Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics.

Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin-based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events. METHODS: The REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization). RESULTS: Between August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL. INTERPRETATION: The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. FUNDING: National Institutes of Health.

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.

BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

Impact of treatment with saxagliptin on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 study.

AIMS: To study the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 trial. METHODS: We randomized 16,492 patients with type 2 diabetes (T2D) to saxagliptin or placebo, added to current antidiabetic medications, and followed them for a median of 2.1 years. Glycaemic instability was defined by: (i) a glycated haemoglobin (HbA1c) increase of ≥ 0.5% post-randomization; (ii) the initiation of new antidiabetic medications for ≥ 3 months; or (iii) an increase in dose of oral antidiabetic medication or ≥ 25% increase in insulin dose for ≥ 3 months. ß-cell function was assessed according to fasting homeostatic model 2 assessment of ß-cell function (HOMA-2ß) values at baseline and at year 2 in patients not treated with insulin. RESULTS: Compared with placebo, participants treated with saxagliptin had a reduction in the development of glycaemic instability (hazard ratio 0.71; 95% confidence interval 0.68-0.74; p < 0.0001). In participants treated with saxagliptin compared with placebo, the occurrence of an HbA1c increase of ≥ 0.5% was reduced by 35.2%; initiation of insulin was decreased by 31.7% and the increases in doses of an oral antidiabetic drug or insulin were reduced by 19.5 and 23.5%, respectively (all p < 0.0001). At 2 years, HOMA-2ß values decreased by 4.9% in participants treated with placebo, compared with an increase of 1.1% in those treated with saxagliptin (p < 0.0001). CONCLUSIONS: Saxagliptin improved glycaemia and prevented the reduction in HOMA-2ß values. Saxagliptin may reduce the usual decline in ß-cell function in T2D, thereby slowing diabetes progression.

Baseline characteristics of the patient population in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 53 trial.

BACKGROUND AND AIMS: SAVOR-TIMI 53 was designed to study the effects of the DPP-4 inhibitor saxagliptin on cardiovascular outcomes in high risk type 2 diabetes patients with diverse levels of diabetes control and background anti-diabetic drugs. The goal of this article is to describe the baseline characteristics of this hypothesis driven study. MATERIALS AND METHODS: A total of 16 496 diabetic patients from North America (31.9%), Western Europe (26.0%), Eastern Europe (17.3%), Latin America (16.4%) and Asia (8.3%), with either established cardiovascular disease (78.3%) or with ≥two additional cardiovascular risk factors (21.7%) were randomised to saxagliptin or placebo. Biomarkers of inflammation and insulin resistance were taken at baseline and 2 years later in order to correlate saxagliptin effect on cardiovascular outcome to its effect on inflammation and insulin resistance. RESULTS: Mean [+/-standard deviation (SD)] age was 65.0 (+/-8.6) years, 66.9% were male, body mass index was 31.2 kg/m² (+/-5.6), mean diabetes duration was 11.9 years (+/-8.9) and the mean HbA1c 8.0% (+/-1.4%). HbA1c < 7% was most prevalent among North Americans (30.8%) and least among Asians (15.1%), whereas HbA1c > 9% was 30.7% in Latin America 27.0% in Asia and 15.1% in North America. Diabetic retinopathy was reported in 12.3% of patients, nephropathy in 17.7% and amputation in 2.5%. Diabetic treatments categories were as follows: no medication (5.4%), 1 oral anti-diabetic drug (OAD) (25.0%), ≥2 OAD (27.7%) and/or insulin (40.9%). The prevalence of micro-albuminuria was twice as high among insulin users compared with users of ≥2 OAD. Baseline statin use (78.3% overall) varied by region. CONCLUSION: The SAVOR-TIMI 53 patient population, with differing background diabetes control and anti-diabetic treatment, provides global representation of diabetic patients with established cardiovascular disease or at high risk for cardiovascular disease and is well-positioned to determine the effect of saxagliptin on cardiovascular events.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Hyaluronidase-induced reductions in myocardial infarct size.

The size of myocardial infarctions following coronary artery occlusion in the rat was determined directly by measurement of creatine phosphokinase activity in homogenized whole left ventricles and by planimetric measurement of the area of the infarctions in histologic sections of serial slices of the left ventricles. Hyaluronidase was shown to produce significant reductions in expected infarct size both 48 hours and 3 weeks after occlusion without impairing fibrosis during the healing phase. Thus, the amount of myocardial necrosis that follows a coronary artery occlusion has been shown directly to be amenable to reduction with a pharmacological intervention.

Fluorocarbons reduce myocardial ischemic damage after coronary occlusion.

Open-chest, anesthetized dogs with occlusions of the left anterior descending coronary artery breathed 100 percent oxygen while they were bled to a hematocrit of 25 percent and infused with an approximately equal volume (40 milliliters per kilogram) of fluorocarbon preparation or Ringer solution. Dogs breathing room air and receiving no treatment served as controls. After undergoing 6 hours of coronary occlusion, animals bled and treated with fluorocarbons developed smaller infarctions than those receiving Ringer solution or no treatment.

A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure.

The objective of this investigation was to characterize the mechanism of peripheral vasoconstriction observed in heart failure and to determine whether it can be attributed to the augmented sympathetic nervous activity, characteristic of this state. The response of the resistance bed in the forearm after release of inflow occlusion (reactive hyperemia), to hand exercise, and to local heating and the response of the calf resistance vessels to arterial occlusion and intra-arterial sodium nitrite and phentolamine were studied in 23 patients with congestive heart failure and 21 normal subjects. In the normal subjects, reactive hyperemia blood flow after varying periods of arterial occlusion greatly exceeded the values observed in patients with heart failure. Local anesthetic blockade and intra-arterial phentolamine did not significantly alter the reactive hyperemia response in heart failure patients, militating against the possibility that increased sympathetic vasoconstrictor activity is responsible for the reduction of this response. Following compensation, the reactive hyperemia response returned toward normal. The striking elevations of the forearm blood flow observed after hand exercise and heating of the forearm in normal subjects were also markedly attenuated in patients with heart failure. Following intra-arterial phentolamine and/or sodium nitrite, peak calf blood flow was still significantly reduced in heart failure. These observations indicate that (1) heart failure is characterized by a striking reduction in the response to a variety of endogenous and exogenous vasodilator stimuli; (2) circulating catecholamines and sympathetic vasoconstrictor activity are not solely responsible for the elevation of peripheral vascular resistance and the reduced response to vasodilator stimuli in heart failure; and (3) heart failure may increase systemic vascular resistance directly by altering the mechanical properties and reducing the dilating ability of the resistance vessels.

Effects of dobutamine on left ventricular performance, coronary dynamics, and distribution of cardiac output in conscious dogs.

The effects of dobutamine ([+/-]-4-[2-[[3-(p-hydroxyphenyl)-1-methyl propyl] amino] ethyl] pyrocatechol hydrochloride), a new synthetic cardioactive sympathomimetic amine, were examined on direct and continuous measurements of left ventricular (LV) diameter (D), pressures (P), velocity of shortening (V), dP/dt, dP/dt/P, arterial pressure, cardiac output, and regional blood flows in the left circumflex coronary, mesenteric, renal, and iliac beds in healthy, conscious dogs. At the highest dose of dobutamine examined, 40 mug/kg/min, the drug increased dP/dt/P from 65+/-3 to 128+/-4 s(-1) and isolength velocity from 72+/-4 to 120+/-7 mm/s without affecting LV end diastolic D significantly. Mean arterial P rose from 92+/-2 to 104+/-3 mm Hg and heart rate from 78+/-3 to 111+/-7 beats/min, while LV end systolic D fell from 24.1+/-1.4 to 19.9+/-1.8 mm, reflecting a rise in stroke volume from 30+/-4 to 42+/-3 ml. Cardiac output rose from 2.41+/-0.23 to 4.35+/-0.28 liter/min, while calculated total peripheral resistance declined from 0.042+/-0.005 to 0.028+/-0.003 mm Hg/ml/min. The greatest increases in flow and decreases in calculated resistance occurred in the iliac and coronary beds, and the least occurred in the renal bed. Propranolol blocked the inotropic and beta(2) dilator responses while vasoconstricting effects mediated by alpha adrenergic stimulation remained in each of the beds studied. When dobutamine was infused after a combination of practolol and phentolamine, dilatation occurred in each of the beds studied. These observations indicate that dobutamine is a potent positive inotropic agent with relatively slight effects on preload, afterload, or heart rate, and thus may be a potentially useful clinical agent. The one property of this drug which is not ideal is its tendency to cause a redistribution of cardiac output favoring the muscular beds at the expense of the kidney and visceral beds.

Early recovery of regional performance in salvaged ischemic myocardium following coronary artery occlusion in the dog.

Although numerous agents have been shown experimentally to protect ischemic myocardium, a critical unanswered question is whether function is preserved in the salvaged tissue. Accordingly, 38 openchest dogs had measurements of percent segment length shortening (%SS) and velocity of segment length shortening either in midmyocardial or subepicardial and subendocardial ischemic segments before and after 60 min of left anterior descending coronary artery occlusion during 5 h of reperfusion; 10 additional dogs were subjected to 3 h of coronary occlusion followed by 72 h of reperfusion. 15 min after coronary artery occlusion, radiolabeled microspheres were injected into the left atrium for measurement of regional myocardial blood flow, and dogs were treated with 1 mg/kg i.v. (n = 23) of an anti-inflammatory drug, flurbiprofen or an equal volume of saline (n = 25). The ischemic myocardium-at-risk for necrosis was determined by injecting methylene blue dye into the left atrium with the coronary artery reoccluded at the end of the reperfusion period, slicing the left ventricle into thin transverse sections, and measuring the areas of each slice that were not perfused (pink unstained tissue) by methylene blue. The quantity of necrotic tissue in each transverse section was measured by planimetry after incubation of the slices in triphenyltetrazolium chloride, and by direct histological examination in dogs with 72 h of reperfusion. Regional myocardial blood flow of the ischemic segments between the ultrasonic dimension crystals was similar in treated (0.34+/-0.03 ml/min per g) and control dogs (0.35+/-0.03 ml/min per g). In saline-treated control dogs subjected to a l-h coronary occlusion, 17.9+/-1.8% of the myocardium-at-risk became necrotic but in flurbiprofen-treated dogs none of the tissue became necrotic. In saline-treated dogs passive lengthening of the previously ischemic segments persisted through 5 h of reperfusion in all three regions of myocardium after a 1-h coronary occlusion. In flurbiprofen-treated dogs regional function returned to normal within 5 min of reperfusion in both the subendocardium (%SS preocclusion = 17.2+/-2.0%; 5 min reperfusion = 17.8+/-3.1%; P = NS) and in the midmyocardium (%SS preocclusion = 17.8+/-2.2%; 5 min reperfusion = 17.9+/-2.3%; P = NS) and was not significantly different after 5 h of reperfusion from what it was before coronary occlusion. In the subepicardium of treated dogs regional function began to improve within 15 min of drug administration even during coronary occlusion. Regional function was not different from preocclusion values after either 5 min or 5 h of reperfusion (%SS preocclusion = 21.0+/-2.4%; 5 min reperfusion = 20.6+/-3.8%; P = NS). In dogs subjected to 3 h of coronary occlusion and 72 h of reperfusion, the administration of flurbiprofen was also associated with significantly smaller infarcts and a significantly more rapid rate of functional recovery than in control dogs.Thus, it appears that flurbiprofen not only decreased the quantity of necrosis in tissue made ischemic after coronary occlusion and then reperfused, but also allowed more rapid recovery of segmental function in ischemic but nonnecrotic tissue and in tissue with patchy necrosis; such recovery did not occur in equally ischemic myocardium in untreated control dogs. Earlier functional recovery of reversibly injured tissue following prolonged periods of ischemia is an additional important role for agents that protect ischemic myocardium from necrosis.

Effect of alterations in the thyroid state on the intrinsic contractile properties of isolated rat skeletal muscle.

Contractile properties of soleus muscles isolated from 31 euthyroid (EU), 20 hyperthyroid (HT), and 18 myxedematous (MY) rats were studied in a myograph. At 100 stimuli/sec maximum isometric tension was essentially identical in EU (17.2 +/-0.5 g/mm(2)) and HT (17.7 +/-0.5 g/mm(2)) muscles, but was significantly depressed in MY muscles (11.5 +/-0.7 g/mm(2)). The rate of tension development was increased in HT (103 +/-4.5 g/sec per mm(2)) as compared to both EU (86.2 +/-4.6 g/sec per mm(2)) and MY (38.4 +/-2.2 g/sec per mm(2)) muscles, while the duration of the active state was shortened in HT (77.1 +/-2.3 msec) as compared to EU (105.1 +/-1.1 msec) muscles and was prolonged in MY muscles (153.3 +/-6.0 msec). The mean rate of isometric relaxation was 26.5 +/-4.9 g/mm(2) per sec in EU muscles, more rapid in HT muscles (33.1 +/-1.3 g/sec per mm(2)), and slower in MY muscles (16.0 +/- g/mm(2) per sec). The fusion frequency was greater in HT muscles, averaging 68.5 +/-3.6 stimuli/sec compared to EU muscles (38.1 +/-1.2 stimuli/sec) and to MY muscles (33.3 +/-4.0 stimuli/sec). At 40 stimuli/sec tension averaged 16.4 +/-0.8 g/mm(2) in EU muscles while at the same frequency tension was reduced in HT muscle, averaging 14.2 +/-0.5 g/mm(2). All differences were significant (P < 0.01). In conclusion, HT and MY result in profound alterations in the intrinsic contractile properties of skeletal muscle. While tension in HT muscles is maintained in vitro at a stimulus frequency of 100 stimuli/sec, the reduction in duration of active state may lower tension in vivo by preventing complete fusion of contractile events. In MY tension is reduced as a consequence of the lowered intensity of the active state. These changes explain, at least in part, the weakness of muscle activity in both HT and MY.

Extent of carotid sinus regulation of the myocardial contractile state in conscious dogs.

The effects of bilateral carotid artery occlusion (BCO) and carotid sinus nerve stimulation (CSNS) on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (V), rate of change of pressure (dP/dt), and cardiac output were studied in conscious dogs instrumented with ultrasonic diameter gauges, miniature pressure gauges, and aortic electromagnetic flow transducers. The effects of BCO and CSNS were also studied after automatic blockade and were compared to similar alterations in pressure produced by norepinephrine, methoxamine, and nitroglycerin. When heart rate was maintained constant with atrial stimulation, BCO had little effect on ventricular contractility, increasing isolength systolic pressure (LV P(iso)) by 36% while isolength velocity of myocardial shortening (V(iso)) decreased by 12% and (dP/dt)/P fell by 8%. These effects could be explained largely by vasoconstriction, since elevating systolic pressure with methoxamine produced similar results, while norepinephrine increased V(iso) by 36% and (dP/dt)/P by 56%. CSNS produced directionally opposite results from BCO; it decreased P(iso) by 15%, V(iso) increased by 11%, while (dP/dt)/P remained almost constant. These effects may be explained largely by vasodilatation since reducing systolic pressure to the same level with nitroglycerin produced similar results. When peripheral vasoconstriction was minimized by phenoxybenzamine pretreatment. BCO produced a slight positive inotropic effect (P(iso) increased by 8%, V(iso) by 4%, and (dp/dt)/P by 10%), while CSNS produced a slight negative inotropic effect (P(iso) decreased by 3%, V(iso) decreased by 5%, and (dP/dt)/P by 7%).Thus, in the normal, healthy, conscious dog, the carotid sinuses exert relatively little control of the inotropic state of the left ventricle; moreover, this small inotropic action is masked by the more powerful effects on peripheral resistance.

Extent of regulation of the heart's contractile state in the conscious dog by alteration in the frequency of contraction.

The effects of alterations in the frequency of contraction over the range from 94 to 220/min on left ventricular pressure, diameter, and dP/dt were studied in 10 dogs instrumented with ultrasonic diameter ganges and miniature pressure gauges. The same dogs were studied on separate days in the conscious state, after general anesthesia with pentobarbital Na, 30 mg/kg, and in the conscious state after pretreatment with propranolol, 3 mg/kg. End diastolic diameter was maintained constant during alterations in frequency by infusing saline intravenously. The maximum increases in peak dP/dt and dP/dt/P in the conscious state were 14 and 10%, respectively. After anesthesia, raising the frequency of contraction from 122 to 220/min caused maximum increases in peak dP/dt and dP/dt/P of 36 and 30%, respectively. In the conscious state after cardiac depression by propranolol, the maximum increases in peak dP/dt and dP/dt/P were 23 and 23%, respectively. Thus, increasing the frequency of contraction of the normal heart of the conscious dog causes only a slight inotropic effect, but this effect is significantly greater in the presence of myocardial depression produced by anesthesia with pentobarbital Na or in the conscious animal after a myocardial-depressing dose of propranolol.

Long-term preservation of ischemic myocardium after experimental coronary artery occlusion.

The results of experiments with indirect methods have suggested that various interventions reduce infarct size after coronary artery occlusion. To determine and quantify directly both the short- and long-term effects of several interventions on myocardial salvage without relying on indirect methods, the left coronary artery was occluded in 880 rats; they were then given either no treatment or one of the following interventions: (a) hyaluronidase, an enzyme that hydrolyzes interstitial glycoproteins, 1,500 National Formulary (NF) U/kg i.v. 5 min and 24 h after occlusion; (b) cobra venom factor, a protein that depletes the third component of complement, 20 U/kg i.v. 5 min after occlusion; (c) a glucocorticoid: hydrocortisone, 50 mg/kg i.v. 5 min after occlusion; or the five-fold more potent methylprednisolone (MP): (i) 50 mg/kg i.v. 5 min after occlusion or (ii) 50 mg/kg i.v. 5 min after occlusion followed by 50 mg/kg i.m. 3, 6, and 24 h after occlusion; or (d) reserpine, an agent that depletes the heart of catecholamines, 0.5 mg/kg i.m. once on each of the 3 days before occlusion. The animals were sacrificed either 2 days after occlusion, i.e., at the time of peak necrosis, or after 3 wk, i.e., after the infarct was completely healed. The amount of preserved myocardium was then assessed by two independent techniques: planimetric measurement of serial histologic sections and creatine kinase activity of the whole left ventricle. The amount of normal myocardium preserved at 21 days postocclusion was significantly increased, by 22.3+/-7.8% (P < 0.025) after the administration of hyaluronidase, by 25.3+/-5.8% (P < 0.005) after cobra venom factor, by 14.5+/-6.9% (P < 0.05) after hydrocortisone, by 20.8+/-8.2% (P < 0.025) after the single dose of MP, by 20.9+/-3.9% (P < 0.001) after the four doses of MP, and by 10.2+/-3.7% (P < 0.05) as a result of pretreatment with reserpine. The four doses of MP significantly thinned the infarct-by 25.6+/-2.9% (P < 0.001)-and although ventricular rupture did not occur, the intervention caused distension of the left ventricle as a result of stretching of the infarcted tissue during scar formation. Thus, myocardium acutely jeopardized by ischemia can be preserved on a long-term basis.

Left ventricular response to severe exertion in untethered dogs.

The left ventricular response to severe exercise was studied by telemetering direct measurements of left ventricular diameter (D) and pressure (P) and aortic blood flow from healthy dogs running at speeds up to 30 mph in the field. Severe exercise increased cardiac output from 101 to 478 ml/kg per min, heart rate from 95 to 297 beats/min, stroke volume from 31 to 44 ml, left ventricular isolength (iso) systolic pressure from 120 to 186 mm Hg, left ventricular end diastolic pressure from 6 to 18 mm Hg, and left ventricular end diastolic diameter from 58.9 to 60.1 mm, while end systolic diameter decreased from 53.0 to 52.2 mm. Two indices of myocardial contractility, (dP/dt)/P increased from 37 to 92 sec(-1), while dD/dt, the velocity of myocardial fiber shortening at isolength, rose from 54 to 119 mm/sec. All of these changes were statistically significant. When, in resting dogs, heart rate was first raised to exercise levels by electrical stimulation, severe exercise subsequently increased left ventricular end diastolic diameter more profoundly, from 55.7 to 59.7 mm, while end systolic diameter remained constant and the increases in left ventricular pressure, (dP/dt)/P and velocity(iso) were roughly comparable to those occurring during exercise in spontaneous rhythm. After propranolol, 1.0 mg/kg, severe exercise resulted in significantly smaller increases in cardiac output (from 82 to 240 ml/kg), in heart rate (from 87 to 186 beats/min), in left ventricular pressure(iso) (from 122 to 150 mm Hg), in (dP/dt)/P (from 32 to 44 sec(-1)), in velocity(iso) (from 47 to 59 mm/sec), and in slightly greater increases in end diastolic diameter, from 59.8 to 62.0 mm and pressure from 8 to 22 mm Hg, while end systolic diameter did not change significantly.Thus, the left ventricle responds to severe exercise with near maximal increases in heart rate and contractility, while significant increases in end diastolic diameter (Frank-Starling mechanism) and stroke volume occur as well. When heart rate was held constant severe exercise produced similar increases in contractility but end systolic size failed to diminish and the increases in end diastolic size were greater. Beta adrenergic receptor blockade interfered with the chronotropic and particularly the inotropic response to severe exercise and while the participation of the Frank-Starling mechanism was somewhat greater, the latter was not sufficient to increase cardiac output normally.

Effects of cardiac depression and of anesthesia on the myocardial action of a cardiac glycoside.

The effects of ouabain (G-strophanthin) 20 mug/kg, on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (dD/dt), and dP/dt were studied in conscious dogs instrumented with ultrasonic diameter gauges and miniature pressure gauges. The effects of ouabain were compared on separate occasions in the same dogs after cardiac depression with propranolol, 3.0 mg/kg, and also after general anesthesia with Na pentobarbital, 30 mg/kg. Maximal pressor effects were observed in the first 10 min, but maximal effects on the contractile state occurred at 30 min after ouabain. At this time, in conscious dogs, ouabain had increased LV isolength systolic pressure by 5%, LV isolength velocity by only 9%, and LV (dP/dt)/P by 21%, while end systolic diameter (ESD) decreased slightly and end diastolic diameter (EDD) and heart rate (HR) were unchanged. After anesthesia, ouabain increased LV systolic pressure by 8%, velocity 32%, (dP/dt)/P by 47%, and ESD decreased by 1.2 mm while EDD rose slightly and HR fell by 26 beats/min. Returning HR to control with atrial pacing decreased EDD 0.9 mm below control. After cardiac depression with propranolol, ouabain caused responses similar to those observed in the anesthetized dogs. Thus, the cardiac glycoside was found to exert only minor inotropic effects on the nonfailing heart of conscious dogs but far more striking inotropic responses in the anesthetized state.

Alterations in the baroreceptor reflex in conscious dogs with heart failure.

The effectiveness of the baroreceptor reflex in conscious dogs with experimental cardiac hypertrophy and heart failure was compared with that in a group of normal conscious dogs. Cardiac hypertrophy and heart failure were produced by tricuspid avulsion and progressive pulmonary stenosis. The sensitivity of the baroreceptor reflex to transient hypertension was assessed by determining the slope of the regression line relating the prolongation of the R-R interval to the rise in systolic arterial pressure during the transient elevation of arterial pressure induced by an intravenous injection of 1-phenylephrine. The mean slope averaged 22.4+/-2.3 msec/nm Hg in 16 normal animals. 23.1 +/-1.5 in five sham-operated animals, and was significantly reduced to 8.3 +/-0.8 in 10 dogs with hypertrophy alone (P < 0.001), and to 3.3+/-0.5 in nine dogs with heart failure (P < 0.001). The response to baroreceptor hypotension was compared during bilateral carotid artery occlusion (BCO) in six normal and six heart failure dogs previously instrumented with Doppler flow transducers on the superior mesenteric and renal arteries. During BCO, in normal dogs arterial pressure increased 52+/-4 mm Hg, heart rate 33+/-2 beats/min, mesenteric resistance 0.17+/-0.03 mm Hg/ml per min, and renal resistance 0.37+/-0.10 mm Hg/ml per min. In the heart failure group all of these variables increased significantly less (P < 0.01); arterial pressure rose 25 +/-3 mm Hg, heart rate 13 +/-4 beats/min, mesenteric resistance 0.04+/-0.007 mm Hg/ml per min, and renal resistance 0.18+/-0.09 mm Hg/ml per min.Thus, in heart failure, all measured systemic and regional circulatory adjustments consequent to baroreceptor hypo- and hypertension are markedly attenuated. This study demonstrates a profound derangement of a major cardiovascular control mechanism in experimental heart failure.