison  of  3 groups, and Tukey’s test for comparison of 6 groups when sex was
a  significant  covariate).  Bivariate  Cox  proportional-hazards  regression analysis was used to determine if any individual variables were significantly associated with time to endpoint in the OccDCM or OvDCM groups. The variables examined included age, BW, sex, LVIDd,  LVIDs,  FS,  and  all  echocardiographic  diastolic  function indices.  A  proportional  hazard  ratio  (risk  ratio,  RR)  with  95% confidence  interval  (CI)  was  calculated  for  each  variable.  Significance was defined as P, .05.


A  total  of  30  Doberman  Pinschers  were  included  in the study, with 10 dogs in each of the 3 groups. Sex, age,
BW,  LV  dimensions,  and  initial  HR  for  each  of  the  3 groups   are   summarized   in   Table 1,   with   significant
differences  among  groups  noted.  Statistical  description of the diastolic function data in the 3 patient groups is
presented in Table 2. Table 3 summarizes the results of the  analysis  of covariance,  including  significant  covari-
ates, LS means with 95% CI, and results of the multiple group  comparisons.  The  LS  means  for  variables  with
continuous   covariates   are   those   calculated   with   the average  values  of  the  continuous  covariates  (age,  BW,
HR).  Separate  LS  means  are  reported  for  males  and females   if   sex   was   a   significant   covariate   for   that
particular variable.

TMF with  separate E  and A waves was obtained in all  30  dogs.  Good  quality  PVF  was  obtained  in  10/10 NL,  9/10  OccDCM,  and  only  5/10  OvDCM  dogs.  Vp was obtained in all NL and OccDCM dogs, but in only 9/10  OvDCM  dogs  because  a  color  M-mode  signal  of adequate depth could not be obtained in 1 dog. Mitral
annular velocities by TDI were obtained in all NL and OccDCM dogs, but in only 8/10 OvDCM dogs, with the 2   poor-quality   recordings   being   due   to   inadequate alignment in highly spherical left ventricles.

For  TMF,  peak  E  was  significantly  higher  in  the OvDCM  and  OccDCM  groups  than  in  the  NL  group (see  Table 3  for  all  group  comparisons).  Age  and  HR were  significant  covariates  such  that  E  decreased  with increasing age and increased with increasing HR. All 3 groups differed significantly with respect to peak A, with OccDCM  having  the  highest  and  OvDCM  having  the lowest peak A. HR was the only significant covariate for peak A, with an increase in HR resulting in an increase in A velocity. The E : A ratio was significantly higher in OvDCM  compared  with  the  other  2  groups.  Age  and BW   were   significant   covariates,  such   that   E : A   decreased  with  increasing  age  and  E : A  increased  with increasing  BW.  DTE was  significantly  different  among all 3 groups, with the shortest DTE
in OvDCM and the longest  DTE in  NL.  Significant  covariates  for  DTE included  age  and  BW,  such  that  DTE increased  with increasing  age  and  BW.  IVRT  had  a  complex  model with sex, age, BW, and HR being significant covariates along   with   some   interactions   (Table 3).   IVRT   was significantly  longer  in  OccDCM  compared  with  both NL  and  OvDCM.  NL  and  OvDCM  did  not  differ.



IVRT   increased   with   increasing   age   and   BW   and decreased  with increasing HR. Females  tended to have
longer  IVRTs  than  males,  but  this  result  depended  on age and group.

Because of the number of missing data points for the PVF parameters, fewer covariates could be examined (ie,
fewer  degrees  of  freedom).  Specifically,  in  the  case  of peak  S  and  S : D  ratio,  the  models  were  noted  to  be
overfitting  the  data  (ie,  all  covariates  significant  and unreasonable   LS   means),   therefore   the   group-effect
alone  (ANOVA)  was  examined  for  these  2  variables. Significant differences among groups were detected only
for  antegrade  flow.  Peak  S  was  significantly  lower  in OvDCM compared with both NL and OccDCM. Peak D  was  significantly  greater  in  OvDCM  compared  with both  NL  and  OccDCM.  S : D  ratio  was  significantly different among all 3 groups, with OvDCM having the lowest S : D ratio, and NL having the highest S : D ratio. No difference was detected among groups for peak AR, AR  dur,  or  ratio  of  TMF  A  duration  to  PVF  AR duration.

Vp was  significantly  lower  in  OccDCM  compared with NL. Vp in OvDCM was lower than normal, but not signifi-cantly  different  than  the  other  2  groups.  There were no significant covariates in the model for Vp.



For  TDI  mitral  annular  velocities,  Em was  significantly  lower  in  OvDCM  compared  with  NL  for  themales. Am
was significantly different among all 3 groups, with   lowest   values   in   OvDCM   and  highest   in   NL, resulting  in  E
m:Am ratio  being  significantly  greater  in OvDCM compared with NL and OccDCM. The systolic myocardial  velocity,   Sm,   was   significantly   different among all 3 groups (highest in NL, lowest in OvDCM). In OccDCM, 7/10 dogs reached a cardiac endpoint: 6 CHF and 1 SD. For the remaining 3 dogs, 2 experienced noncardiac death (1 died secondary to hemorrhage from a pulmonary mass; 1 was euthanized for an intrathoracic mass), and 1 remained occult at the time of analysis. For those  that  experienced  CHF  or  SD,  the  mean  time  to endpoint   was   177+132   days   (mean + standard deviation),  with  a  median  of  143  days  and  a  range  of 47–357  days.  Of  all  the  variables  examined,  only  DTE was significantly associated with time to onset of CHF or SD in OccDCM (RR 0.83, CI 0.7–0.98, P5 .03).



In  OvDCM,  9/10  dogs  experienced  cardiac  death:  5 were euthanized due to refractory CHF,  and  4 experienced  SD.  The  remaining  1  dog  was  euthanized for appendicular osteosarcoma  with stable CHF  at the time. The mean time to cardiac death was 77+64 days, with a median  of 62 days  and a range  of 13–214 days. Variables   significantly   associated   with   survival   time included  age  (RR  0.55,  CI  0.29–0.94, P 5 .03),  LVIDd (RR 1.15, CI 1.02–1.35, P5.02), and LVIDs (RR 1.24, CI  1.06–1.54, P5 .005).  None  of  the  diastolic  indices
were associated with survival time on bivariate analysis.



Diastolic dysfunction in DCM may be the result of: (1) impaired relaxation due to abnormal calcium handling and abnormal kinetics of actin-myosin interactions, (2) increased myocardial stiffness (reduced compliance) due to myocardial fibrosis, and (3) increased chamber stiffness due to cardiac remodelling and eccentric hypertrophy, resulting in operation of the LV on a steeper portion of the passive diastolic pressurevolume curve. 3,26,27 Abnormal diastolic function plays a dominant role in the onset of CHF, as increased LV end-diastolic volume and pressure eventually lead to increased pulmonary venous pressure and pulmonary edema. Increases in LV filling pressure correlate closely with congestive signs and exercise tolerance in humans, independent of the severity of systolic dysfunction. 5,28 Evaluation of diastolic function is now an important part of monitoring human DCM patients, specifically for assessing prognosis and therapeutic response. There are few reports describing assessment of diastolic function in clinical canine DCM patients,4,21,22 and none Table 3. Doppler echocardiography results by Analysis of Covariance: Least squares means with 95% confidence intervals. Normal Occult DCM Overt DCM Significant Covariates Transmitral flow n 5 10 n 5 10 n 5 10 E (cm/s) 71.6 (62.7–81.7) 96.9 (84.8–110.7)a 94.3 (82.8–107.3)a A,b HRc A (cm/s) 56.5 (50.7–62.9) 67.1 (60.0–75.1)a 47.7 (42.4–53.8)a, d HRc E : A 1.4 (1.2–1.6) 1.4 (1.3–1.6) 2.0 (1.8–2.2)e, d A,b BW,c BW 3 Gr A dur (milliseconds) 75.5 (68.0–82.9) 85.5 (79.0–92.1) 90.4 (82.1–98.8) A,b HRb DTE (milliseconds) 142.1 (129.5–154.7) 97.5 (86.5–108.5)e 79.0 (68.3–89.7)e, f A,c BWc Isovolumic Relaxation Time n 5 10 n 5 10 n 5 10 IVRT (milliseconds) M 76.4 (56.7–103.0) 95.4 (76.4–119.2)a 73.0 (61.5–86.7)f sex, A,c BW,c HR,b sex 3 A, A 3 BW, HR 3 Gr F 86.7 (74.2–101.4) 111.3 (90.6–136.9)a 73.0 (50.0–106.6)f Pulmonary venous flow n 5 10 n 5 9 n 5 5 S (cm/s) 50.6 (45.5–55.6) 44.2 (38.9–49.5) 34.4 (27.3–41.6)a, f n/a D (cm/s) 39.8 (31.0–48.5) 43.2 (33.3–53.1) 59.6 (48.7–70.5)a, f A,b BW,b HR,b A 3 Gr, BW 3 BW, BW 3 Gr S : D 1.0 (0.9–1.1) 0.8 (0.7–0.9)e 0.6 (0.5–0.7)e, f n/a AR (cm/s) 27.7 (25.0–30.7) 26.4 (23.6–29.5) 24.3 (20.9–28.4) HRc AR dur (milliseconds) 57.7 (52.9–62.5) 59.9 (54.8–65.0) 61.8 (55.0–68.6) A dur : AR dur 1.4 (1.3–1.6) 1.5 (1.3–1.7) 1.4 (1.2–1.6) Flow propagation velocity n 5 10 n 5 10 n 5 9 Vp (cm/s) 58.9 (48.9–70.9) 40.2 (33.4–48.4)a 45.6 (37.5–55.4) Lateral mitral annular velocities by TDI n 5 10 n 5 10 n 5 8 E m (cm/s) M 19.5 (15.3–23.6) 15.3 (12.8–17.7) 14.9 (13.2–16.7)a A,b BW,c A 3 BW, sex 3 Gr F 14.9 (12.9–16.9) 17.0 (14.9–19.1) Not estimable Am (cm/s) M 9.2 (7.3–11.6) 7.1 (5.8–8.7)a 5.3 (4.6–6.0)e, f sex, BWc F 12.6 (10.8–14.8) 9.1 (7.7–10.7)a Not estimable Em : Am 1.5 (1.2–1.7) 1.9 (1.6–2.2) 2.6 (2.2–3.2)e, fSm (cm/s) 19.5 (17.3–21.9) 10.6 (9.4–11.9)e 7.5 (6.6–8.5)e, d BWc Abbreviations are explained in the first footnote to Table 2; M, male; F, female; A, age; BW, body weight; Gr, group; n/a, not applicable (analysis of variance performed in place of analysis of covariance due to too few observations). Data are presented as least squares mean (95% confidence interval). a P , .05 versus normal group. b Negative (inverse) relationship between variable and covariate. c Positive (direct) relationship between variable and covariate. d P , .001 versus occult DCM group. e P , .001 versus normal group. fP , .05 versus occult DCM group. 86 O’Sullivan, O’Grady, and Minors reporting the use of a combination of echocardiographic techniques designed to potentially overcome the limitations of individual indices. The results of this study provide some insight into characterization of diastolic function in normal Doberman Pinschers and the
presence of diastolic dysfunction in Dobermans with DCM.

Diastolic function may be assessed noninvasively by echocardiographic examination of TMF because it reflects the instantaneous pressure differences between the left atrium (LA) and ventricle, which in turn are related to the rate of myocardial relaxation and compliance of the 2 chambers.29 Abnormal patterns of TMF, although not specific for a particular disease, distinguish various stages of diastolic dysfunction and change along a continuum with progression of myocardial disease. Early diastolic dysfunction is characterized by impaired LV relaxation, causing reduced early filling (decreased E wave) and increased dependence on atrial contraction (increased A wave), resulting in E : A ratio
,1 and prolonged IVRT and DTE. With disease progression, LV compliance begins to decrease, and LA and LV filling pressures increase as a result, causing pseudonormalization of TMF (normal E : A ratio, normal to short IVRT and DTE). In advanced diastolic dysfunction, there is very poor LV compliance, a further increase in LV filling pressure, and often atrial systolic dysfunction, resulting in a restrictive TMF pattern (increased E wave, decreased A wave, E : A ratio $2,
and short IVRT and DTE).5,29,30

The normal Doberman Pinschers in this study had a similar E : A ratio but longer DTE compared with normal dogs of various breeds described in 2 other reports. 18,19 Differences in breed, BW, HR, age, and FS among studies may account for these findings. The symptomatic Dobermans in this study (OvDCM) displayed features of a restrictive TMF pattern (E : A ratio $2, shortened DTE), suggesting markedly reduced compliance and high filling pressures, consistent with advanced diastolic dysfunction. This conclusion is in agreement with findings in moderately to severely sympto- matic human DCM patients, in whom higher E and lower A velocities, higher E : A ratios, and shorter DTE than asymptomatic or mildly symptomatic patients are reported. 31,32 As a group, the dogs with occult DCM displayed features of multiple patterns such that the group did not fit neatly into one TMF pattern. This observation is likely the result of examining patients at different stages of the occult disease process, in which varying degrees of abnormal relaxation and changes in compliance are occurring. 33 When examined individually, 1 dog had an impaired relaxa- tion pattern (E : A ratio,1 and longest IVRT) and 1 dog tended toward a restrictive pattern (highest E : A ratio, short DTE,
and shortest IVRT), whereas the remaining dogs had some of the features of a pseudonormal pattern. Groups
of asymptomatic to mildly symptomatic humans typically demonstrate impaired relaxation or pseudonormal filling patterns, suggesting mild and moderate diastolic dysfunction, respectively. 31,32 The occult DCM dogs in this study represent a typical example of patients in which additional indices of diastolic function may be
necessary to draw conclusions.

Evaluation of PVF is a complementary means of assessing LV diastolic function. PVF is dependent on the pressure gradient between the PV and LA and consists of antegrade systolic flow (S) associated with atrial relaxation and displacement of the mitral annulus apically during ventricular contraction, antegrade early diastolic flow (D) during LV filling, and retrograde late diastolic flow (AR) associated with atrial contraction (Fig 2). 34,35 Most normal adult humans exhibit greater systolic than diastolic PVF (S : D ratio $1) and an AR wave ,35 cm/s,15,35 whereas several reports in
normal dogs describe a tendency for greater diastolic than systolic antegrade PVF, resulting in an average S : D ratio ,1, but similar AR velocities. 18,19,36 In the present study, mean S : D ratio in the normal group was 1, with 50% of the dogs having S : D ,1 and 50% .1. AR velocities were comparable with other studies. Potential reasons for higher S and S : D ratio in the normal dogs of this study include differences in HR or sample volume depth within the PV compared with other studies.

Diastolic dysfunction produces alterations to PVF patterns. With impaired relaxation, LV pressure and, thus, LA pressure fall more slowly, resulting in reduced diastolic PVF, normal or increased systolic flow, and S : D ratio .1. With disease progression, systolic PVF is blunted because of increased LA pressure and decreased LA compliance, diastolic PVF increases and decelerates rapidly due to increased LA pressure and decreased LV compliance (resulting in an S : D ratio ,1), and velocity and duration of the AR wave increase. This pattern is observed with pseudonormal or restrictive TMF pat- terns. However, if atrial systolic dysfunction is present with advanced disease, there may be loss of a prominent 15,29 AR wave in the face of restrictive filling. Blunted systolic PVF is detected in 42–64% of human DCM 14,37,38 patients, and increased duration of PVF AR wave (specifically AR duration . TMF A duration) is reportedly a sensitive and specific marker of increased 38,39 LV end-diastolic pressure. The dogs with DCM in this study exhibited reduced S : D ratios compared with the normal group, with the OvDCM group also exhibiting blunted systolic PVF. This observation would appear to complement the TMF findings and provide further evidence of diastolic dysfunction. However, no significant differences were detected for retrograde PVF, including the velocity and duration of the AR wave and ratio of TMF A duration to PVF AR duration. This lack of difference may be technical in origin given that the much smaller AR wave is more difficult to record 24 and most likely to be disturbed by wall motion artifact. Atrial systolic dysfunction also may account for the lack of large AR waves in some dogs, particularly those in the group with overt DCM. Recording of PVF proved to be technically challenging in dogs with DCM in this study, and adequate recordings were possible in 9/10 OccDCM and in only half of OvDCM. Feasibility of PVF recording by experienced human sonographers is reported to range from 80–95% for antegrade flow, and

anywhere from only 40% up to 90% for retrograde 40,41 flow. Beginners may expect success in only 40–50% 6 of patients overall. Other factors that may have contributed to unobtainable recordings include cardiac enlargement, and hence depth limitation and distortion of the angle of PVF, poor image quality in some animals, wall motion artifact, presence of mitral re- gurgitation disrupting the S wave, and influence of respiration on cardiac image motion.

Vp is a preload-independent index of LV relaxation that has been validated in both humans and a canine 42 model. It is strongly negatively correlated with the time constant of LV relaxation, one potential gold standard 42–44 for assessment of LV relaxation. The normal value 15 for an adult human generally is .45 cm/s. Values in normal dogs were reported to range from 45 to 70 cm/s by 1 group, which is consistent with the findings in the 45 normal Dobermans in this study. A delay in LV flow propagation has been described in human patients with DCM and other cardiac diseases characterized by 43,46 diastolic dysfunction, and in an experimental canine 47 model of acute myocardial ischemia. This delay has 43,44,46,47 been linked directly to asynchrony of relaxation. In this study, Vp was significantly lower in OccDCM compared with NL, supporting the presence of impaired relaxation in occult DCM (Fig 3). Vp for OvDCM, while lower than NL and approaching that of OccDCM, was not statistically different from either group. Vp is proposed to be preload independent with LV relaxation being its primary determinant; however, other physio- logic determinants of Vp may include HR, age, and 42,46,48 percentage of segmental wall dyssynergy. The lack of significantly decreased Vp in OvDCM may be related to the small number of subjects studied and high variability in the measurement of this parameter.

The examination of myocardial motion with TDI is a novel means of assessing diastolic function. In the same way that Doppler echocardiography is used to record low amplitude, high velocity blood flow, it also may be applied to high amplitude, low velocity wall motion. Global LV diastolic function may be assessed from the mitral annular position in the apical 4-chamber view, and specifically longitudinal fiber shortening and 15 expansion are evaluated. The PW TDI display of mitral annulus motion appears as a mirror image of the TMF display, with early (Em) and late (Am) diastolic waves. A systolic wave (Sm) coincident with ventricular contraction also is present (Fig 4). A wide range of normal values has been reported for TDI indices in 49 humans. There is 1 report in the veterinary literature 20 on normal TDI values in dogs. TDI values obtained from the basal LV free wall in that report were lower than those for the normal Dobermans in this study, which may be related to the different methodology used. 20 Chetboul et al used color TDI and off-line analysis, generating average tissue velocity curves from the basal LV free wall myocardium, whereas this study used real- time PW TDI and measured peak velocities from the mitral annulus, which may yield higher values. The values in the normal dogs in this study are very similar 49 to those reported in humans obtained by PW TDI. An

interesting finding in the work by Chetboul et al a strong association between breed and TDI indices, with rather different values noted for different breed groups (Dobermans not reported), suggesting 20 breed-specific normal values may be warranted.

Human patients with various cardiac diseases having impaired relaxation as a component, including DCM, may have reduced Em velocities, independent of TMF 15,16 pattern. Earlier investigations suggested that Em was 16,50,51 independent of preload, whereas studies since that 52,53 time have challenged this assumption. It appears however that preload-dependence is much less pro- nounced in the presence of abnormal relaxation. This observation suggests that Em still is useful in differen- tiating normal from pseudonormal LV filling. In this study, Em was significantly reduced in the males in the overt phase of disease compared with the normal males. The clinical relevance of this finding is uncertain given the relatively small magnitude of difference and the large amount of overlap in values among groups. The other diastolic indices, including TMF, PVF, and Vp, suggest the presence of impaired relaxation in the DCM groups, hence it is problematic that TDI did not consistently indicate the same. TDI perhaps was insensitive in detecting abnormal relaxation for technical reasons because myocardial motion is caused not only by contraction and relaxation, but also by translation and rotation of cardiac structures, thus Em reflects more 15 than simply motion due to relaxation. Em velocities simply may be too variable, particularly in a small sample of dogs, to yield meaningful group differences. Translation-independent TDI indices such as the nega- tive myocardial velocity gradient, defined as the difference in early diastolic myocardial velocity between the endocardium and epicardium divided by myocardial wall thickness, are likely more sensitive indicators of 54 relaxation abnormalities. Accurate TDI indices may be difficult to obtain because of poor imaging and poor alignment with the LV free wall in dogs with dilated hearts, as was the case in 2 dogs in this study. Reduced Am velocities are found in patients with pseudonormal and restrictive TMF patterns as a result of increased LV end-diastolic pressure, which increases atrial afterload 17,53 and depresses atrial function. Our findings suggest progressively increasing atrial afterload and decreasing atrial function among the 3 groups (NL Am . OccDCM Am . OvDCM Am). Clearly, more efforts are required to establish normal diastolic TDI values in Dobermans and to elucidate the utility of these measures in this disease. Although not a primary objective of this study, systolic mitral annular velocities discriminated among the 3 groups, with reduced Sm in OccDCM, and further reduced Sm in OvDCM. Reduced Sm has been proposed in human patients to be a very sensitive and early 49,55,56 indicator of systolic dysfunction. At least 1 veterinary group has demonstrated the clinical utility of TDI in dogs. Chetboul et al found reduced early diastolic and systolic myocardial velocity gradients in preclinical Golden Retrievers with the dystrophin gene mutation for GRMD compared with normal Golden 4 Retrievers.

With respect to the prognostic utility of diastolic indices, DTE was significantly associated with time to onset of CHF or SD in OccDCM. For each unit decrease in DTE, there was a 17% increase in risk of CHF or SD. Shortening of DTE suggests rapid equilibration of LV and LA pressures during early filling because of decreased LV compliance. A short DTE (#125 milliseconds) has been described as the most powerful independent predictor of hospitalization for CHF and all-cause mortality in asymptomatic human patients with LV systolic dysfunction, regardless of E : A 12 ratio and systolic function indices. In an earlier study by the same group, DTE and pulmonary capillary wedge pressure (PCWP) were strongly negatively correlated in both asymptomatic and symptomatic LV systolic 57 dysfunction patients, again regardless of E : A ratio. Thus, a short DTE, suggesting decreased LV compliance and increased PCWP, should be predictive of the onset of CHF. Further investigation into the utility of this measurement and, in particular, serial measurements is warranted in a larger series of dogs. In the OvDCM group, age, LVIDd, and LVIDs were significantly associated with survival time. Younger age was associ- ated with poorer survival time, which has been reported 58 in at least 1 other study of DCM in dogs. Although it might be inferred that the disease may be more aggressive and rapidly progressive in younger animals, this has yet to be documented. Our study suggests a 15% and 24% increase in risk of death for every millimeter increase in LVIDd and LVIDs, respectively. There is little information in the veterinary literature available to corroborate the prognostic utility of echocardiography. A few retrospective studies have failed to find associa- tions between echocardiographic indices and survival 58,59 times, whereas Borgarelli et al suggested that in- creased LV end-systolic volume index (ESV-I) is 23 a significant predictor of poor survival. None of the diastolic parameters were individually predictive of survival in this study. This finding is in contrast to a multitude of information in the human literature supporting the utility of restrictive TMF patterns, short DTE, and blunted systolic PVF as predictors of poor prognosis. The lack of significant findings with respect to diastolic indices is likely a reflection of the small number of dogs in this study and the restriction to a rather simplistic attempt at elucidating associations through bivariate analysis.

Several limitations of this study require acknowledge- ment. A small number of dogs were included, and it is well recognized that small sample sizes are, by nature, underpowered to detect anything but substantive differences among groups. With respect to survival analysis in particular, we were limited to investigating the effect of single parameters alone. This study must be regarded, therefore, as a preliminary evaluation of the potential prognostic utility of these parameters. Follow- up studies in larger numbers of dogs are required. The results of this study are applicable to DCM in Dober- man Pinschers and may not represent the events occurring in other breeds. Echocardiographic indices of diastolic function are influenced by a number of factors that may contribute to variability. Technical factors including sonographer experience, sample vol- ume position, Doppler beam alignment, and gain and filter settings may affect diastolic measurements. Al- though every effort was made to standardize these factors, they may still have influenced the variability of the recordings. Physiologic factors including age, BW, HR, and sex were addressed in the analysis of co- variance such that group effects should not be con- founded by these known influences. All diastolic parameters were measured as close as possible to end- expiration with the use of a respiratory monitor, thus effects of respiration should have been minimized. Many of the diastolic indices, particularly TMF and PVF, are affected by loading conditions, thus varying degrees of mitral regurgitation and differences in medical therapy certainly may have influenced the results. Di- astolic function parameters are known to change over time during the course of disease; however, repeat echocardiographic evaluations were not performed for this study. Direct proof of increasing degrees of diastolic dysfunction across groups would involve follow-up and sequential measurement of the same dogs from the normal phase through the occult and overt phases of DCM. No invasive measurements were performed to provide de- finitive evidence of diastolic dysfunction; therefore con- clusions regarding the presence of diastolic dysfunction are presumptive, albeit based on data accepted as representative of diastolic function.

In conclusion, TMF, IVRT, and antegrade PVF were significantly different among the 3 groups of dogs and suggested increasing levels of diastolic dysfunction with disease progression. Shorter DTE was associated with shorter time to CHF or SD in the occult DCM group. Further investigation into the clinical utility of this parameter is warranted. PVF proved to be the most technically challenging of the diastolic indices, particu- larly the retrograde component and particularly in dogs with very enlarged hearts. As such, it is anticipated to have limited utility in the routine clinical assessment of canine DCM patients. Low Vp in the group with occult DCM distinguished this group from normal dogs and supported the presence of impaired relaxation. The utility of this index as an aid in the diagnosis of DCM may warrant further investigation. Diastolic mitral annular motion by TDI had a limited ability in distinguishing diseased dogs in this study. More extensive work in larger numbers of dogs is required to establish normal ranges and potential normal variability for these parameters.



Funding for this project was provided by The Pet Trust, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada. The authors thank Rhonie Horne for technical assistance, William Sears and Gabrielle Monteith for statistical assistance, and all Doberman owners who participated in this study.



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