臺灣博碩士論文加值系統

退化性黏液性二尖瓣疾病(myxomatous mitral valve disease，MMVD)是最常見的狗的心臟疾病，尤其在小型犬盛行。MMVD有慢性黏液性二尖瓣退化的特徵，造成瓣膜小葉的增厚及在收縮期的不完全並置，並繼發二尖瓣逆流(mitral regurgitation，MR)，最後發生鬱血性心衰竭(congestive heart failure，CHF)。交替脈是在一致的搏動速率下，動脈脈搏有強弱搏動交替的現象。此現象在有CHF的病患可見。本研究的目的是使用High-Definition Oscillometry (HDO)裝置(HDO®)研究患有MMVD小型犬的交替脈盛行率及交替脈與CHF的關係。在本研究中納入22隻經檢查而診斷具有黏液性二尖瓣疾病的小型犬，並在同一次門診中有使用HDO裝置檢查的記錄，而HDO裝置可記錄血壓，並透過軟體記錄脈波。根據美國獸醫內科醫學院(American College of Veterinary Internal Medicine，ACVIM)建議的分級系統對有MMVD的犬隻進行CHF的分級。共有12隻(54.6%)病犬呈現有交替脈，且根據Cochran-Armitage趨勢檢定，有CHF級數愈高交替脈盛行率愈高的顯著趨勢(p<0.05)。未接受藥物治療的8隻病犬中，3隻(37.5%)呈現有交替脈，除了有同整體的趨勢外，根據Fisher精準檢定，有無交替脈的兩組間的CHF分級具有顯著的差異(p<0.05)。總結，使用HDO裝置進行脈波分析可識別交替脈的存在，而在有MMVD的小型犬，有交替脈者的CHF分級愈高。

Degenerative myxomatous mitral valve disease (MMVD) is the most common canine heart disease. The prevalence is higher in small-breed dogs. MMVD is characterized by chronic myxomatous mitral valve degeneration resulting in thickening and incomplete apposition of the valve leaflets during systole with secondary mitral regurgitation (MR) and congestive heart failure (CHF) eventually. Mechanical alternans is a phenomenon of alternating strong and weak beats with a constant beat-to-beat interval. The phenomenon has been recognized in patients with CHF. The purpose of the study is to investigate the prevalence and the interaction with CHF of mechanical alternans in small-breed dogs with MMVD using High-Definition Oscillometry (HDO) device (HDO®). In the present study, 22 small-breed dogs diagnosed with MMVD were included which examinations by using HDO device, by which blood pressures and pulse waveforms (via software) can be recorded, were performed at the same visit. The degree of CHF were classified according to the American College of Veterinary Internal Medicine (ACVIM) recommendations for dogs with MMVD. Twelve patients (54.6%) showed mechanical alternans, and there is an increasing trend in the prevalence of mechanical alternans with increasing CHF classes according to Cochran-Armitage trend test (p<0.05). When taking treatment into account, 3 of 8 patients (37.5%) without treatment showed mechanical alternans, and besides the same increasing trend, there is significant difference in CHF classes between groups with and without mechanical alternans according to Fisher’s exact test (p<0.05). In conclusion, the present of mechanical alternans can be detected by using HDO device, and small-breed dogs with mechanical alternans had higher CHF classes.

致謝辭 i
摘要 ii
Abstract iii
目次 iv
圖次 v
表次 vi
第一章 緒言 1
第二章 文獻探討 2
第一節 狗的黏液性二尖瓣疾病(myxomatous mitral valve disease，MMVD) 2
第二節 心臟交替現象(cardiac alternans) 5
第三節 High-Definition Oscillometry (HDO) 7
第三章 材料與方法 9
第一節 樣本來源 9
第二節 心衰竭分級 10
第三節 使用HDO裝置的測量 11
第四節 交替脈的判定 12
第五節 統計分析 13
第四章 結果 14
第五章 討論 26
第六章 結論 29
參考文獻 30
附錄 38

1.Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23:1142-1150.
2.Sisson D, Ettinger SJ. The physical examination In: Fox PR, Sisson D,Moïse NS, eds. Textbook of canine and feline cardiology: principles and clinical practice. 2nd ed. Philadelphia: Saunders, 1999;46-64.
3.Erhardt W, Henke J, Carr A, et al. Techniques In: Egner B, Carr A,Brown S, eds. Essential facts of blood pressure in dogs and cats: a reference guide. 4th ed. Babenhausen: VBS VetVerlag, 2007;28-65.
4.Egner B. High Definition Oscillometry: Non-invasive Blood Pressure Measurement and Pulse Wave Analysis. Handb Exp Pharmacol 2015;229:243-264.
5.Taylor SS, Sparkes AH, Briscoe K, et al. ISFM Consensus Guidelines on the Diagnosis and Management of Hypertension in Cats. J Feline Med Surg 2017;19:288-303.
6.Kodama M, Kato K, Hirono S, et al. Changes in the occurrence of mechanical alternans after long-term beta-blocker therapy in patients with chronic heart failure. Jpn Circ J 2001;65:711-716.
7.Kodama M, Kato K, Hirono S, et al. Mechanical alternans in patients with chronic heart failure. J Card Fail 2001;7:138-145.
8.Buchanan JW. Chronic valvular disease (endocardiosis) in dogs. Adv Vet Sci Comp Med 1977;21:75-106.
9.Detweiler DK, Luginbuhl H, Buchanan JW, et al. The natural history of acquired cardiac disability of the dog. Ann N Y Acad Sci 1968;147:318-329.
10.Detweiler DK, Patterson DF. The prevalence and types of cardiovascular disease in dogs. Ann N Y Acad Sci 1965;127:481-516.
11.Gagna C, Meier D, Ru G, et al. Pathology of mitral valve in regularly slaughtered pigs: an abattoir survey on the occurrence of myxoid degeneration (endocardiosis), fibrosis and valvulitis. Zentralbl Veterinarmed A 1998;45:383-395.
12.Reef VB, Bain FT, Spencer PA. Severe mitral regurgitation in horses: clinical, echocardiographic and pathological findings. Equine Vet J 1998;30:18-27.
13.Pedersen HD, Haggstrom J. Mitral valve prolapse in the dog: a model of mitral valve prolapse in man. Cardiovasc Res 2000;47:234-243.
14.Kvart C, Haggstrom J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med 2002;16:80-88.
15.Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc 2007;231:1061-1069.
16.Borgarelli M, Savarino P, Crosara S, et al. Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease. J Vet Intern Med 2008;22:120-128.
17.Pouchelon JL, Jamet N, Gouni V, et al. Effect of benazepril on survival and cardiac events in dogs with asymptomatic mitral valve disease: a retrospective study of 141 cases. J Vet Intern Med 2008;22:905-914.
18.Chetboul V, Serres F, Tissier R, et al. Association of plasma N-terminal pro-B-type natriuretic peptide concentration with mitral regurgitation severity and outcome in dogs with asymptomatic degenerative mitral valve disease. J Vet Intern Med 2009;23:984-994.
19.Serres FJ, Chetboul V, Tissier R, et al. Doppler echocardiography-derived evidence of pulmonary arterial hypertension in dogs with degenerative mitral valve disease: 86 cases (2001-2005). J Am Vet Med Assoc 2006;229:1772-1778.
20.Carlsson C, Haggstrom J, Eriksson A, et al. Size and shape of right heart chambers in mitral valve regurgitation in small-breed dogs. J Vet Intern Med 2009;23:1007-1013.
21.Chiavegato D, Borgarelli M, D'Agnolo G, et al. Pulmonary hypertension in dogs with mitral regurgitation attributable to myxomatous valve disease. Vet Radiol Ultrasound 2009;50:253-258.
22.Stepien RL. Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs. J Small Anim Pract 2009;50 Suppl 1:34-43.
23.Lord P, Hansson K, Kvart C, et al. Rate of change of heart size before congestive heart failure in dogs with mitral regurgitation. J Small Anim Pract 2010;51:210-218.
24.Borgarelli M, Zini E, D'Agnolo G, et al. Comparison of primary mitral valve disease in German Shepherd dogs and in small breeds. J Vet Cardiol 2004;6:27-34.
25.Borgarelli M, Tarducci A, Zanatta R, et al. Decreased systolic function and inadequate hypertrophy in large and small breed dogs with chronic mitral valve insufficiency. J Vet Intern Med 2007;21:61-67.
26.Swenson L, Haggstrom J, Kvart C, 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.
27.Olsen LH, Fredholm M, Pedersen HD. Epidemiology and inheritance of mitral valve prolapse in Dachshunds. J Vet Intern Med 1999;13:448-456.
28.Borgarelli M, Haggstrom J. Canine degenerative myxomatous mitral valve disease: natural history, clinical presentation and therapy. Vet Clin North Am Small Anim Pract 2010;40:651-663.
29.Haggstrom J, Kvart C, Hansson K. Heart sounds and murmurs: changes related to severity of chronic valvular disease in the Cavalier King Charles spaniel. J Vet Intern Med 1995;9:75-85.
30.Pedersen HD, Haggstrom J, Falk T, et al. Auscultation in mild mitral regurgitation in dogs: observer variation, effects of physical maneuvers, and agreement with color Doppler echocardiography and phonocardiography. J Vet Intern Med 1999;13:56-64.
31.Pedersen HD, Kristensen B, Norby B, et al. Echocardiographic study of mitral valve prolapse in dachshunds. Zentralbl Veterinarmed A 1996;43:103-110.
32.Bonagura JD, Schober KE. Can ventricular function be assessed by echocardiography in chronic canine mitral valve disease? J Small Anim Pract 2009;50 Suppl 1:12-24.
33.Traube L. Ein Fall von Pulsus Bigeminus nebst Bemerkungen uber die Leberschwellungen bei Klappenfehlern und uber acute Leberatrophie. Ber Klin Wochenschr 1872;9:185-188.
34.Windle JD. The incidence and prognostic value of the pulsus alternans in myocardial and arterial disease. Quart J Med 1913;6:453-462.
35.Dilly SG, Lab MJ. Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. J Physiol 1988;402:315-333.
36.Smith JM, Clancy EA, Valeri CR, et al. Electrical alternans and cardiac electrical instability. Circulation 1988;77:110-121.
37.Verrier RL, Nearing BD. Electrophysiologic basis for T wave alternans as an index of vulnerability to ventricular fibrillation. J Cardiovasc Electrophysiol 1994;5:445-461.
38.Armoundas AA, Tomaselli GF, Esperer HD. Pathophysiological basis and clinical application of T-wave alternans. J Am Coll Cardiol 2002;40:207-217.
39.Dumitrescu C, Narayan P, Efimov IR, et al. Mechanical alternans and restitution in failing SHHF rat left ventricles. Am J Physiol Heart Circ Physiol 2002;282:H1320-1326.
40.Blatter LA, Kockskamper J, Sheehan KA, et al. Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes. J Physiol 2003;546:19-31.
41.Armoundas AA, Hohnloser SH, Ikeda T, et al. Can microvolt T-wave alternans testing reduce unnecessary defibrillator implantation? Nat Clin Pract Cardiovasc Med 2005;2:522-528.
42.Martin DT, Shoraki A, Nesto RW, et al. Influence of diabetes and/or myocardial infarction on prevalence of abnormal T-wave alternans. Ann Noninvasive Electrocardiol 2009;14:355-359.
43.Ren L, Fang X, Wang Y, et al. T-wave alternans and heart rate variability: a comparison in patients with myocardial infarction with or without diabetes mellitus. Ann Noninvasive Electrocardiol 2011;16:232-238.
44.Merchant FM, Armoundas AA. Role of substrate and triggers in the genesis of cardiac alternans, from the myocyte to the whole heart: implications for therapy. Circulation 2012;125:539-549.
45.Euler DE. Cardiac alternans: mechanisms and pathophysiological significance. Cardiovasc Res 1999;42:583-590.
46.Weiss JN, Karma A, Shiferaw Y, et al. From pulsus to pulseless: the saga of cardiac alternans. Circ Res 2006;98:1244-1253.
47.Weiss JN, Nivala M, Garfinkel A, et al. Alternans and arrhythmias: from cell to heart. Circ Res 2011;108:98-112.
48.Qu Z, Nivala M, Weiss JN. Calcium alternans in cardiac myocytes: order from disorder. J Mol Cell Cardiol 2013;58:100-109.
49.Lu HH, Lange G, Brooks CM. Comparative studies of electrical and mechanical alternation in heart cells. J Electrocardiol 1968;1:7-17.
50.Spear JF, Moore EN. A comparison of alternation in myocardial action potentials and contractility. Am J Physiol 1971;220:1708-1716.
51.Gilbert JL, Janse MJ, Lu HH, et al. Production and abolition of alternation in mechanical action of the ventricle. Am J Physiol 1965;209:945-950.
52.Floyd WL, Dillon ML. Observations on sustained pulsus alternans during hypothermia. Am Heart J 1967;73:765-776.
53.Wohlfart B. Analysis of mechanical alternans in rabbit papillary muscle. Acta Physiol Scand 1982;115:405-414.
54.Hirayama Y, Saitoh H, Atarashi H, et al. Electrical and mechanical alternans in canine myocardium in vivo. Dependence on intracellular calcium cycling. Circulation 1993;88:2894-2902.
55.Huser J, Wang YG, Sheehan KA, et al. Functional coupling between glycolysis and excitation-contraction coupling underlies alternans in cat heart cells. J Physiol 2000;524 Pt 3:795-806.
56.Kockskamper J, Blatter LA. Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes. J Physiol 2002;545:65-79.
57.Kockskamper J, Zima AV, Blatter LA. Modulation of sarcoplasmic reticulum Ca2+ release by glycolysis in cat atrial myocytes. J Physiol 2005;564:697-714.
58.Florea SM, Blatter LA. The role of mitochondria for the regulation of cardiac alternans. Front Physiol 2010;1:141.
59.Surawicz B. Effect of Ca on Duration of Q-T Interval and Ventricular Systole in Dog. Am J Physiol 1963;205:785-789.
60.Badeer HS, Ryo UY, Gassner WF, et al. Factors affecting pulsus alternans in the rapidly driven heart and papillary muscle. Am J Physiol 1967;213:1095-1101.
61.Florea SM, Blatter LA. Regulation of cardiac alternans by beta-adrenergic signaling pathways. Am J Physiol Heart Circ Physiol 2012;303:H1047-1056.
62.Smith RM, Visweswaran R, Talkachova I, et al. Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart. Am J Physiol Heart Circ Physiol 2013;305:H9-18.
63.Lab MJ, Lee JA. Changes in intracellular calcium during mechanical alternans in isolated ferret ventricular muscle. Circ Res 1990;66:585-595.
64.Orchard CH, McCall E, Kirby MS, et al. Mechanical alternans during acidosis in ferret heart muscle. Circ Res 1991;68:69-76.
65.Parmley WW, Tomoda H, Fujimura S, et al. Relation between pulsus alternans and transient occlusion of the left anterior descending coronary artery. Cardiovasc Res 1972;6:709-715.
66.Weber KT, Janicki JS, Fishman AP. Aerobic limit of the heart perfused at constant pressure. Am J Physiol 1980;238:H118-125.
67.Hashimoto H, Suzuki K, Miyake S, et al. Effects of calcium antagonists on the electrical alternans of the ST segment and on associated mechanical alternans during acute coronary occlusion in dogs. Circulation 1983;68:667-672.
68.Uno K. Mechanisms of pulsus alternans: its relation to alternation of regional contraction and elevated ST segment. Am Heart J 1991;122:1694-1700.
69.Murphy CF, Lab MJ, Horner SM, et al. Regional electromechanical alternans in anesthetized pig hearts: modulation by mechanoelectric feedback. Am J Physiol 1994;267:H1726-1735.
70.Kotsanas G, Holroyd SM, Young R, et al. Mechanisms contributing to pulsus alternans in pressure-overload cardiac hypertrophy. Am J Physiol 1996;271:H2490-2500.
71.Zima AV, Blatter LA. Inositol-1,4,5-trisphosphate-dependent Ca(2+) signalling in cat atrial excitation-contraction coupling and arrhythmias. J Physiol 2004;555:607-615.
72.Shkryl VM, Maxwell JT, Blatter LA. A novel method for spatially complex diffraction-limited photoactivation and photobleaching in living cells. J Physiol 2012;590:1093-1100.
73.Brooks WW, Bing OH, Litwin SE, et al. Effects of treppe and calcium on intracellular calcium and function in the failing heart from the spontaneously hypertensive rat. Hypertension 1994;24:347-356.
74.Narayan P, McCune SA, Robitaille PM, et al. Mechanical alternans and the force-frequency relationship in failing rat hearts. J Mol Cell Cardiol 1995;27:523-530.
75.Wilson LD, Jeyaraj D, Wan X, et al. Heart failure enhances susceptibility to arrhythmogenic cardiac alternans. Heart Rhythm 2009;6:251-259.
76.Shkryl VM, Maxwell JT, Domeier TL, et al. Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes. Am J Physiol Heart Circ Physiol 2012;302:H2310-2320.
77.de Diego C, Chen F, Xie LH, et al. Cardiac alternans in embryonic mouse ventricles. Am J Physiol Heart Circ Physiol 2008;294:H433-440.
78.Edwards JN, Blatter LA. Cardiac alternans and intracellular calcium cycling. Clin Exp Pharmacol Physiol 2014;41:524-532.
79.Shiferaw Y, Sato D, Karma A. Coupled dynamics of voltage and calcium in paced cardiac cells. Phys Rev E Stat Nonlin Soft Matter Phys 2005;71:021903.
80.Meyer O, Jenni R, Greiter-Wilke A, et al. Comparison of telemetry and high-definition oscillometry for blood pressure measurements in conscious dogs: effects of torcetrapib. J Am Assoc Lab Anim Sci 2010;49:464-471.
81.Martel E, Egner B, Brown SA, et al. Comparison of high-definition oscillometry -- a non-invasive technology for arterial blood pressure measurement -- with a direct invasive method using radio-telemetry in awake healthy cats. J Feline Med Surg 2013;15:1104-1113.
82.Bramlage CP, Schlumbohm C, Pryce CR, et al. Prenatal dexamethasone exposure does not alter blood pressure and nephron number in the young adult marmoset monkey. Hypertension 2009;54:1115-1122.
83.Schmelting B, Niehoff M, Egner B, et al. High Definition Oscillometry: a novel technique for non-invasive blood pressure monitoring in the cynomolgus monkey (Macaca fascicularis). J Med Primatol 2009;38:293-301.
84.Mitchell AZ, McMahon C, Beck TW, et al. Sensitivity of two noninvasive blood pressure measurement techniques compared to telemetry in cynomolgus monkeys and beagle dogs. J Pharmacol Toxicol Methods 2010;62:54-63.
85.Sant Cassia EV, Boswood A, Tordiffe AS. Comparison of High-Definition Oscillometric and Direct Arterial Blood Pressure Measurement in Anesthetized Cheetahs (Acinonyx Jubatus). J Zoo Wildl Med 2015;46:506-516.
86.Serres F, Chetboul V, Tissier R, et al. Comparison of 3 ultrasound methods for quantifying left ventricular systolic function: correlation with disease severity and prognostic value in dogs with mitral valve disease. J Vet Intern Med 2008;22:566-577.
87.O'Gara P, Sugeng L, Lang R, et al. The role of imaging in chronic degenerative mitral regurgitation. JACC Cardiovasc Imaging 2008;1:221-237.
88.Wilson JR, Lanoce V, Frey MJ, et al. Arterial baroreceptor control of peripheral vascular resistance in experimental heart failure. Am Heart J 1990;119:1122-1130.
89.Laragh JH. Hormones and the pathogenesis of congestive heart failure: vasopressin, aldosterone, and angiotensin II. Further evidence for renal-adrenal interaction from studies in hypertension and in cirrhosis. Circulation 1962;25:1015-1023.
90.Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101:370-377.
91.Packer M, Gottlieb SS, Blum MA. Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med 1987;82:4-10.
92.Hamlin RL. Pathophysiology of the failing heart In: Fox PR, Sisson D,Moïse NS, eds. Textbook of canine and feline cardiology: principles and clinical practice. 2nd ed. Philadelphia: Saunders, 1999;205-215.
93.Adler K, Egner B, Hellmann K. Prevalence of primary diseases and evidence of endothelial dysfunction in cats with hypertension. ISFM. Barcelona, 2013.
94.Adler K, Egner B, Hellmann K. Efficacy of amlodipine on endothelial dysfunction in cats with hypertension. FECAVA. Munich, 2014.
95.Brown S, Atkins C, Bagley R, et al. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 2007;21:542-558.