Failure in the Dog
By Charles R. Wallace, B.Ch.E., D.V.M., and William F. Hamilton,• The dog has been widely used in experi-mental procedures designed to approximate congestive failure of the circulatory system. It is not generally realized that many dogs are affected by spontaneous heart disease that resembles human congestive failure and other forms of human heart disease. Although the life span of dogs is relatively short in com-parison to that of man, the more rapid aging process allows chronic as well as acute circu-latory failure to develop. These conditions are more commonly found in house pets and hunting dogs, as contrasted to pound dogs with relatively shorter life spans. These con-siderations prompted us to describe our stud-ies of spontaneously occurring heart disease in dogs.
Methods
SOURCE AND SELECTION OF DOGS
Through the cooperation of the veterinary pro-fession of this area, especially the members of the Georgia-Carolina Veterinary Medical Association, flogs with suspected cardiovascular involvement have been referred to the Department of Physi-ology, Medical College of Georgia, for diagnosis and therapy.
Tentative diagnoses were based on the history, physical examination, radiograms, electrocardio-grams, and the hematological and urological exami-nations. Dogs considered to have primaiy cardio-vascular conditions were then further studied for salt retention, venous and right heart pressures, pro- and postmortem heart size, electrolyte and protein levels of body fluids, blood volumes, cardiac outputs, and other factors, both before and during therapy. The extent of study of the individual dog varied, depending on the suscepti-bility of the owner to persuasion.
PROCEDURE
Sodium and potassium levels in the urine, feces, and various body fluids were determined by stand-From the Department of Physiology, Medical College of Georgia, Augusta, Georgia.
Supported by Grants HTS-5044 and H-240, U. S. Public Health Service.
Received, for publication February 8, 1962.
Circulation Research, Volume XI, August 1962
arc! flame photometry using a Coleman Model 21 Flame Photometer. Specific gravities of these fluids were determined by the "falling drop" method of Barbour and Hamilton.1 Protein con-centrations were estimated from the specific gravi-ties by the method of Weech et id.2 Albumin and globulin contents were determined by hanging strip electrophoresis.3
Blood volumes were estimated by Evans blue dye (T 1824).4 Cardiac outputs were determined either by Fiek,5 dye-dilution,5 or aortic arch pulse-pressure methods.0 Total heart volumes were esti-mated from radiograms by the method of Hamil-ton et al.7 Routine venous pressures were measured by a saline manometer with a 20-gauge needle in the right jugular vein with the dog lying on the left side. The horizontal plane through the sternum and spine was used as the zero pressure reference.8 Right heart pressures were measured by catheterization with a no. 16 radiopiique cathe-ter* inserted through a 16-T needle in the right jugular vein. Pressures were recorded by Statham strain gauges and a Sanborn Twin-Viso or nn Electronics for Medicine multichannel oscillograph-ic recorder.
Digitnlization of dogs, usually by the oral route, was controlled by clinical response and by elec-trocardiographic (ECGr) characteristics. The ini-tial arbitrary dose of U.S.P. digitalis leaf was 22 mg./Kg. body weight given twice daily for two days. The total daily maintenance dosage, arrived at by individual bioassay, was 14 mg./Kg. body weight or more given in single or divided doses. Digitalization usually was found to be adequate with minimal toxicity as soon as the P-R interval was increased from the normal range of 0.08 to 0.12 second to 0.14 to 0.1S second. With further increased dosages of digitalis, arrhythmias would develop. Intravenous digitalization (oua-bain) was controlled by continuous ECG moni-toring to measure the P-R interval and to detect arrhythmias.
Right and left ventricular wall thicknesses were measured at the center of the free walls excluding papillary muscles as shown at locations (a.) and (b) in figure 1. Weights of the right and left ventricles were obtained by trimming: away the free walls along the projected contour of the septum, as shown by the broken lines in figure 1, approximating the method of Lewis.9
•A. E. Afford, Barrington, New Jersey.
301
WALLACE, HAMILTON TABLE 1
CLINICAL AND PHYSIOLOGICAL FINDINGS IN VARIOUS GROUPS OF DOGS
DOG* I RHYTHMC MEAD RAPE
A. Ml DOCS IN CONGESTIVE FAILURE MF 1 BD MF 8 G MF 9 C MF10 MT MF18 M T MF50 C MF33 CS MF54GS MFS6 BT MF57CS MF70C MF7S H MFB5 P MF93 BT MF94 MT MF104 H 176 160 192 240 142 150 176 196 1G6 200 132 96 196 122 164 134 EVS. AVN A F N AF, EVS E V S N N AF. EVS EVS, HB AF.EVS E V S N N N N N 83 90 67 90 90 7 8 0 90 65 64 3 0 7 0 2 7 0 317 71 88 8 10 6 9 15 9 14 0 10 10 6 16 11 11
B. Ml DOGS NOT IN CONGESTIVE FAILUR M 8G M 9 C 160 N 40 MIO MT 192 AF 80 MI7 S M20MT M31 0 M78 H
C, HEARTWORM DOGS IN CONGESTIVE FAILURE PAPF s/b 45/6 47/45 4 5P HF 5 HF 6 H HF13 ST HF26H HF27 H HF28 BO HF3SES HF36 BX HF39 M HF40 H HF41 B HF46 H HF49 P HF52 BX HF69 BO HF74 H HF73 PT EVS, B EVS EVS EVS HF102 CS 146 | EVS 90 75 2 1 0 330 248 210 88 256 244 105 92 82 90 96 270 9? 106 75 18 12 22 15 7 12 10 IS 10 12 12 15 B I S 9 7 15 ft 61/28 5 5 * O 93/36 94p.° 6 « / 4 2° 96/67 108/62 88/4$ 9 0 / 5 0 ° 108/51 125/60 158/59 80/53 10O/74N 135/79 105/bo I 2 7 / * 9S 159/113° 153/102 164/111 106/70 145/9 T 135/8B 205/140 140/85 160" 3. 1 *. 2 3. 5 6.6 3.2 3. 3 3.4 4. 7
| RHYTHMC I M E ADR A P E PAPF I FAPG
I I I I
D HEARTWORM DOGS NOT IN CONGESTIVE FAILURE
H15 B H1 9 H H21 B H22 CS H23-H H28 BO H36 BX H37BX H45 PT H55 H H71 M H73 BX H76 PT BO 106 80 116 114 88 64 84 100 76 80 92 76 112 104 88 72 76 86 74 102 70 N N H B N N N N N N N N N N N E V S N N N N N N N N 63 86 86 SO 71 94 45 214 271 72 90 115 88 6 0 98 96 9 0 73 90 86 90 90 74 90 3 1 1 3 3 3 D 0 5 2 3 0 3 0 3 2 2 2 1 3 3 0 0 3 2 2 0 2 1 1 2 36/12 52/22 55 p 65 P 55/30 50/24 2 4 p 22/10 40 p 22/11°
s&
45/25 23/10 2SP.0 37P.Q 27 28/12 34/9 29/12 4 3P 55/15° 25*.5 30/10 4 0p 3 8p 3 4p 23/5 33/17 31/30 28/13 55/30 220/165 116/94 150/80 151/91 160/115 14V70 H77 PT H79 ES H80 IS HS1 BD H82 PT 104 EVS 98 3 5 5 / 1 5 ° 209/190 H83 MC 96 0 25*.55/15°° 175/135 H84 BX 90 0 3 0 / 1 0 165/115 H86 M H87 M 72 N 2 38p 151/81 K88 PT 76 N 90 2 3 4p 142/70 H95 M H96 M H97 M H I 0 0 M HI 05 HE. DOGS WITH CONGENITAL CARDIOVASCULAR DEFECTS
CF30 H I 130 I CF33BX J 172 | AF. EVS (ruLMOHlC •TIHOtll) 95 167 233 76 12 12 2 24 15 10 35/30"1 37/71 58/21°! 144/2°.u 55-184 50-SCR , 7 -C43 CS
F DOGS WITH MISCELLANEOUS CONDITIONS 207/110 MS 2 H MS 3 SS MS 4 CS MSI 2 MT MS25 DP <M MS34 ES (M MS44 BX MS48 G MS58 BT MS60 IS MSB 9 PB 116 190 98 IB0 HHOBI 160 184 96 152 86 wTwa N N N N > N EVS N N N N N 7 0 9 0 83 90 49 72 90 M 120 93 1 2 IS 2 0 2 10 7 17 2 6 0 / 3 0 36/15 49/25 3 3P 3 2 p 33/26 160/87 140/84 142/78 4 . 1 5 . 1 4 . 5 3 . 9 4 . 7 5.3 4 . 9
(A) Case number and breed of dog. Case number prefix for MI dogs: not in failure (M), in failure ( M F ) ; for heartworm dogs: not in failure (H), in failure ( H F ) ; for clogs with congenital cardiovascular defects: not in failure (C), in failure (CF). Breed desig-nations: beagle (B), bulldog (BD), Boston terrier (BT), boxer (BX), Chihuahua (C), cocker spaniel (CS), Doberman pinscher (DP), English setter (ES), Great Dane (GD), German shepherd (G), Gordon setter (GS), mixed hound ( H ) , Irish setter (IS), mixed (M), mixed terrier (MT), Pekingese ( P ) , pit bull (PB), pointer (PT), springer spaniel (SS). (B) Heart rate. (C) Bhythm: normal (N), atrial fibrillation (AF), atrio-ventricular nodal rhythm (AVJST), bundle-branch block (BBB), second-degree heart block (HB). (D) Mean electrical axis based on QRS of bipolar leads I and I I I . (E) Mean right atrial pressure in mm. Hg. (F) Systolic and diastolic pulmonary arterial pressure in mm. Hg. (G) Systolic and diastolic femoral arterial pressure in mm. Hg. (H) Plasma volume in cc./Ivg. body weight. (I) Blood volume in cc./Kg. body weight. (J) Sodium concentration in mEq./L. (K) Potassium concentration in mEq./L. (L) Protein concentration in Gm./lOO ce. plasma. (M) Protein concentration in Gm./lOO ec. ascitic fluid. (N) Pressure in aortic arch in mm. Hg. (O) Pressure in carotid artery in mm. Hg. (P) Systolic pressure derived from right ventricular pressure. (Q) With sodium pentobarbital anesthesia. (E) Moribund. (S) With digitalis. (T) Left ventricular pressure in mm. Hg. (TJ) Left and right ventricular pressure in mm. Hg.
CiTculftUon Research, Volume XI. August 19GS
ETIOLOGY
Twenty of our dogs had mitral insufficiency (MI), 44 hud heartworms (Dirofilaria ivimitis), and 4 had congenital cardiovascular anomalies. Several dogs with miscellaneous conditions were also studied.
The valvular insufficiencies were due to degenera-tive lesions commonly referred to as "warty valves."10 Heartworms are nematodes more com-monly found in dogs from the Gulf of Mexico and Atlantic coastal areas, mosquitoes being the intermediate host of the parasite. These dogs develop sclerosis of the pulmonary arterial sys-tem,11 causing pulmonary hypertension.12 Two of the congenital cardiovascular conditions were rare in dogs. CF-30 had several arteriovenous fistulas in the cervical region. CF-32 had a pul-monary artery arising from the left common carotid artery midway in the neck, with the aorta overriding an interventricular septal defect. Three other anomalies observed were pulmonic stenosis, aortic stenosis, and patent ductus arteriosus. Per-sistent left anterior vena cava was observed in two dogs, M-53 and H-76.
The miscellaneous conditions are briefly de-scribed in table 3, part F. In MS-4, about 75 per cent of the lung tissue was nonfunctional due to adenocarcinoma. In MS-44, a sarcoma dis-placed the heart laterally against the right thoracic wall, severely hindering cardiac filling. In MS-58, a heart base tumor constricted the pulmonary artery.
Results
MITRAL INSUFFICIENCY DOGS (TABLE 1 , PARTS A AND B)
These dogs gradually worsened clinically, and symptoms persisted from many months to several years. They had harsh coughs, tired easily, and voluntarily limited their physical activity. During the last few months of life, they had severe pulmonary edema with cough-ing spells, dyspnea, nausea, convulsions, and fainting. Seventeen of the 20 MI dogs ob-served developed a severely congested state with ascitic fluid at an average age of IOV2 years. Twelve (71 per cent) of these in fail-ure also had evident interstitial edema, and six (35 per cent) had thoracic fluid. Of the 20 MI dogs studied, 16 (80 per cent) were house pets, and 15 (75 per cent) were males. The average heart rate, with the dog unanes-thetized, calm, and recumbent, was 166 (96 to 240) in MI dogs in failure and 144 (98 to 192) in those not in failure. Cardiac
arrhyth-Cut
FIGURE 1
Locations for measuring ventricular wall thick-ness (a and b) and for removal of ventricular ivalls for weights (broken lines).
mias were observed in nine (53 per cent) of the dogs in failure. The average of the mean electrical axis (MEA) of the QRS complex was 100 (7 to 317) degrees in MI dogs in failure and 66 (14 to 90) degrees in those not in failure. The average jugular venous pressure was 14 (8 to 23) cm. saline in MI dogs in failure and 5 (1 to 8) cm. saline in those not in failure.
HEARTWORM DOGS (TABLE 1 , PARTS C AND D)
These dogs tired easily and had a soft cough. Owners of hunting dogs noticed the loss of stamina. The rate of development of the congested state was evidently dependent not only on the number of heartworms but also on the susceptibility of the individual dog. Heartworm dogs exhibited more wasting and dehydration of the body tissues than MI dogs. Occasionally a clog with heartworms will die in a severely emaciated state with-out developing congestive failure. Of the 44 heartworm dogs observed, 28 (64 per cent) were hunting dogs and 16 (36 per cent) were house pets. Thirty-four (77 per cent) were Circulation Research, Volume XI, August 1962
WALLACE, HAMILTON
males. Eighteen (41 per cent) of these dogs were in the congested state with ascitic fluid at an average age of 5.5 (3 to 10) years. In addition to ascitic fluid, eight had evident interstitial edema and six had thoracic fluid. The average heart rate was 136 (76 to 188) in dogs in failure and 88 (70 to 118) in dogs not in failure. Arrhythmias were present in nine (50 per cent) of the dogs in failure and in two (6 per cent) of the dogs not in failure. The average MEA was 154 (75 to 350) de-grees in heartworm dogs in failure and 97 (60 to 271) degrees in heartworm dogs not in failure. The average jugular pressure was 17 (9 to 30) cm. saline in dogs in failure, and 4 (2 to 8) cm. saline in those not in failure. DOGS WITH CONGENITAL
CARDIOVASCULAR DEFECT
CF-30, with the arteriovenous fistulas, had a continuous tachycardia, tired very easily, and had ascitic fluid for many weeks. Over 5 IJ. of thoracic fluid were removed during the first two weeks of observation. CP-32, with the abnormal origin of the pulmonary artery, had severe pulmonary edema after any activity. CF-33, with pulmonic stenosis, and C-43, with patent ductus arteriosus, developed more severe clinical symptoms with increasing body size, especially after they were six months old.
ELECTROLYTE AND PROTEIN CONCENTRATION (TABLE 1) Sodium (Na)
The Na concentration of the abnormal body fluids (ascitic, thoracic, and interstitial edema fluids) was essentially the same as that of the plasma, which is given in table 1. Hyponatre-mia- was observed in four dogs (11 per cent) in the congested state. The plasma Na
(inBq./L.) in these dogs was as follows: MF-9, 130; HF-13, 109; HF-26, 131; and MF-104, 118. All other dogs had an average
normal plasma Na of 144 (138 to 147) inEq./L.
Potassium (K)
The K concentrations were variable, even in the same dog from day to day, in contrast to the stability of the Na levels. The K level
of ascitic and other abnormal fluids varied no more than 0.5 mEq./L. from plasma. The average plasma K in the MI and heartworm dogs in failure Mras 4.8 (3.6 to 5.7) and 5.5 (4.2 to 6.8) mEq./L., respectively. Six MI and six heartworm dogs not in failure had aver-age plasma K levels of 4.7 (3.8 to 5.6) and 4.9 (4.2 to 5.8) mEq./L., respectively. These K levels are considered to be in the normal range of 3.5 to 6.3 (mean 4.7) found by Leveque in normal dogs.13
Protein
The average protein concentration of the plasma of the MI dogs in failure was 4.8 Gm./lOO cc, which was much lower than the range of 6.5 to 7.0 Gm./lOO cc. found in nor-mal dogs at this laboratory. In the heartworm dogs in failure, the plasma protein concen-tration was 6.0 Gm./lOO cc. The average pro-tein concentration of the ascitie fluid in the MI dogs was 3.0 Gm./lOO cc. as compared to 3.8 Gm./lOO cc. in the heartworm dogs. The average protein concentration of the thoracic fluid in the MI dogs was 2.0 Gm./lOO cc. as compared to 2.4 Gm./lOO cc. in the heartworm dogs. The average protein concentration of the interstitial edema fluid in the MI dogs was 0.8 Gm./lOO ce. as compared to 0.5 in the heartworm dogs. Edema fluid collected from various locations would vary in protein con-centration because of trauma from the needle and digital pressure necessary to obtain the sample. There was no correlation of protein concentration with the dependence of parts of the body. In HF-40, lymph collected by cannulation of an engorged lymph duct of the liver had 0.5 Gm./lOO cc. less protein than the plasma.
The average albumin-to-globulin ratio (A/G) of the ascitic fluid and the plasma of five MI dogs in failure was 0.51 and 0.45, re-spectively. In four heartworm dogs in failure, these A/G ratios were 0.35 and 0.27, respec-tively. During periods of recovery, these ratios increased with increasing protein con-centrations. The average A/G ratio of the plasma of 38 normal dogs (78 determinations) by the same method was 0.46. (Personal com-Circulation Research, Volume XI. August 196S
munication from Dr. W. S. Harms, Medical College of Georgia, Augusta, Georgia.) SODIUM EXCRETION (TABLE 2)
In normal dogs, about 90 per cent of the ingested Na is excreted in the urine. In the dogs in congestive failure, the urine Na ex-cretion was greatly reduced, as shown in table 2. Although urine volumes were below normal, the more important cause of the low Na ex-cretion was the low urinary Na concentration. In these dogs, the Na excretion was not de-pendent on the intake. For example, heart-worm dog HF-46 excreted 31 and 29 niEq. of Na in the urine on two successive days when the Na intake was 34 and 73 mEq., respec-tively.
The marked increase of urinary Na excre-tion by digitalis therapy in dogs MF-10, HF-5, HF-39, HF-46, and CF-30 is shown in table 2. In contrast, in clogs MF-10 and HF-5, the urinary Na excretion was very low during the oral administration of Na-absorbing resin.* HF-5 retained Na for a few days fol-lowing an insecticidal bath in malathion,T an anticholinesterase compound, as shown in fig-ure 3. This preparation has proved very effec-tive for tick control.
In the dogs with miscellaneous conditions, the urinary Na excretion was below normal in those with retained fluids (ascitic or tho-racic fluids). This abnormality occurred re-gardless of venous pressure. MS-4, with adeno-carcinoma involving about 75 per cent of the lung tissue, had a central venous pressure of 20 cm. saline and right ventricular systolic pressure of 60 mm. Hg, but did not exhibit fluid retention.
RIGHT HEART CATHETERIZATION VALUES (TABLE 1)
The average right at rial pressure (RAP) was 11.5 mm. Hg in the dogs in failure as compared to 2.5 mm. Hg in those not in fail-ure. The MI dogs in failure had a narrow *Ciirbo-Kesiii, donated by Eli Lilly & Company, Indianapolis, Indiana.
tEctotiiion, donated by Allied Laboratories, Inc., Indianapolis, Indiana. Eetothion is malathion (16% per cent) phis Kotenone and cube resins to immo-bilize insects.
Circulation Research, Volume XI, August 1962
range of right ventricular systolic pressure (RVSP) of 40 to 56 mm. Hg (average 46 mm. Hg in nine dogs). Heartworm dogs in failure had a much higher average RVSP of 90 mm. Hg (range of 55 to 158 mm. Hg). Heartworm dogs not in failure had an average RVSP of 42 mm. Hg. The average pulmonary wedge
pressure (PWP) Mras 14 mm. Hg in seven
dogs in failure and 8 mm. Hg in seven dogs not in failure.
FEMORAL ARTERY PRESSURES (TABLE 1)
Pressures were usuallj' obtained secondarily to other procedures with the dogs in light surgical plane of anesthesia from morphine sulfate, 5 mg./Kg. body weight, subcutane-ously, and sodium pentobarbital, by vein in 3 per cent solution. These dogs are very sensi-tive to pentobarbital, which must be given very carefully to produce light anesthesia. So as not to kill the animal, it has been found best to administer at first not more than 10 mg./Kg. bod3r weight. Pressures were within normal limits but. tended to be lower during the last few days before death, as in MF-1, CF-33, and MF-54. Pressures tended to be higher when morphine sulfate was not used. Prominent pulse pressures of 86 and 97 mm. Hg, respectively, were observed in CF-30, with the arteriovenous fistulas, and C-43, with the patent ductus arteriosus.
T 1824 SPACE (TABLE 1)
In 12 conscious dogs in failure, the average plasma and blood volumes were 75 and 118 cc./Kg. body weight, respectively. Seven dogs not in failure, or after recovery, had average plasma and blood volumes of 59 and 95 cc./ Kg. body weight, respectively, the usual nor-mal figure. MS-25, a MI dog with purulent pleuritis, had a normal blood volume of 87 ec./Kg. body weight and normal venous pres-sure, but had ascitic fluid, thoracic fluid, and interstitial edema. MS-34, a MI dog with splenic infarction and loss of blood into the abdominal cavity, had a blood volume of only 70 cc./Kg. body weight, but also had thoracic fluid.
PRE- AND POSTMORTEM HEART SIZES
The average premortem heart size calcu-lated from radiograms of 22 dogs in
WALLACE, HAMILTON
TABLE 2
SODIUM INTAKE AND EXCRETION FOR VARIOUS GROUPS OF DOGS
D O G SOOIUM INTAKE (MEO) URINE URINE VOLUME I CONCN. (LITER) I (MEC/U URINE N A EXCRETION TOTAL (MEO) N A FECAL NA EXCRETION (MEW TOTAL N A EXCRETION (MEQ)
A. Ml DOGS IN CONGESTIVE FAILURE MF 1 MF 8 MF 9 MF10 MF18 MF29 MF53 MF54 MF57 34 34 5 8 22 68 87 114 O.08 0.17 0.45 0.55 0.13 1.33 0.38 1.02 25 60 2 M 118 1 3 1 7 3 35 2 S3 f 0 6 0 (DIGITALIZED) 1 6 (BAR THERAPY) 1 2 3 3
B. Ml DOGS NOT IN CONGESTIVE FAILURE M 8 M 9 M 17 M 20 M 31 74 28 125 13-145 44-180 9 39 (DIARRHEA) 12 42 • 75 +72 C. HEARTWORM DOGS IN HF S HF 6 HF13 HF26 HF27 HF28 HF36 HF39 HF46 68 68 73 104 60 34 73 102 34 73 68 68 73 (5 0.80 2.50 2.30 0.48 0.50 0.58 0.38 0.75 1.35 1.24 1.04 1.26 1.85 1.15 CONGESTVE i i 100 1 1 1 3 62 7 28 11 125 25 28 67 34 46 VE FA 9 250 3 1 1 36 3 8 169 31 29 85 62 53 [LURE 13 368 4 1 36 9 11 166 91 40 125 ( 92 ( 73 (DIGITAL.IZED) (BAR THERAPY) 12 3 (DIGITALIZEO) 4 P. HEARTWORM DOGS NOT IN CONGESTIVE FAILURE
H 5 H28 H37 H55 102 68 54 107 118 1.90 1.60 0.35 1.20 0.96 55 36 112 83 too 106 58 39 96 96 104 85 72 90 81 41 57 +32 +16 23 (DIARRHEA)
E. DOGS WITH CONGENITAL CARDIOVASCULAR DEFECTS CF30 CF33 68 51 73 0.48 0.65 0.95 2 122 23 1 79 22 2 116 (DIGITALIZED 30 F. DOGS MS 2 MS 3 MS 4 MS25 MS34 MS44 MS48 MS58 WITH 68 27 34 68 41 MISCELLANEOUS 0.55 0.69 0.56 0.99 0.18 7-16 18 146 4 4 1 48 7 CONDITIONS 80 3 2 47 1 118 11 6 69 3 II 2 119 58 3 • 10 +38
• 2ti hour period.
Circulation fteaea-rch. Volume XI. August 196S
tive failure was 49 (30 to 64) cc./Kg. body weight as compared to 27 (15 to 41) cc./Kg. body weight in 20 dogs not in failure or after recovery. In the series of normal dogs studied by Hamilton et al., the average heart size was 18 cc./Kg. body weight.7
The average heart weight (Gm./Kg. body weight) without contents of 15 MI dogs that had been in failure was 12.2; of 17 heartworm dogs that had been in failure, 10.8; of 16 heartworm dogs that had not been in failure, 8.4; and of 15 miscellaneous dogs without heart disease, 7.4. Dogs with congenital cardiovascular defects had heart weights as follows: CF-30, 11.9; CF-33, 10.8; and C-43, 12.1. Northup et al. found an average heart weight of 7.6 Gm./Kg. body weight in 346 normal dogs.
The same range of left ventricular wall thickness from 6 to 15 mm. was found in the Ml, heartworm, and miscellaneous dogs; how-ever, heart weight was much higher in the dogs with cardiac stress, as indicated in the preceding paragraph. The range of right ven-tricular wall thickness in the MI dogs and the dogs with miscellaneous conditions was 3 to 7 mm., as compared to a range of 4 to 11 mm. in the heartworm dogs. The average ra-tios of left to right ventricular wall thickness in the miscellaneous dogs without heart dis-ease was 2.4; in the MI dogs in failure, 1.9; in the hea.rtworm dogs not in failure, 1.9; and in the heartworm dogs in failure, 1.6. Although the average heart weight of the MI dogs was higher than that of the miscel-laneous dogs, the ratio of left to right ven-tricular wall thickness was less because of dilation of the left ventricle of the MI dogs. The low ratio of left to right ventricular wall thickness in the heartworm dogs in failure was from hypertrophy of the right wall.
In figure 2, the ratios of the left to right ventricular weight are plotted against the total ventricular weights of the dogs at au-topsy. There is no significant difference in the ventricular weight ratios of the miscella-neous dogs without heart disease, the heart-worm dogs not in failure, and the MI dogs in failure, although total heart weight on a Circulation Research, Volume XI, August 196S
1 5
-<1 |O - ft
DHeortworm DOO> in foilurt O M I Oogs In tollurt • Muctllantoui c* • COogt witn coi.gamtal
cordie-votculor d t l t c U
o 0 O
0 05 1.0 1.5 2.0 2.5 3.0 RATIO OF LEFT TO RIGHT VENTRICULAR WEIGHT
FIGURE 2
Relationship of ratio of left to right ventricular weight to total heart weight of various groups of dogs. Aortic stenosis (AS), arteriovenotis fistulas
(AY), patent ductus arteriosus (PDA), pseudo-pulmonary artery (PPA).
body weight basis was higher in the last two groups of dogs than the miscellaneous dogs. As shown in figure 2, predominant left ven-tricular masses were found in few dogs.
Most of the heartworm dogs in failure and certain dogs with congenital defects, CF-32 with the abnormal origin of the pulmonary artery, and CF-33 with pulmonic stenosis had severe right ventricular hypertrophy, with maximal hypertrophy approaching a threefold increase of right ventricular mass. A large series of normal dogs had an average left to right ventricular weight ratio of 1.46 deter-mined by the Lewis method.15
CARDIAC INDICES (TABLE 3)
A limited number of cardiac indices were measured and are summarized in table 3. The pulse-pressure method was not suitable
be-TABLE3 CARDIAC INDICES n r
Ml DOGS IN FAILURE
HEARTWORM DOGS IN FAILURE
MF 1 M F 10 HF 5 HF 74 HEARTWORM DOGS NOT IN FAILURE H 5 H 73 H 75 H 76 H 82 H 84 3. 3 (TICK) 3. 5 cov.i 3. 8 (ovo 5.3 (••,«> 6.5 tF!C 5. 7 iric 4.8 (.1C 4.7 (PIC 4.8 (PIC 6.0 ( r . PULMONIC STENOSIS DOG CF 33
TABLE 4 EFFECT OF THERAPY ON VARIOUS DOGS IN CONGESTIVE FAILURE
CTIOI_OOV A. Ml DOGS B. HEARTWORM DOGS C. DOGS WITH CONGENITAL CARDIO-VASCULAR DEFECTS • o o N O . M F I M F 8 MFIO MFI8 MF20 MF29 MF53 MF5« MF57 MF78 H F 5 H F 6 HF13 HF27 HF28 HF35 HF39 HF40 HF46 HF74 CF30 CF32 CF33 CAGE <OAV«> 3 19 5 8 5 7 3 5 4 8 16 1 4 7 R E S T <KO) + 0.5 — + 5.0 0 0 0 . 0 0 . 0 + 2.5 -0 . -0 0.0 — - 4 . 1 0 0 + 52 0.0 NA-ABSORBIN 4-15 — 7 - ^ 5 7 8 0 . 5 5 . 4 3.5 2.7 2.6 2.2 2 . 4 9 RESIN (KQ) -1.0 -1.5 -5.0 -2.4 -1.0 -1.6WITH — - 1 . 3 W I c <OAV«> , 7 9 3 MO. 6 MO. 3 MO. 4 MO. 5 MO. 3 MO. - 18 19 m £ 10 s 3 M0. 2 M0. 2 M0. 4 M0. , -j WITH -WITH — 9 lOITALI 221 22 8 22 44 55 66 25 38 50 14 7 22 40t 20 2 0 22 22} 2 9 J 36$ 14 - 1 4 - 1 5 15 CKANQC (KG) - 1 8 0 . 0 —2. 9 0 . 0 - 4 . 5 0 . 0 - 2 . 6 - 0 . 6 - 1 . 8 • • »
-CXPIRCD ONE MONTH LATCR
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EXPIRED
LATER AS OUTPATIENT
EXPIRED
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EXPIRED
EXPIRED FIVB MONTHS
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CUTHAMASIA APTER ONE YEAR
THERAPY AS OUTPATIENT
CXPIRCD AFTER ONE YEAR
THERAPY AS OUTPATIENT
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CXPIRCO AFTER ONE MOMTH OP
DIGITALIS THEPJAPY
•TJ.S.P. digitiilis leaf, mg./Kg./body weight, unless otherwise (Denoted. tDigoxin, Mg./Kg./bocly weight.
tGitnlin, Aig./Kg./borly weight. §Digitoxin, Mg./Kg./body weight.
cause of arrhythmias and poor pulse charac-teristics and could not be used in calculating the stroke volume. The cardiac output of CF-33 with pulmonic stenosis (6 mm. diameter) was about one-half normal. The average car-diac index of four dogs in failure by the Fick and dye methods was 4.0, as compared to an average cardiac index of 5.4 in six dogs not in failure.
THERAPY
Paracentesis to remove ascitic fluid was done only when necessary to relieve severe respiratory distress. Thoracic fluid was usii-ally removed daily when present. After
ob-serving effects of restriction of physical activity by cage rest, or as the primary ther-apy, either sodium-absorbing resin (SAR) or digitalis was administered. In a few dogs, these two methods were combined. Hydro-chlorothiazide (HC) was used with digitalis in a limited number of dogs. A high protein intake was encouraged by feeding lean beef, horsemeat, milk, eggs, and palatable commer-cial dog foods. Water intake was not re-stricted.
Cage Rest (Table 4)
Only two dogs improved with cage rest. MF-78 recovered from pulmonary edema with Circulation Research, Volume XI, August 1962
no aseitic fluid present at that time. HF-28 lost 4.1 Kg. body weight with loss of aseitic fluid during an eight-day rest period. Con-gestive failure again developed in this dog during continued cage rest about two months later because of multiple eraboli from dead heartworms in the pulmonary arteries.
Sodium-absorbing Resin (SAR) (Table 4)
Earlier work at this laboratory has shown that negative sodium balance can be produced in dogs in experimental congestive states by oral administration of SAR.16 As the SAR dosage was increased, the urinary volume in-creased, but the urinary Na excretion de-creased, and the fecal Na excretion increased. Work by "Weston and others has shown similar results in man.17
Occasionally, the use of SAR in dogs in fail-ure will lower the plasma Na concentration. In MF-10, the plasma Na decreased from 144 to 134 mEq./L., then returned to normal four days after SAR therapy was stopped. In HF-6, the plasma Na decreased from 138 to 120 mEq./L. Potassium levels were not affected during these changes in the Na levels.
After it was demonstrated that cage rest was of little or no therapeutic value in MF-1, HF-6, and HF-27, SAR therapy caused rapid body weight losses (diuresis), as shown in ta-ble 4. SAR was used as initial therapy in MF-10, HF-5, CF-30, and CF-33. Typical physiological changes in these dogs when SAR produced negative Na balance and body weight loss are shown in figure 3.
Digitalis (Table 4)
U.S.P. digitalis leaf was used for therapy except for limited use of digitoxin, digoxin, gitalin, and ouabain. After unsuccessful pe-riods of cage rest in MF-10, HF-5, HF-39, and CF-30, digitalis therapy caused rapid body weight losses, as shown in table 4. Typ-ical physiologTyp-ical changes in these dogs when digitalis produced negative Na balance are shown in figure 3.
The minimal effective daily maintenance dosage of digitalis was found to be 14 ing./ Kg. body weight. With continued use, it was found that the dosage of digitalis had to be Circulation Research, Volume XI. August 1962
increased, as shown in table 4 for MF-56, MF-57, and HF-74. These dogs were carefully monitored by BCG for a year, at which time the maintenance dosage of digitalis had to be increased 50 to 100 per cent.
Initial digitalization was usually done orally, but in some cases ouabain (maximum dose of 1 mg.), digitoxin (maximum dose of 1 mg.), and digoxin (maximum dose of .1.6 mg.) were given intravenously with ECG monitoring for a two- to four-hour period. Occasional toxicity, as shown by arrhythmias, was counteracted by slow intravenous drip of KC1. with continuous ECG monitoring.
Discussion
A series of dogs with chronic valvular dis-ease (mitral insufficiency), Dirofilariasis, congenital cardiovascular defects, and other conditions have been studied. Dogs in con-gestive heart failure exhibited tachycardia, increased cardiac size, decreased salt and water excretion, increased blood volume, de-creased plasma protein, accumulation of ex-tracellular fluid, increased central venous pressure, and increased right ventricular pressure.
The tachycardia was often accompanied by arrhythmias. Betopic ventricular systoles were commonly observed in these dogs, re-gardless of etiology of cardiac disease. Atrial fibrillation was observed in 5 of the 17 MI dogs in failure and in the dog with pulmonii: valve stenosis. None of the dogs with pulmo-nary hypertension from heartworms developed atrial fibrillation. From gross examination of the heart, the greatly increased size of the left atrium in the MI dogs was probably an im-portant factor in development of atrial fibril-lation. The atrial endocardium of the MI dogs had many impingement plaques and often had been torn, with hemorrhage into the atrial wall.
The mean electrical axis of the QRS com-plex in the dogs studied varied considerably as in normal dogs.18 The average mean elec-trical axis of the MI dogs in failure Avas 100 degrees; of the heartworm dogs not in failure, 97 degrees; and of the heartworm dogs in
PROTEIN Igm/IOOcc) 10 20 MARCH 30 10 FEBRUARY FIGURE 3
Physiological affects on dog HF-5 of sodium-absorbing resin •ind digitalis therapy during two periods of congestive heart failure. Net daily sodium balance is indicated by value at bottom of each bar, which is derived by first plotting the sodium intake (>-<.) and then subtracting graphically the excreted sodium. Loss of ascitic fluid ('), sodium-absorbing resin (S.A.R.), plasma volume (P.V.), blood volume (B.V.).
failure, 154 degrees. The right axis deviation of the heartworm dogs in failure correlated with the right ventricular enlargement ob-served by radiogram and at autopsy, and with the average RVSP of 90 mm. Hg. Often the heart from a dog with severe pulmonary hypertension had a double apex. The similar MEA of the MI dogs in failure and the heart-worm dogs not in failure correlated with the average RVSP of 46 and 42 mm. Hg, respec-tively, and with the similax ratio of left to right ventricular wall mass.
Heart volume varied considerably, but was much larger in the dogs with cardiac disease than in normal dogs. The heart volume was 30 cc./Kg. body weight or larger in dogs in failure, as compared to 18 cc./Kg. body weight in normal dogs. Dogs not in failure had heart volumes less than 40 cc./Kg. body weight. After therapy, several dogs evidently
compensated while the heart size remained above 40 cc./Kg. body weight, as shown in figure 3. Heart volumes decreased very slowly even after removal of excess blood volume, removal of excess extracellular fluids, and reduction of venous pressure, regardless of the type of therapy. These calculated heart volumes were diastolic, and any changes in systolic size were not measurable. Due to the method, it is not possible to detect small changes of total heart volume, which could be associated with significant changes in stroke volume. Diastolic heart volumes decreased over a period of months in compensated dogs. In terminal eases, the extent of dilation was not uniform, but the diastolic heart volume approached three times normal. The maxi-mum heart volume observed was 64 cc./Kg. body weight in CF-30.
Right ventricular hypertrophy was evident
Circulation Research, Volume XI, August tset
in the heartworin dogs in failure by increased right ventricular mass and wall thickness. Although left ventricular mass was also in-creased in MI dogs in failure, wall thickness was within normal range, but dilation was prominent. Increased systolic pressure is perhaps the strongest stimulus to hypertrophy in these spontaneous failure dogs, as observed in the heartworm dogs with pulmonary hyper-tension and in CF-32 and CF-33, in compari-son to MI dogs with increased left myocardial work at normal systolic pressures.
Urinary sodium excretion was greatly re-duced in the dogs in congestive failure because urine volumes were about one-half normal and the average urinary Na concentration was usually less than 20 mEq./L. During recov-ery, urinary Na excretion increased and much of the ascitic pool was removed while the ve-nous pressure was still elevated. After re-moval of most of the extracellular fluids, the venous pressure decreased rapidly during a two- to three-day period. This drop of venous pressure just before complete removal of the aseitic pool is shown in figure 3.
During these periods of reduced Na excre-tion, the blood volume increased and the plasma protein concentration decreased. Dur-ing formation of ascitic fluid the plasma pro-tein concentration continued to decrease. The minimal plasma protein concentration ob-served in dogs in congestive failure was 4.2 Gm./lOO cc. These changes of protein con-centration are shown in figure 3. With the increase of Wood volume, the total blood pro-tein remained the same or increased, even though the protein concentration decreased. Total protein in the blood and extracellular fluids was much higher than total blood pro-tein in a normal dog or a dog after recovery. For example, HF-5 had approximately 190 6m. of protein in the plasma and ascitic fluid when in failure as compared to 120 Gm. of protein in the plasma after recovery. During periods of increased Na excretion and loss of excess extracellular fluids, the blood volume decreased and the plasma protein concentra-tion increased. After loss of the excess fluids, the rate of increase of plasma protein dimin-Circulation Research, Volume XI, August 1962
ished rapidly. Changes in blood volume were caused by plasma rather than red blood cell volume changes.
Interstitial edema in the dogs in failure had very low protein concentration varying from 0.4 to 1.2 Gm./lOO cc. Inflammatory edema from a dog had 3.2 Gm./lOO cc. and edema fluid adjacent to extensive mammary tumors in another dog had 1.6 Gm./lOO cc. Edema in the dog was very transient and edema fluid was the extracellular fluid first reduced with successful therapy. If thoracic fluid was not removed by thoracocentesis, it was more difficult to reduce therapeutically than ascitic fluid. However, thoracic fluid did not recur after removal by thoracocentesis if the dog was in negative sodium balance. Dogs in congestive failure had increased venous pressure. Limited observations of six dogs during the period just before ascitic fluid was detected indicated sodium and water retention before maximum venous pressure developed. MF-8 initially had pulmonary edema and 11 cm. saline venous pressure. Nineteen days later, the dog had much ascitic fluid and 15 cm. saline venous pressure. Plasma protein had decreased from 5.6 to 4.7 Gm./lOO cc. MF-9, MF-10, HF-5, HF-2S, and HF-36 exhibited similar changes. These changes in HF-28 during a period of Na re-tention are shown in figure 4.
The right ventricular systolic pressure was increased in all the dogs in congestive failure. In nine MI dogs, the average 1WSP was 46 mm. Hg. MF-78, with severe pulmonary edema, had a RVSP of 48 nun. Hg, which decreased to 35 mm. Hg with cage rest and loss of the pulmonary edema. Pulmonary hypertension was prominent in the heart-worm dogs. In dogs with heartheart-worm micro-filaria in the blood, but not in failure, the average RVSP was 42 mm. Hg. In heart-worm dogs in failure, the average RVSP was 90 mm. Hg. It was evident that the right ventricle could function at much higher sys-tolic pressures than found in the MI dogs in failure. In the dogs in failure the aver-age right ventricular diastolic pressure was 10 mm. Hg. Diastolic overloading may have been
WALLACE, HAMILTON BODY 2 4 WEIGHT ~0 (kg) 18 80 SODIUM 6 BALANCE 40 (meq) 20 + 0 2 0 VENOUS | g PRESSURE ,2 (cm. water) Q 4 HEART ..SWl 2 6 V O L U M E( c c l, ,o l ) | 4 7 5. P V ( « / » . M><ir.i)| 6 8 -B.V. (ee/»gbo<,.t)| I I I " >—< No intake D Urinary No 3 9 - -720-- 6 3 -1150 —130 —160 PLASMA ASCITIC FLUID PROTEIN 7 (gm/IOOcc) 6 5 4 TIME (days) ° 410 2 0 30 4 0 50 60 FIGURE 4
Physiological changes in clog HF-28 during ac-cumulation of ascitic fluid. Plasma volume (P.V.), blood volume (B.V.).
a more important factor in right ventricular function in these dogs in failure considering the greatly increased diastolic heart volume observed by radiogram. Although myocardial degeneration and necrosis was often observed, it was sometimes conspicuously absent. Elim-ination of excess extracellular fluids and re-duction of venous pressure by therapy allowed these dogs to compensate.
Pulmonary hypertension in the heartworm dogs developed over a period of months de-pending on the number of heart-worms and, more importantly, the individual susceptibil-ity of the dog. The most rapid increase of RVSP was observed terminally in HP-75. When first observed, the RVSP was 111 mm. Hg; two weeks later, 125 mm. Pig; and six weeks later, 158 mm. Hg. At autopsy the lungs had severe edema, congestion, and hem-orrhage. In dogs with natural infestation, the RVSP increased from 38 to 55 mm. Hg during 4 months in HP-5, from 22 to 29 mm. Hg during 12 months in H-55, from 33 to 47 mm. Hg during 12 months in H-71, and from 37 to 50 mm. Hg during 7 months in H-87.
Mechanical blockage in the pulmonary arter-ies or pulmonic valve due to the physical presence of the live heartworms was not sig-nificant. In IIF-27, the maximum pressure drop from the right ventricle to the bifurca-tion of the pulmonary artery (PA) was 8 mm. Hg. A large number of heartworms could be palpated in the PA, which dilated during sys-tole to about 4 cm. diameter. Over 200 adult heartworms were removed by pulmonary arteriotomy. It was also observed in these dogs that the same degree of pulmonary hy-pertension was present after surgical removal of the heartworms; therefore, the pathological changes in the pulmonary arterial system were shown to be the cause of the pulmonary hypertension.
Observations on the regression of pulmo-nary hypertension in dogs previously infested with heartworms are limited. In HP-5, the RVSP decreased from 61 to 38 mm. Hg in nine months, then increased to 55 mm. Hg during a four-month period. This dog then maintained a constant RVSP of 55 mm. Hg for two years. The dog was sacrificed and no heartworms were found on autopsy, but the intimal fibrosis of the PA and the presence of heartworm microfilaria in the blood indicated an earlier infestation by heartworms. HP-74, after 15 months on intensive digitalis therapy, has had a reduction of RVSP from 90 to 70 mm. Hg. The clinical response of this animal has been most remarkable; it has progressed from a severe, congested state in which it was unable to walk to being an active mother of a large litter of puppies. The RVSP in H-80 decreased from 37 to 30 mm. Hg in 6 months after surgical removal of heart-worms and treatment with an arsenical compound.* The RVSP in H-82 decreased from 55 to 43 mm. Hg in 10 months, probably due to natural death of the heartworms. In H-97, after surgical removal of heartworms and treatment with arsenic, the RVSP lias remained at 51 mm. Hg for two months. The use of these nematodes to produce pul-*Sodium Caparsolate, Abbott Laboratories, North Chicago, Illinois.
Circulation Research, Volume XI, August 19GX
monary hypertension in the dog is an impor-tant research tool. Adult heartworms can be removed by right ventriculotomy or pulmo-nary arteriotomy from a donor dog, main-tained temporarily in saline with 10 per cent plasma, and then be transplanted into the re-cipient dog. Heartworms can be maintained several days in modified Earl's solution and 10 per cent plasma.18 The easiest method of inserting a heartworm is to fold it over the grooved end of a one-eighth inch diameter plastic rod about 15 inches long and push it carefully down a jugular to the right atrium. The RVSP increased from 30 to 35 mm. Hg in two months in a dog in which 41 heart-wornis were transplanted. In another dog given 5 heartworms, the RVSP increased from 28 to 37 mm. Hg in five months.
Summary
Spontaneous cardiovascular disease has been found in dogs from the Savannah River Valley area, predominantly in the male house pet and hunting dog. The causes have been Dirofilariasis, chronic mitral valvular disease, and congenital cardiovascular defects. Car-diac stress in these dogs caused marked salt and water retention, increased blood volume, increased central venous and right heart pres-sures, and cardiac dilation and hypertrophy. These compensatory mechanisms were similar to those in man. Cardiac dilation was more pronounced in spontaneous failure than in ex-perimental failure. Regression of cardiac di-lation was very slow even after apparent com-pensation and clinical improvement. Plasma protein concentrations were decreased, but total extracellular protein mass was markedly increased. Sodium and potassium plasma con-centrations were within normal range. Hypo-natremia was occasionally observed in dogs as in man.20 Dirofilariasis was characterized by marked pulmonary hypertension, caused primarily by pulmonary vascular changes rather than mechanical blockage. There was massive hypertrophy of the right ventricular myocardium. Heartworm dogs in congestive failure have a similar range of right heart pressure to experimental pulmonic stenosis Circulation Research, Volume XI. August 1962
dogs in failure.21 Cage rest was of little thera-peutic value in these dogs in congestive fail-ure. Clinical response and physiological changes were remarkable with the use of salt-absorbing resin or digitalis compounds caus-ing negative sodium balance. Digitalization of the dog x'equired vigorous individual treat-ment controlled by clinical symptoms and P-R interval of the electrocardiogram. Acquired tolerance to digitalis required increased do-sage levels every few months. The veterinary practitioner who recognizes the necessity of individual digitalization and the importance of detection and removal of thoracic fluid will be rewarded with improved clinical ther-apy of congestive heart failure. Experimental dogs during periods of severe cardiac stress can benefit from adequate digitalization. The similarity of biochemical and physiological changes in spontaneous heart disease, as it occurs in man and in dogs, affords aji avenue for clinical research. This applicability to man is enhanced because the dog can be more comprehensively studied.
References
1. BARBOUB, H. G., AND HAMILTON, W. F . : Falling
drop method for determining specific gravity. J. Biol. Chem. 69: 625, 1926.
2. WEECH, A. A., REEVES, E. B., AND GOETTSCH,
E.: Relationship between specific gravity and protein content in plasma, serum, and transu-date from dogs. J. Biol. Chem. 113: 167, 1936.
3. BECKMAN-SPINCO INSTRUCTIONAL MANUAL,
RIM-5: Model R. Paper Electrophoresis System, Beckman-Spinco Division, Stanford Industrial Park, Palo Alto, California.
4. GREGERSEN, M. I., GIBSON, J. G., AND STEAD,
E. A.: Plasma volume determination with dyes; errors in colorimetry; use of blue dye T-1824. Am. J. Physiol. 113: 54, 1935. 5. HAMILTON, W. F., et al.: Comparison of the
Fick and dye injection methods of measuring the cardiac output in man. Am. J. Physiol. 153: 309, 1948.
6. REMINGTON, J. W.: Volume quantitation of the aortic pressure pulse. Fed. Proc. 11: 750, 1952.
7. HAMILTON, W. F., JR., DOW, P., AND HAMILTON,
W. F . : Measurement of volume of dog's heart by x-ray: Effect of hemorrhage, of epi-nephrine infusion, and of buffer nerve sec-tion. Am. J. Physiol. 161: 466, 1950.
314
8. GUYTON, A. C, AND GREGANTI, T. P . : Physiologic
reference point for measuring circulatory pres-sures in the dog—particularly venous pressure. Am. J. Physiol. 185: 137, 1956.
9. LEWIS, T.: Observations upon ventricular hyper-trophy, with especial reference to prepon-derance of one or other chamber. Heart 5: 367, 1913.
10. MUNICH, J.: Antomischo Untersuchungen iiber Endokarditis valvularis beim Hunde. Inaugural Dissertation, Miinchen, 1935.
11. HENNIGAR, G. R., AND FERGUSON, R. W. P . :
Pulmonary vascular sclerosis as a result of Dirofilaria immitis infection in dogs. J. Am. Vet. M. A. 131: 336, 1957.
12. WALLACE, C. R.: Pathophysiology of canine
congestive heart failure (abstr.). Physiologist 2: 119, 1959.
13. LEVEQUE, P. E.: Auricular fibrillation by acetyl-choline injection during hypopotassemin. J. Pharmacol. & Exper. Therap. 120: 38, 1957.
14. NORTHUP, D. W., VAN LIERE, E. J., AND STICKNEY, J. C.: Effect of age, sex, and body
size on the heart weight-body weight ratio in the dog. Anat. Kec. 128: 411, 1957. 15. HERMANN, G. R.: Experimental heart disease:
WALLACE, HAMILTON
1. Methods of dividing hearts; with sectional and proportional weights and ratios for two hundred normal dogs' hearts. Am. Heart J. 1: 213, 1925.
16. HAMILTON, W. F., ELLISON, R. G., PICKERING, R. W., HAGUE, E. E., AND RUCKER, J. T.:
Hemodynamics and endocrine responses to experimental mitral stenosis. Am. J. Physiol.
176: 445, 1954.
17. WESTON, R. E., et al.: Metabolic studies on
the eifects of ion exchange resins in edematous patients with cardiac and renal disease. Am. J. Med. 14: 404, 1953.
18. LOMBARD, E. A., AND WITHAM, A. C.:
Electro-cardiogram of the anesthetized dog. Am. J. Physiol. 181: 567, 1955.
19. EARL, P. R.: Filariae from the dog in vitro. Ann. New York Acad. Sc. 77: 163, 1959.
20. FRIEDBERG, C. K.: Diseases of the Heart, ed.
2. Philadelphia, W. B. Saunders Co., 1956, p. 275.
21. DAVIS, J. 0., HYATT, R. E., AND HOWELL, D. S.:
Right-sided congestive heart failure in dogs produced by controlled progressive constriction of the pulmonary artery. Circulation Research 3: 252, 1955.
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