Spontaneous baroreflex control of heart rate during exercise and muscle metaboreflex activation in heart failure.

In heart failure (HF), there is a reduced baroreflex sensitivity at rest, and during dynamic exercise there is enhanced muscle metaboreflex activation (MRA). However, how the arterial baroreflex modulates HR during exercise is unknown. We tested the hypothesis that spontaneous baroreflex sensitivity (SBRS) is attenuated during exercise in HF and that MRA further depresses SBRS. In seven conscious dogs we measured heart rate (HR), cardiac output, and left ventricular systolic pressure at rest and during mild and moderate dynamic exercise, before and during MRA (via imposed reductions of hindlimb blood flow), and before and after induction of HF (by rapid ventricular pacing). SBRS was assessed by the sequences method. In control, SBRS was reduced from rest with a progressive resetting of the baroreflex stimulus-response relationship in proportion to exercise intensity and magnitude of MRA. In HF, SBRS was significantly depressed in all settings; however, the changes with exercise and MRA occurred with a pattern similar to the control state. As in control, the baroreflex stimulus-response relationship showed an intensity- and muscle metaboreflex (MMR)-dependent rightward and upward shift. The results of this study indicate that HF induces an impairment in baroreflex control of HR at rest and during exercise, although the effects of exercise and MRA on SBRS occur with a similar pattern as in control, indicating the persistence of some vagal activity.

Muscle metaboreflex attenuates spontaneous heart rate baroreflex sensitivity during dynamic exercise.

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Dynamic exercise attenuates spontaneous baroreflex sensitivity (SBRS) in the control of heart rate (HR) during rapid, spontaneous changes in blood pressure (BP). Our objective was to determine whether muscle metaboreflex activation (MRA) further diminishes SBRS. Conscious dogs were chronically instrumented for measurement of HR, cardiac output, mean arterial pressure, and left ventricular systolic pressure (LVSP) at rest and during mild (3.2 km/h) or moderate (6.4 km/h at 10% grade) dynamic exercise before and after MRA (via partial reduction of hindlimb blood flow). SBRS was evaluated as the slopes of the linear relations (LRs) between HR and LVSP during spontaneous sequences of at least three consecutive beats when HR changed inversely vs. pressure (expressed as beats x min(-1) x mmHg(-1)). During mild exercise, these LRs shifted upward, with a significant decrease in SBRS (-3.0 +/- 0.4 vs. -5.2 +/- 0.4, P<0.05 vs. rest). MRA shifted LRs upward and rightward and decreased SBRS (-2.1 +/- 0.1, P<0.05 vs. mild exercise). Moderate exercise shifted LRs upward and rightward and significantly decreased SBRS (-1.2 +/- 0.1, P<0.05 vs. rest). MRA elicited further upward and rightward shifts of the LRs and reductions in SBRS (-0.9 +/- 0.1, P<0.05 vs. moderate exercise). We conclude that dynamic exercise resets the arterial baroreflex to higher BP and HR as exercise intensity increases. In addition, increases in exercise intensity, as well as MRA, attenuate SBRS.

Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise.

Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex (MMR). In normal dogs during mild exercise, MMR activation causes large increases in cardiac output (CO) and mean arterial pressure (MAP); however, in heart failure (HF) although MAP increases, the rise in CO is virtually abolished, which may be due to an impaired ability to increase left ventricular contractility (LVC). The objective of the present study was to determine whether the increases in LVC seen with MMR activation during dynamic exercise in normal animals are abolished in HF. Conscious dogs were chronically instrumented to measure CO, MAP, and left ventricular (LV) pressure and volume. LVC was calculated from pressure-volume loop analysis [LV maximal elastance (E(max)) and preload-recruitable stroke work (PRSW)] at rest and during mild and moderate exercise under free-flow conditions and with MMR activation (via partial occlusion of hindlimb blood flow) before and after rapid ventricular pacing-induced HF. In control experiments, MMR activation at both workloads [mild exercise (3.2 km/h) and moderate exercise (6.4 km/h at 10% grade)] significantly increased CO, E(max), and PRSW. In contrast, after HF was induced, CO, E(max), and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, E(max) and PRSW did not change. In addition, MMR activation caused no significant change in CO, E(max), or PRSW at either workload. We conclude that MMR causes large increases in LVC in normal animals but that this ability is abolished in HF.

Muscle metaboreflex control of ventricular contractility during dynamic exercise.

When oxygen delivery to active skeletal muscle is insufficient for the metabolic demands, afferent nerves within muscles are activated, which elicit reflex increases in heart rate (HR), cardiac output (CO), and arterial pressure (AP), termed the muscle metaboreflex (MMR). To what extent the increases in CO are the result of increased ventricular contractility is unclear. A widely accepted index of contractility is maximal left ventricular elastance (Emax), the slope of the end-systolic pressure-volume relationship, such as during rapidly imposed reductions in preload. The objective of the present study was to determine whether MMR activation elicits increases in Emax. Experiments were performed using conscious dogs chronically instrumented to measure left ventricular pressure and volume at rest and during mild or moderate treadmill exercise with and without partial hindlimb ischemia to elicit MMR responses. At both workloads, MMR activation significantly increased CO, HR, AP, and maximum rate of change of left ventricular pressure. During both mild and moderate exercise, MMR activation increased Emax to 159.6 +/- 8.83 and 155.8 +/- 6.32% of the exercise value under free-flow conditions, respectively. We conclude that the increase of ventricular elastance associated with MMR activation indicates that a substantial increase in ventricular contractility contributes to the rise in CO during dynamic exercise.

Continuous left ventricular ejection fraction monitoring by central aortic pressure waveform analysis.

Left ventricular ejection fraction (EF) is perhaps the most clinically significant index of global ventricular function. EF is measured in clinical practice via imaging methods such as echocardiography. However, these methods generally require a well-trained operator and expensive capital equipment. Thus, EF measurements are only obtained in the clinical setting and are usually made few and far between. To expand the measurement of this critical hemodynamic variable, our overarching hypothesis is that EF may be continuously (i.e., automatically) monitored by mathematical analysis of routinely measured blood pressure waveforms. Here, we introduce a novel technique for estimating the absolute EF by model-based analysis of only a central aortic pressure (CAP) waveform. We then demonstrate the validity of the technique with respect to five conscious dogs in which reference EF was independently measured before and after chronic pacing induced heart failure. With further successful testing, the technique may potentially be utilized for continuous EF monitoring in research and clinical settings in which an aortic catheter is employed as well as for ambulatory EF monitoring in conjunction with recently developed implantable devices for measuring CAP.

The functional and histological effects of clenbuterol on the canine skeletal muscle ventricle.

BACKGROUND: We investigated the anabolic effects of the sympatho-mimetic drug clenbuterol upon pumping chambers constructed from latissimus dorsi muscle (LDM). METHODS AND RESULTS: In control and treatment groups (n = 4 dogs each), skeletal muscle ventricles (SMVs) were constructed followed by a 3-week recuperative delay and 6-7 weeks of electrical conditioning at 2 Hz to induce phenotypic expression of fatigue resistant slow muscle fibers. The treatment group received oral administration of clenbuterol (8 microg/kg, 2x/day) during this period. The clenbuterol group increased significantly in body weight as compared with the control group (P < 0.05). In a terminal experiment, the SMVs were assessed with a mock circulation device to determine pumping performance and also were examined with regard to fiber type distribution and area in the SMVs and their contralateral in situ LDMs. Initially the clenbuterol group performed better than the control group, but by the end of a 60-min fatigue test, there were no significant differences. With regard to fiber type distribution and areas, the SMVs of the clenbuterol group exhibited a fast fiber distribution similar to unconditioned muscles (28% +/- 4%), whereas the control group showed complete transformation (100%) to slow fibers. The fast fibers of the clenbuterol group were larger than control (P < 0.05), but the slow fibers were not significantly different. CONCLUSIONS: At the dose given, clenbuterol does induce hypertrophy and preserves the normal percentages of fiber types, possibly by hyperplasia, but it does not affect chronic pumping performance of skeletal muscle ventricles in the canine model.

Doxorubicin-induced canine CHF: advantages and disadvantages.

BACKGROUND: The dog is the most commonly used laboratory animal for heart surgery research. It has been difficult, however, to develop a canine chronic heart failure model, particularly without associated significant tachycardia. Our objective is to utilize intracoronary doxorubicin at various doses to evaluate a chronic model of left ventricular dysfunction and develop a dose-response relationship. METHODS: In 18 dogs, we evaluated their hemodynamic function, placed an in-dwelling intracoronary catheter, and then administered four weekly infusions of doxorubicin at 5 mg (n = 6), 10 mg (n = 6), or 15 mg (n = 6). Hemodynamic measurements were taken again at 4-5 weeks after infusion, and a final measurement at 14-18 weeks. RESULTS (See table): In the low dose group, all six animals survived the post-infusion period. Cardiac output changed from 2.9 +/- 0.2 to 2.2 +/- 0.5. The medium dose group had a mortality of 33% (2/6 dogs), with a moderate decrease in cardiac output (3.1 +/- 0.4 to 2.3 +/- 0.3 L/min). The high dose group had a mortality of 67% (4/6 dogs), with a dramatic decrease in cardiac output (3.0 +/- 0.2 L/min to 1.6 +/- 0.7 L/min (p < 0.05). None of the dogs developed a significant tachycardia. CONCLUSION: This study reconfirms that doxorubicin, when given into the coronary arteries, induces cardiac dysfunction. It appears to be dose-dependent, but more importantly, in doses where the LV dysfunction yields overt heart failure; the mortality over 14 weeks is significant and likely unacceptable for most chronic heart failure studies.

Circulatory assistance with a permanent implantable IABP: initial human experience.

PURPOSE: The Kantrowitz CardioVAD (KCV) is an electrically powered, pneumatically driven circulatory assist device which provides diastolic augmentation and systolic unloading to the failing heart. It consists of a 60cc-pumping chamber, a percutaneous access device (PAD), and an external controller. The pumping chamber, is surgically implanted in the descending thoracic aorta with the patient on cardiopulmonary bypass. Its physiologic function is analogous to that of the intra-aortic balloon pump (IABP). METHODS: Between 1997 and 2000, 5 men (age 59 to 73) with end-stage cardiomyopathy refractory to maximal drug treatment and with documented hemodynamic improvement on an IABP were enrolled in a feasibility study. RESULTS: Mean bypass time was 157 minute (range 120 to 196 minute); mean cross-clamp time was 101 minute (range 69 to 144). Patient 1 died intra-operatively. Compared with preoperative values, at 1 month, cardiac index increased (1.7 to 2.6 L/min/m(2)) and there were significant decreases in creatinine (2.6 to 1.5 mg/dL), pulmonary capillary wedge pressure (PCWP) (32 to 14 mm Hg), and right atrial pressure (RA) (19 to 9 mm Hg). NYHA class improved (IV to II). The mean increase in cardiac index with the KCV OFF to ON was 0.53 L/min/m(2) (36%). Two patients were discharged home. The device was used intermittently without thromboembolic complications. The only device related complications were attributed to PAD design and have been corrected. CONCLUSION Our initial human trial demonstrates successful implantation of the KCV in end-stage patients, the ability of the device to be used intermittently without anticoagulation, and documents hemodynamic and functional improvement in the status of these patients.

Skeletal muscle ventricle aortic counterpulsation: function during chronic heart failure.

BACKGROUND: Skeletal muscle ventricles (SMVs) are pumping chambers formed from latissimus dorsi muscle. The SMV aortic counterpulsator model has been proven to be stable in the long term and provide effective diastolic pressure augmentation in normal dogs. This study seeks to prove that the aortic counterpulsator model can function effectively in chronic heart failure. METHODS: In 6 dogs, pericardium-lined SMVs were created from latissimus dorsi muscle and electrically conditioned for fatigue resistance. Each SMV was attached to the descending thoracic aorta with a two-limb bifurcated graft and the aorta ligated between the limbs. The SMV was stimulated to contract during cardiac diastole at 1:2 to 1:3 ratio. Rapid ventricular pacing was initiated at 220 to 230 beats/min for 7 weeks to induce chronic heart failure. RESULTS: SMV contraction resulted in augmentation of the diastolic pressure time-index by 12.1% (32.8+/-15.4 versus 36.1+/-14.7 mm Hg-s, p < 0.05) at baseline, then by 33.6% (12.9+/-4.4 versus 16.8+/-4.3 mm Hg-s, p < 0.05) after 7 weeks of rapid ventricular pacing. After 7 weeks of rapid ventricular pacing, SMV counterpulsation provided significant afterload reduction with increases in peak left ventricular ejection velocity and stroke volume of 22.7% (142+/-55 versus 168+/-45 mL/s, p < 0.05) and 6.2% (13.0+/-5.1 versus 13.7+/-5.2 mL, p < 0.05), respectively. Coronary blood flow was measured in 3 animals at the 7-week measurement; augmentation averaged 47.6% (0.357+/-0.29 versus 0.432+/-0.26 mL/beat, p < 0.05). CONCLUSIONS: The SMV aortic counterpulsator provides improved cardiac assistance relative to the failing heart.