Microsoft word - copertina + lectio sisson.doc

UNIVERSITÀ DEGLI STUDI DI TORINO
It is my distinct pleasure to be here today. Much of my academic life has been devoted to studying heart disease and heart failure in companion animals. Initially, and with modest expectations, I strived to learn how animals with heart failure could be treated more effectively. Later, my attention became focused on the early recognition of developing heart disease in order to optimize treatment and develop more effective preventative strategies. Along the way, I began to appreciate how little I could accomplish working alone and how much was possible through the amplifying power of effective team building and collaboration. In that context, the list of people to whom I am professionally and personally indebted is too long to cite in this brief presentation. Nonetheless, I have learned to value and appreciate the contributions of those individuals who have more 2nd and 3rd author citations than first author publications on their curriculum vitae. Moreover, without their contributions I would have The heart is a marvelous organ with two important mechanical functions: 1) to receive blood from the pulmonary and systemic venous reservoirs (diastolic performance) and, 2) to propel blood in a forward direction through the pulmonary and systemic vasculature (systolic performance). Heart failure is the clinical condition a patient experiences when the heart is injured and can no longer pump blood at a rate required to meet the needs of the metabolizing tissues and to maintain normal arterial and venous pressures at rest or with exercise. Systolic dysfunction predominates in most patients with heart failure. Impaired systolic ejection can result from primary myocardial failure, as seen in dogs with dilated cardiomyopathy; chronic volume overload, as occurs in dogs with chronic mitral valve; or chronic pressure overload due to outflow tract obstruction or hypertension. Impaired diastolic filling of the heart can result from excessive pericardial restraint, obstructions to venous inflow, impaired myocardial relaxation, or reduced ventricular compliance, as commonly observed in cats with In an individual patient, heart failure may be characterized as acute or chronic, as right- or left-sided, and, paradoxically, as a low or high output state. Despite these obvious differences, the vast majority of heart failure patients share similar and predictable physiologic responses when cardiac performance is impaired regardless of the cause. Such responses were initially viewed as compensatory mechanisms but it is now clear that they are maladaptive reactions that evolved primarily to deal with the acute challenges of salt and water deprivation or the traumatic loss of blood. After three decades of study, it is now widely accepted that the chronic operation of these physiologic responses in patients with heart disease has a detrimental effect on survival and quality of life. When cardiac output is depressed and blood pressure falls, the adrenergic nervous system is activated. This results in an elevated heart rate, augmented myocardial contractility, and the selective redirecting of blood flow to vital centers. The systemic effects of generalized sympathetic stimulation include arteriolar constriction which helps maintain tissue perfusion pressures. The survival advantage of this response in an individual experiencing the trauma of blood loss is obvious. The consequences in subjects with heart failure can be quite different. Myocardial performance, already compromised by underlying heart disease, is negatively impacted by the resulting mismatch of afterload to contractility. This consequence is exaggerated in patients with chronic heart failure wherein down- regulation of cardiac β1-receptors further diminishes the contractile response. Adrenergic venous constriction results in increased venous return (preload) augmenting cardiac output, but the resulting increases in venous and capillary pressures aid the development of symptomatic congestion. Chronic exposure to high norepinephrine levels contributes to pathologic vascular and cardiac remodeling, promotes arrhythmogenesis and induces premature death of myocytes. In dogs with heart failure due to dilated cardiomyopathy (DCM) and degenerative valve disease (DVD), and in cats with hypertrophic cardiomyopathy (HCM), we found that plasma epinephrine and norepinephrine concentrations are persistently and markedly elevated compared to normal dogs and cats. The same has been found in human patients with a variety of forms of heart disease. Most importantly, beta-adrenergic receptor blockade has been proven to improve cardiac performance, slow the progression of heart disease and to improve survival time in patients with heart failure. In patients with heart disease, a variety of complex and interrelated mechanisms result in expansion of the total blood volume. Diminished organ perfusion is interpreted as volume depletion and the body conserves sodium and water in an attempt to augment preload and increase cardiac output. The effector processes are quite elegant. Elaboration of renin from the juxtaglomerular apparatus in the kidney (as a result of increased sympathetic activity or decreased effective renal perfusion) increases the production of the peptide hormone, angiotensin II, via angiotensin converting enzyme in the lungs and a variety of tissues. Angiotensin II, in addition to its potent vasoconstricting effects, stimulates aldosterone production resulting in sodium and water retention. Studies conducted in my laboratory show substantial elevations of plasma renin activity and serum aldosterone levels in dogs with overt congestive heart failure due to mitral regurgitation (MR) and dilated cardiomyopathy (DCM), as well as in cats with hypertrophic or restrictive cardiomyopathy (HCM, RCM). Activation of RAAS is particularly marked in dogs and cats with acquired heart disease when furosemide is used to alleviate congestive signs. In most dogs and cats with less severe heart disease (NYHA class I and II), plasma renin activity and aldosterone concentrations are within the These observations provided some impetus for evaluating a variety of ACE inhibiting drugs in dogs and cats with heart disease, now widely accepted as the standard of therapy. Less progress has been realized in embracing beta-receptor blocking drugs in animals despite the fact that such therapy is now routinely advised for human patients with chronic heart Vascular tone is modulated by the endothelium-derived vasodilators, nitric oxide and prostacyclin, and by the complex actions of potent endothelium-derived vasopeptide, endothelin. Three related peptides, endothelin-1, endothelin-2 and endothelin-3 comprise the endothelin family. The active mature peptide, endothelin-1 (ET-1) is derived from inactive big endothelin-1 by the action of a membrane-bound metallopeptidase, endothelial converting enzyme (ECE) and is the predominant circulating form of endothelin produced by endothelial cells. The mature peptide has two intramolecular disulfide bridges linking cysteine residues, producing a double ring structure. Endothelin-1 acts via two receptors, ETA and ETB, to exert complex biological effects serving to maintain normal vascular tone. Vasoconstriction of smooth muscle, increases in myocardial contractility, and aldosterone secretion are among the more prominent effects mediated by ETA receptor stimulation. The structure of the 21 amino acid sequence of ET-1 is highly conserved in mammals so that canine ET-1 is identical to human ET-1, and feline ET-1 differs by only one amino acid switch at position seven where leucine is substituted for methionine. The biologic significance of this switch is uncertain. Using this assay, we demonstrated that plasma ET-1 levels more than double in dogs with CHF due to DVD or DCM and increase more than three-fold in cats with cardiomyopathy and Therapeutic strategies based on blocking ET receptors and inhibition of endothelin converting enzyme have, as yet, not produced convincing clinical benefits, but a number of studies are still in progress. Interestingly, we have observed that plasma endothelin levels declined substantially following treatment with conventional therapy (digoxin, furosemide, and an ACE inhibitor), suggesting that specific therapy may not be necessary. In addition to its mechanical functions, the heart is an endocrine organ. This fact is of great importance to cardiologists, general practitioners and to patients with heart disease. Atrial and brain (B-type) natriuretic peptides are initially elaborated from cardiac m-RNA as long peptide sequences, termed pre-proANP and pre-proBNP, respectively. Removal of a signal peptide from each yields shorter peptides, termed proANP and proBNP which, in healthy animals, are stored in membrane bound granules in the atria for later release. The mature, active ANP and BNP peptide hormones are cleaved from the carboxy- or C-terminal ends of the proANP and proBNP molecules and released into the circulation together with their respective amino- or N-terminal fragments, usually termed NT-proANP and NT- proBNP. The structures of mature ANP and BNP are similar in that both contain a 17 amino acid ring closed by a disulfide bond between two cysteine residues. However, the sequence and number of amino acids comprising ANP and BNP are dissimilar as they are encoded by different genes. In healthy cats and dogs, circulating forms of BNP and ANP are derived Sudden rises in plasma ANP and BNP levels are accomplished by their release from atrial storage granules mainly by the stimulus of atrial stretch. Interestingly, the physiologic actions of ANP and BNP generally oppose those exerted by the renin-angiotensin-aldosterone system. Atrial and B-type natriuretic peptides act via the A-type natriuretic peptide receptor, NPR-A, to induce natriuresis and diuresis by inhibiting tubular sodium transport in the inner medullary collecting duct of the kidney. This same receptor type mediates vasorelaxation of systemic and pulmonary arterioles, thereby decreasing systemic and pulmonary vascular resistance. Additional actions of ANP and BNP mediated by NPR-A include direct inhibition of the release of renin by the kidney and the release of aldosterone from the adrenal cortex. Sustained increases in circulating ANP and BNP are seen in dogs and cats with heart disease. N-terminal fragments of proANP and proBNP are removed more slowly from the circulation than their C-terminal counterparts as clearance of these peptides is more dependent on renal excretion. As a result, NT-proANP and NT-proBNP plasma levels are higher than and not as labile as their C-terminal counterparts. In general, the N-terminal peptides are more sensitive markers of heart disease and their levels tend to correlate more closely with the Heart failure in human patients is characterized by substantial elevations of both ANP and BNP, and a large number of studies of human subjects have shown that measurement of plasma natriuretic peptide concentrations, especially BNP, are helpful for discriminating patients with dyspnea due to heart failure from those with pulmonary disease or other disorders. Several assays measuring BNP or NT-proBNP have been developed and approved by regulatory agencies in the European Union and the United States for identifying human patients with heart failure. In humans, circulating BNP concentrations are elevated in asymptomatic patients with systolic left ventricular (LV) dysfunction, in patients with LV diastolic dysfunction, in patients with ventricular hypertrophy due to systemic or pulmonary hypertension, and in patients with hypertrophic cardiomyopathy. The utility of measuring circulating BNP levels to screen patients for early LV dysfunction is gaining acceptance worldwide. Studies of human patients with CHF have proven that plasma BNP levels are particularly useful in formulating an accurate prognosis, particularly when measured before For almost a decade, I and my collaborators have been working to develop similar assays for use in dogs and cats. The amino acid sequence of active C-terminal ANP is remarkably similar in different species. Human, canine, feline, bovine, porcine and ovine ANP share the same 28 amino acid sequence. Though more variable, there is also sufficient homology between the N-terminal amino acid sequence of ANP, that some of the assays developed to measure NT-proANP in humans can be used for the same purpose in dogs and cats. In contrast to the homology demonstrated by ANP in different species, the structure of BNP is quite variable in different mammals. The amino acid sequences of mature BNP in dogs and cats are markedly different from the human BNP sequence. For this reason, assays designed to measure BNP in humans tend not to work well in dogs and cats. The structure of mature feline BNP is sufficiently homologous with canine BNP to permit the use of the canine antibody assay, but cat-specific BNP antibodies improve the sensitivity and specificity of the The mean BNP concentrations of human patients with NYHA class III and IV heart failure is eight to ten-fold higher than the cutoff value for subjects without heart failure. In a recently reported study of cats with myocardial disease, we found that measures of plasma BNP levels have similar diagnostic potential in this species. Plasma BNP levels, elevated more than ten-fold, distinguished cats with heart failure from control cats better than plasma ANP levels, which were increased four- to five-fold. The diagnostic potential of plasma BNP levels does not appear quite as promising in dogs. Plasma BNP concentrations do not increase markedly until the later stages of heart failure (NYHA class III and IV) in dogs with degenerative valvular disease (DVD) and the magnitude of the change is less dramatic than that observed in cats and humans. We have observed similar patterns in dogs with DVD and dilated cardiomyopathy (DCM), suggesting that there may be a species difference in the The ultimate clinical utility and prognostic value of natriuretic peptide assays remains uncertain in dogs and cats. It is likely, based on our preliminary data, that the measurement of plasma BNP will aid the early identification of cats with hypertrophic cardiomyopathy. Such testing also might clarify the status of cats with equivocal results when evaluated by other diagnostic modalities, including echocardiography.

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