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H K Hammond

Publications and source records attributed to H K Hammond.

At least 19 recordsLinked to original sources
PubMed2001

Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials.

The current published clinical literature on angiogenic gene therapy for the treatment of myocardial ischemia does not include a single randomized, placebo-controlled trial. Based on current clinical literature, it is an unproven therapy. Successful animal studies combined with published reports of good outcomes in patients enrolled in uncontrolled trials has led to the expectation that angiogenic gene therapy will ultimately become a clinical reality. The next important landmark in the field will be the publication of data showing a favorable effect of angiogenic gene transfer in placebo-controlled, blinded clinical trials.

Adenoviridae↗
PubMed2000

Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity.

BACKGROUND: We tested the hypothesis that intracoronary injection of a recombinant adenovirus encoding adenylyl cyclase type VI (AC(VI)) would increase cardiac function in pigs. METHODS AND RESULTS: Left ventricular (LV) dP/dt and cardiac output in response to isoproterenol and NKH477 stimulation were assessed in normal pigs before and 12 days after intracoronary delivery of histamine followed by intracoronary delivery of an adenovirus encoding lacZ (control) or AC(VI) (1.4x10(12) vp). Animals that had received AC(VI) gene transfer showed increases in peak LV dP/dt (average increase of 1267+/-807 mm Hg/s; P=0.0002) and cardiac output (average increase of 39+/-20 mL. kg(-1). min(-1); P<0.0001); control animals showed no changes. Increased LV dP/dt was evident 6 days after gene transfer and persisted for at least 57 days. Basal heart rate, blood pressure, and LV dP/dt were unchanged, despite changes in cardiac responsiveness to catecholamine stimulation. Twenty-three hour ECG recordings showed no change in mean heart rate or ectopic beats and no arrhythmias. LV homogenates from animals receiving AC(VI) gene transfer showed increased AC(VI) protein content (P=0.0007) and stimulated cAMP production (P=0.0006), confirming transgene expression and function; basal LV AC activity was unchanged. Increased cAMP-generating capacity persisted for at least 18 weeks (P<0.0002). CONCLUSIONS: Intracoronary injection of a recombinant adenovirus encoding AC provides enduring increases in cardiac function.

Adenoviridae↗
PubMed2000

Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

Angiogenesis Inducing Agents↗
PubMed1999

Cardiac-directed adenylyl cyclase expression improves heart function in murine cardiomyopathy.

BACKGROUND: We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy. METHODS AND RESULTS: Transgenic mice with cardiac-directed expression of AC type VI (ACVI) were crossbred with mice with cardiomyopathy induced by cardiac-directed Gq expression. Gq mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired beta-adrenergic receptor (betaAR)-dependent and AC-dependent cAMP production. Gq/AC mice showed improved basal cardiac function in vivo (P=0.01) and ex vivo (P<0.0005). When stimulated through the betaAR, cardiac responsiveness was increased (P=0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol (P=0.03) and forskolin (P<0.0001). CONCLUSIONS: Increasing myocardial ACVI content in cardiomyopathy restores cAMP-generating capacity and improves cardiac function and responsiveness to betaAR stimulation.

Adenylyl Cyclases↗
PubMed1999

Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenic mice.

BACKGROUND: The cellular content of cAMP generated by activation of adenylylcyclase (AC) through the beta-adrenergic receptor (betaAR) is a key determinant of a cell's response to catecholamine stimulation. We tested the hypothesis that increased AC content, independently of betaAR number, increases responsiveness to catecholamine stimulation in vivo. METHODS AND RESULTS: Transgenic mice with cardiac-directed expression of ACVI showed increased transgene AC expression but no change in myocardial betaAR number or G-protein content. When stimulated through the betaAR, cardiac function was increased, and cardiac myocytes showed increased cAMP production. In contrast, basal cAMP and cardiac function were normal, and long-term transgene expression was not associated with abnormal histological findings or deleterious changes in cardiac function. CONCLUSIONS: The amount of AC sets a limit on cardiac beta-adrenergic signaling in vivo, and increased AC, independent of betaAR number and G-protein content, provides a means to regulate cardiac responsiveness to betaAR stimulation. Overexpressing an effector (AC) does not alter transmembrane signaling except when receptors are activated, in contrast to receptor/G-protein overexpression, which yields continuous activation and has detrimental consequences. Our findings establish the importance of AC content in modulating beta-adrenergic signaling in the heart, suggesting a new target for safely increasing cardiac responsiveness to betaAR stimulation.

Adenylyl Cyclases↗
PubMed1999

Beta-adrenergic receptors and receptor signaling in heart failure.

Cardiac beta-adrenergic receptors, which respond to neuronally released and circulating catecholamines, are important regulators of cardiac function. Congestive heart failure, a common clinical condition, is associated with a number of alterations in the activation and deactivation of beta-adrenergic receptor pathways. Studies with failing hearts from humans and animals indicate that such alterations include changes in the expression or function of beta-adrenergic receptors, G-proteins, adenylyl cyclases, and G-protein receptor kinases. The net effect of these alterations is the substantial blunting of beta-adrenergic receptor-mediated cardiac response. An important unanswered question is whether the loss of cardiac beta-adrenergic receptor responsiveness is a contributing cause, or a result, of ventricular dysfunction. Even though this question remains unanswered, the concept of targeting the beta-adrenergic pathway in the failing heart is becoming increasing popular and several new therapeutic strategies are in development.

Animals↗
PubMed1998

Increased expression of adenylylcyclase type VI proportionately increases beta-adrenergic receptor-stimulated production of cAMP in neonatal rat cardiac myocytes.

Cellular content of cAMP generated by activation of adenylylcyclase (AC; EC 4.6.1.1) is a key determinant of functional responsiveness in the heart and other tissues. We have tested two hypotheses regarding the relationship between AC content and beta-adrenergic receptor (betaAR)-mediated signal transduction in cardiac myocytes. First, that AC content limits adrenergic signal transduction, and, second, that increased AC, independent of (betaAR) number and G-protein content, yields a proportional increase in betaAR-mediated transmembrane signaling. We used recombinant adenovirus to increase AC isoform VI (ACVI) expression in neonatal cardiac myocytes. Cells that overexpressed ACVI responded to agonist stimulation with marked increases in cAMP production in proportion to protein expressed. In parallel experiments performed on cells transfected with lacZ (control) or ACVI, [3H]forskolin binding, used to assess AC protein expression, was amplified 6-fold, while betaAR-stimulated cAMP production from these cells was increased 7-fold. No changes in betaAR number, or in the heterotrimeric GTP-binding proteins, Galphas or Galphai2, were observed. Previous studies indicate that increased cardiac expression of betaAR or Galphas does not yield proportional increases in transmembrane adrenergic signaling. In contrast, the current data demonstrate that increased ACVI expression provides a proportional increase in beta-adrenergic signal transduction. Our results show that the amount of AC sets a limit on transmembrane beta-adrenergic signaling. We speculate that similar functional responses are possible in other cell types in which AC plays an important physiological role.

Adenylyl Cyclases↗
PubMed1998

Dissociation between regional dysfunction and beta-adrenergic receptor signaling in heart failure.

We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered beta-adrenergic receptor (beta-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 +/- 3 days). Heart failure was documented by decreased LV fractional shortening (P < 0.0001) and increased left atrial pressure (P < 0.0001). In heart failure, despite marked differences in basal regional function (percent wall thickening: IVS, 33 +/- 10% vs. PLW, 13 +/- 7%; P = 0.0003), there were no differences between the two regions in beta-AR responsiveness, measured by regional wall thickening in response to dobutamine infusion and any measurement of adrenergic signaling. Adenylyl cyclase activity, beta-AR number, and beta-AR/Gs coupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 +/- 0.20 vs. 0. 12 +/- 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 +/- 0. 15 vs. 0.13 +/- 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.

Adenylyl Cyclases↗
PubMed1997

Adenylyl cyclase and G protein receptor kinase expression during development of heart failure.

We examined alterations in left ventricular (LV) G protein receptor kinase (GRK) and adenylyl cyclase (AC) isoform expression during the development of pacing-induced congestive heart failure (CHF). AC isoform and GRK expression were assessed 4 (mild CHF) and 28 (severe CHF) days after initiation of pacing. LV beta-adrenergic receptor (beta-AR) number and G protein content were unchanged by mild CHF. LV AC isoform mRNA content was unaltered by mild CHF, but there were increases in total GRK activity (P < 0.01), total GRK5 protein content (P < 0.04), and GRK5 mRNA (P = 0.003); total GRK2 protein content and GRK2 mRNA were unchanged. Mild CHF was associated with decreased beta-AR coupling (P < 0.01) and reduced beta-AR stimulation of AC (P < 0.05). Severe CHF was associated with LV beta-AR downregulation (P = 0.0001) and uncoupling (P < 0.001) and marked generalized reduction of AC activity (mean P = 0.01). LV ACVI isoform mRNA content was reduced (P = 0.002), but ACII and ACV isoform mRNA contents were unaffected. Persistent elevations in LV total GRK activity (P < 0.01), total GRK5 protein content (P < 0.001), and GRK5 mRNA (P = 0.01) were found; in contrast, total GRK2 protein content was unchanged and GRK2 mRNA was reduced (P = 0.02). These studies indicate that increased GRK activity is an early charge in heart failure that predates alterations in AC isoform expression. Impaired hormonal stimulation of AC, associated with beta-AR uncoupling, may result from increased GRK5 expression. AC downregulation is isoform specific and accompanies severe but not mild CHF.

Adenylyl Cyclases↗
PubMed1996

Regional deficits of myocardial blood flow and function in left ventricular pacing-induced heart failure.

BACKGROUND: Pacing-induced congestive hear, failure has become a preferred model for the study of the pathogenesis of dilated cardiomyopathy. However, little is known regarding regional myocardial blood flow and function during the development of heart failure in this model. METHODS AND RESULTS: To determine whether regional differences in myocardial blood flow are associated with regional dysfunction in ventricular pacing-induced heart failure, regional myocardial blood flow (radioactive microspheres) and regional wall thickening (transthoracic echocardiography) were measured in pigs studied at weekly intervals during the progression of heart failure induced by rapid pacing from the lateral wall of the left ventricle (220 +/- 9 bpm for 26 +/- 4 days). Echocardiography and hemodynamic measurements with the pacemaker off showed progressive, severe global left ventricular dysfunction. During pacing over the 3- to 4-week period, a progressive decrease in systolic wall thickening in the lateral wall occurred compared with the interventricular septum (IVS; P = .001); at 21 to 28 days, the difference was 50% (lateral wall, 14 +/- 6%; IVS, 28 +/- 6%; P = .0001). A difference in subendocardial blood flow per beat between the left ventricular lateral wall (the site of stimulation) and the IVS was found immediately on the initiation of pacing (IVS, 0.009 +/- 0.002 mL.min-1.g-1.beat-1; lateral wall, 0.005 +/- 0.001 mL.min-1.g-1.beat-1; P = .001), a difference that was sustained during pacing throughout the study. Subendocardial blood flow per beat was normal in both regions with the pacemaker off throughout the study. CONCLUSIONS: These data indicate that regional myocardial ischemia is associated with the development of contractile dysfunction of the paced wall during prolonged rapid left ventricular pacing and that regional stunning contributes to persistent global left ventricular dysfunction when pacing is discontinued.

Adenosine Diphosphate↗
PubMed1996

Endotoxin-induced cardiac depression is associated with decreased cardiac dihydropyridine receptors in rabbits.

Endotoxin depresses left ventricular (LV) contractility independently of alterations in loading conditions, acidosis, or hypoxia (Hung and Lew, 1993a). We evaluated if endotoxin-induced LV depression is associated with a decrease in functional L-type calcium channels, as reflected by the number of dihydropyridine receptors measured by [3H]-PN200-110 binding. New Zealand white rabbits were instrumented with sonomicrometers to measure the end-systolic pressure-volume relationship after i.v. saline (group 1, n = 6), 5 micrograms/kg endotoxin (group II, n = 6), or 10 micrograms/kg endotoxin (group III, n = 6). The end-systolic volume (ESV) measured at a matched end-systolic pressure did not change significantly over 6 h in group I (ESV changed by < 5 +/- 2% S.E.) and group II (ESV changed by < 3 +/- 2%), but increased markedly in group III (ESV increased 70 +/- 24%, P < 0.05), indicating LV systolic depression. We measured [3H]-PN200-110 binding in crude membrane homogenates from the left ventricle. There was a dose-dependent decrease in Bmax: 75 +/- 5 fmol/mg protein in group I, 62 +/- 3 fmol/mg in group II, and 56 +/- 5 fmol/mg in group III (P = 0.02 by ANOVA). Since the majority of dihydropyridine receptors are functional L-type calcium channels in rabbits (Lew et al., 1991), we conclude that a decreased number of dihydropyridine receptors contributes to endotoxin-induced LV depression.

Animals↗
PubMed1996

Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart.

Increased coronary blood vessel development could potentially benefit patients with ischemic heart disease. In a model of stress-induced myocardial ischemia, intracoronary injection of a recombinant adenovirus expressing human fibroblast growth factor-5 (FGF-5) resulted in messenger RNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved, effects that persisted for 12 weeks. Improved blood flow and function were associated with evidence of angiogenesis. This report documents, for the first time, successful amelioration of abnormalities in myocardial blood flow and function following in vivo gene transfer.

Adenoviruses, Human↗
PubMed1996

Subcellular compartmentalization of Gs alpha in cardiac myocytes and its redistribution in heart failure.

Intracellular compartmentalization of G proteins may contribute to regulating signal transduction pathways in normal and failing myocardium. To test this hypothesis, we used postembedment immunogold electron microscopy to characterize the subcellular distribution of Gs alpha in normal canine and porcine left ventricular myocytes and in myocytes from a pacing-induced heart failure model in pigs in which beta-adrenergic signaling is impaired. Gs alpha was highly compartmentalized in normal canine myocytes and was localized specifically to the sarcolemma, intercalated disks, T-tubule and sarcoplasmic reticulum (SR) triads, and myoplasm. The highest Gs alpha concentration was observed in the intercalated disks. Only 20 +/- 5% of total cellular Gs alpha was localized to the sarcolemma. The triads and myoplasm compartments contained 45 +/- 13 and 27 +/- 8% of total cellular Gs alpha, respectively. The distribution of Gs alpha in normal porcine and canine myocytes was similar. However, in failing porcine myocytes Gs alpha was redistributed from the sarcolemma and T-tubule and SR triads to the myoplasm. The proportion of total cellular Gs alpha in the sarcolemma fell from 22 +/- 5 in normal to 11 +/- 4% in failing myocytes (P < 0.005), and the proportion in T-tubule and SR triads fell from 55 +/- 5 to 40 +/- 5% (P < 0.01), with a quantitatively corresponding increase in the proportion in the myoplasm from 19 +/- 3 to 43 +/- 4% (P < 0.0001). Thus redistribution of Gs alpha from the sarcolemma and the T-tubule and SR triads, where it may transduce beta-adrenergic signals, to internal sites where such actions may be precluded, might contribute to the pathophysiology of heart failure.

Animals↗
PubMed1995

Detection of regional left ventricular dysfunction in early pacing-induced heart failure using ultrasonic integrated backscatter.

BACKGROUND: It has been demonstrated that cyclic variation of ultrasonic integrated backscatter (CVIBS) may be useful in detecting altered physical conditions in the heart. However, no previous study has examined serial changes of CVIBS in the myocardium during the development of left ventricular dysfunction. METHODS AND RESULTS: We examined alterations of CVIBS in pacing-induced cardiac dysfunction. Eight pigs (36 +/- 2 kg) were studied before and sequentially during sustained rapid ventricular pacing (225 +/- 9 beats per minute). CVIBS was measured in the IVS and left ventricular PLW before pacing and daily for 4 days after onset of pacing. Five additional pigs (35 +/- 10 kg) were examined after 14 days of pacing. Regional function and CVIBS were assessed with pacemakers inactivated. A quantitative integrated backscatter imaging system (two-dimensional format) was used. Over 4 days of pacing, the magnitude of CVIBS progressively decreased in the PLW but was unchanged in the IVS, findings that persisted at 14 days. Percent wall thickening in the PLW progressively decreased to a greater degree than percent wall thickening in the IVS. A linear relation between the magnitude of CVIBS and percent wall thickening was found. At 14 days, blood flow to the two regions was similar but regional differences in CVIBS persisted. CONCLUSIONS: Rapid left ventricular pacing produces abnormalities of regional myocardial function within 48 hours of pacing. Regional myocardial dysfunction is accompanied by a reduction in CVIBS in the same region.

Animals↗
PubMed1995

Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart.

To determine whether beta-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and beta-adrenergic receptor kinase activity in the heart, we examined the effects of chronic beta 1-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial beta-adrenergic receptor-G-protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling associated with chronic reduction in beta-adrenergic receptor agonist activation were found. First, there was coordinate downregulation of Gi alpha 2 and Gs alpha mRNA and protein expression in the left ventricle; reduced G-protein content was also found in the right atrium. Second, in the left ventricle, there was a twofold increase in beta-adrenergic receptor-dependent stimulation of adenylyl cyclase and a persistent high affinity state of the beta-adrenergic receptor. Finally, there was a reduction in left ventricular beta-adrenergic receptor kinase activity, suggesting a previously unrecognized association between the degree of adrenergic activation and myocardial beta-adrenergic receptor kinase expression. The heart appears to adapt in response to chronic beta-adrenergic receptor antagonist administration in a manner that would be expected to offset reduced agonist stimulation. The mechanisms for achieving this extend beyond beta-adrenergic receptor upregulation and include alterations in G-protein expression, beta-adrenergic receptor-Gs interaction, and myocardial beta-adrenergic receptor kinase activity.

Adaptation, Biological↗
PubMed1994

Effects of dobutamine and arbutamine on regional myocardial function in a porcine model of myocardial ischemia.

OBJECTIVES: The present study was performed to determine the mechanisms for catecholamine-induced wall motion abnormalities and to compare the diagnostic efficacy of two catecholamines: arbutamine and dobutamine. BACKGROUND: Catecholamine stress echocardiography is used to induce regional wall motion abnormalities for the detection of coronary artery disease, but the mechanism by which these abnormalities occur is unknown. METHODS: Ten pigs were instrumented with left circumflex coronary artery ameroid constrictors, sonomicrometers to measure transmural wall thickening in the left circumflex (ischemic) and left anterior descending (control) coronary artery beds and a pressure gauge to measure left ventricular pressure and its first derivative (dP/dt). Myocardial blood flow was measured by microspheres. RESULTS: At 38 +/- 6 days (mean +/- SEM) after surgery, percent wall thickening was normal at rest in both beds but abnormal in the left circumflex coronary artery bed during atrial pacing. These findings were associated with reduced myocardial blood flow in the ischemic bed during atrial pacing. Dobutamine infusion increased percent wall thickening, with no differences between the two beds (p = 0.63). In contrast, arbutamine infusion increased percent wall thickening only in the nonischemic bed, with no effect on percent wall thickening in the ischemic bed (p = 0.03). Although the endocardial/epicardial blood flow ratio tended to be reduced in the left circumflex artery bed during catecholamine infusion (p = 0.07), both agents were similar in this effect. Despite differences in function between the beds, there was no difference in transmural myocardial blood flow between the two beds during catecholamine infusion. When examined at matched metabolic demands, arbutamine elicited greater differences in percent wall thickening than dobutamine between the two beds (p < 0.01). CONCLUSIONS: Arbutamine was able to provoke regional differences in function in a manner superior to dobutamine. This occurred independently of altered transmural myocardial blood flow or differences in hemodynamic effects between the agents. Differences in their inotropic properties may be important in explaining their different effects on ischemic myocardium.

Animals↗