Influence of cardiac nerve status on cardiovascular regulation and cardioprotection.

Neural elements of the intrinsic cardiac nervous system transduce sensory inputs from the heart, blood vessels and other organs to ensure adequate cardiac function on a beat-to-beat basis. This inter-organ crosstalk is critical for normal function of the heart and other organs; derangements within the nervous system hierarchy contribute to pathogenesis of organ dysfunction. The role of intact cardiac nerves in development of, as well as protection against, ischemic injury is of current interest since it may involve recruitment of intrinsic cardiac ganglia. For instance, ischemic conditioning, a novel protection strategy against organ injury, and in particular remote conditioning, is likely mediated by activation of neural pathways or by endogenous cytoprotective blood-borne substances that stimulate different signalling pathways. This discovery reinforces the concept that inter-organ communication, and maintenance thereof, is key. As such, greater understanding of mechanisms and elucidation of treatment strategies is imperative to improve clinical outcomes particularly in patients with comorbidities. For instance, autonomic imbalance between sympathetic and parasympathetic nervous system regulation can initiate cardiovascular autonomic neuropathy that compromises cardiac stability and function. Neuromodulation therapies that directly target the intrinsic cardiac nervous system or other elements of the nervous system hierarchy are currently being investigated for treatment of different maladies in animal and human studies.

The Physiopathology of Cardiorenal Syndrome: A Review of the Potential Contributions of Inflammation.

Inter-organ crosstalk plays an essential role in the physiological homeostasis of the heart and other organs, and requires a complex interaction between a host of cellular, molecular, and neural factors. Derangements in these interactions can initiate multi-organ dysfunction. This is the case, for instance, in the heart or kidneys where a pathological alteration in one organ can unfavorably affect function in another distant organ; attention is currently being paid to understanding the physiopathological consequences of kidney dysfunction on cardiac performance that lead to cardiorenal syndrome. Different cardiorenal connectors (renin-angiotensin or sympathetic nervous system activation, inflammation, uremia, etc.) and non-traditional risk factors potentially contribute to multi-organ failure. Of these, inflammation may be crucial as inflammatory cells contribute to over-production of eicosanoids and lipid second messengers that activate intracellular signaling pathways involved in pathogenesis. Indeed, inflammation biomarkers are often elevated in patients with cardiac or renal dysfunction. Epigenetics, a dynamic process that regulates gene expression and function, is also recognized as an important player in single-organ disease. Principal epigenetic modifications occur at the level of DNA (i.e., methylation) and histone proteins; aberrant DNA methylation is associated with pathogenesis of organ dysfunction through a number of mechanisms (inflammation, nitric oxide bioavailability, endothelin, etc.). Herein, we focus on the potential contribution of inflammation in pathogenesis of cardiorenal syndrome.

Impact of chronic kidney disease on myocardial blood flow regulation in dogs.

BACKGROUND/AIMS: Chronic kidney disease (CKD) increases cardiovascular risk possibly due to coronary microvessel dysfunction and impaired myocardial flow reserve. This study investigated the effects of CKD on the regulation and transmural distribution of myocardial blood flow along with oxygen demand during intravenous dobutamine-induced increases in cardiac work. METHODS: CKD was produced in dogs by a two-stage subtotal nephrectomy (kidney ablation-infarction model). Serum creatinine and blood urea nitrogen were evaluated during the development of CKD along with systemic blood pressure (tail-cuff plethysmography). After 5 weeks, the CKD dogs were staged according to the International Renal Interest Society staging system; all dogs were anesthetized and surgically prepared for blood flow studies. Data analyses were performed between sham control (CTR) and stage 1 and 2 CKD dogs. RESULTS: At baseline, myocardial blood flow and diastolic aortic pressure were similar for all groups. During intravenous dobutamine, myocardial blood flow was markedly higher than CTR even though hematocrit levels declined with the severity of CKD. In the CTR dogs, myocardial blood flow increased in direct relation to cardiac work. However, in the CKD dogs (stage 1 and 2), maximum blood flow was achieved with low-dose dobutamine, indicating that coronary autoregulation is more readily exhausted with minimal increases in cardiac work during CKD. CONCLUSION: We report that CKD markedly impairs coronary vascular reserve and myocardial blood flow regulation which could contribute to greater cardiovascular risk and poor clinical outcomes in CKD patients.

Influence of cardiac decentralization on cardioprotection.

The role of cardiac nerves on development of myocardial tissue injury after acute coronary occlusion remains controversial. We investigated whether acute cardiac decentralization (surgical) modulates coronary flow reserve and myocardial protection in preconditioned dogs subject to ischemia-reperfusion. Experiments were conducted on four groups of anesthetised, open-chest dogs (n = 32): 1- controls (CTR, intact cardiac nerves), 2- ischemic preconditioning (PC; 4 cycles of 5-min IR), 3- cardiac decentralization (CD) and 4- CD+PC; all dogs underwent 60-min coronary occlusion and 180-min reperfusion. Coronary blood flow and reactive hyperemic responses were assessed using a blood volume flow probe. Infarct size (tetrazolium staining) was related to anatomic area at risk and coronary collateral blood flow (microspheres) in the anatomic area at risk. Post-ischemic reactive hyperemia and repayment-to-debt ratio responses were significantly reduced for all experimental groups; however, arterial perfusion pressure was not affected. Infarct size was reduced in CD dogs (18.6 ± 4.3; p = 0.001, data are mean ± 1 SD) compared to 25.2 ± 5.5% in CTR dogs and was less in PC dogs as expected (13.5 ± 3.2 vs. 25.2 ± 5.5%; p = 0.001); after acute CD, PC protection was conserved (11.6 ± 3.4 vs. 18.6 ± 4.3%; p = 0.02). In conclusion, our findings provide strong evidence that myocardial protection against ischemic injury can be preserved independent of extrinsic cardiac nerve inputs.

Role of the autonomic nervous system in cardioprotection by remote preconditioning in isoflurane-anaesthetized dogs.

AIMS: Remote ischaemic preconditioning (rIPC) protects cardiac and non-cardiac tissues against ischaemic injury. Although there is increased demand to investigate its potential clinical applicability, fundamental mechanisms responsible for rIPC-mediated protection remain unresolved. We examined in isoflurane-anaesthetized dogs whether an intact cardiac nervous system was necessary to mediate rIPC protection against ischaemic injury. METHODS AND RESULTS: Dogs were randomly allocated to six groups: 1, control (CON, no-rIPC); 2, rIPC (4 × 5 min renal artery occlusion/reperfusion); 3, autonomic ganglionic blockade with hexamethonium (HEX, no-rIPC; 20 mg/kg iv); 4, HEX + rIPC; 5, cardiac decentralization by surgical ablation of extracardiac nerves (DCN, no-rIPC); and 6, DCN + rIPC. All dogs underwent 60 min coronary occlusion and 180 min reperfusion; cardiac haemodynamic parameters were monitored. Regional blood flow (microspheres) in the heart and kidneys was assessed. Necrotic tissue was visualized using triphenyltetrazolium staining and related to anatomic risk zone size (area at risk; P = NS between groups) and coronary collateral blood flow. Infarct size (% AAR) was 29 ± 5 (mean ± 1 SD) in CON and 15 ± 4 in rIPC dogs (P = 0.001 vs. CON); 24 ± 3 in HEX vs. 12 ± 2 in HEX + rIPC (P = 0.001 vs. HEX); and 20 ± 2 in DCN vs. 12 ± 4 in DCN + rIPC (P = 0.001 vs. DCN). In CON dogs, infarct size was inversely related to coronary collateral flow; this relation was shifted downwards in all groups pre-treated with rIPC. CONCLUSION: We report robust myocardial protection by rIPC against ischaemic injury in canines that was not abrogated by either pharmacological or surgical decentralization of cardiac nerves.

Coronary vasoregulation in health and disease.

The present article reviews pertinent contributions from the Coronary Physiology Research Group at the Quebec Heart Institute to the understanding of coronary physiology in health and disease. Mechanisms that contribute to regulation of coronary blood flow and its distribution across the ventricular wall are discussed. Data from animal studies of ischemia-reperfusion injury are also presented and discussed in the context of current concepts regarding postischemic myocardial protection strategies. Future research directions regarding the cardiac nervous system and its importance in the regulation of coronary blood flow, cardiac function and myocyte injury during acute myocardial infarction are also discussed.

Influence of acute renal failure on coronary vasoregulation in dogs.

Impaired renal function is associated with an increased risk for cardiovascular events and death, but the pathophysiology is poorly defined. The hypothesis that coronary blood flow regulation and distribution of ventricular blood flow could be compromised during acute renal failure (ARF) was tested. In two separate groups (n = 14 each) of dogs with ARF, (1) coronary autoregulation (pressure-flow relations), vascular reserve (reactive hyperemia), and myocardial blood flow distribution (microspheres) and (2) coronary vessel responses to intracoronary infusion of select endothelium-dependent and -independent vasodilators were evaluated. In addition, coronary pressure-flow relations and vascular reserve after inhibition of nitric oxide and prostaglandin release were evaluated. Under resting conditions, myocardial oxygen consumption increased in dogs with ARF compared with no renal failure (NRF; 11.8 +/- 9.2 versus 5.0 +/- 1.5 ml O(2)/min per 100 g; P = 0.01), and the autoregulatory break point of the coronary pressure-flow relation was shifted to higher diastolic coronary pressures (60 +/- 17 versus 52 +/- 8 mmHg in NRF; P = 0.003); the latter was shifted further rightward after inhibition of both nitric oxide and prostaglandin release. The endocardial/epicardial blood flow ratio was comparable for both groups, suggesting preserved ventricular distribution of blood flow. In dogs with ARF, coronary vascular conductance also was reduced (P = 0.001 versus NRF), but coronary zero-flow pressure was unchanged. Vessel reactivity to each endothelium-dependent/independent compound also was blunted significantly. In conclusion, under resting conditions, coronary vascular tone, reserve, and vessel reactivity are markedly diminished with ARF, suggesting impaired vascular function. Consequently, during ARF, small increases in myocardial oxygen demand would induce subendocardial ischemia as a result of a limited capacity to increase oxygen supply and thereby contribute to higher risk for adverse coronary events and mortality.

Comparison of neutron activated and radiolabeled microsphere methods for measurement of transmural myocardial blood flow in dogs.

BACKGROUND: The 'gold standard' radioactive microsphere (RM) technique for measurement of organ blood flow under various experimental conditions is inaccessible to many researchers due to increasing environmental concerns regarding safety and disposal of low-level radioactive waste materials. A new method using neutron activated microspheres (NAM) has recently been described. METHODS: We compared regional myocardial blood flows using the new formulation STERIspheres (NAM; 15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) with RM (15.0 +/- 0.1 [SD] microm; density 1.5 gr/mL) under different experimental conditions during acute ischemia-reperfusion injury in dogs. Random paired combinations of four different RM and NAM were co-injected into the left atrium during autoregulation, coronary occlusion and flow-mediated hyperemia (reperfusion) in the same animal. The left ventricle was divided into non-ischemic and ischemic regions and further subdivided into endocardial, mid-myocardial and epicardial portions. After gamma-counting, blood and myocardial tissue samples (n = 180) were dried and then shipped to a core facility for neutron activation and analysis. NAM-RM blood flow data were directly compared by ANOVA and regression analysis; Bland and Altman analysis was also performed to assess mean differences in blood flow with NAM-RM. RESULTS: A direct relation for blood flow between NAM-RM was observed; the slope of the relation (1.17 RM +/- 0.04 [SEE]) was different from unity but the intercept (0.06 +/- 0.06 [SEE]) was not different from the origin. Intermethod mean differences were minimal between NAM-RM in the low to normal range of blood flow and were increased at the higher blood flow levels the latter being of minor physiological consequence. A direct relation for endo/epicardial blood flow ratios between NAM-RM was also observed; the slope of the relation (0.98 RM +/- 0.04 [SEE]) and the intercept (0.03 +/- 0.06 [SEE]) were not different from unity or the origin, respectively. CONCLUSIONS: RESULTS show that in addition to limiting production of radioactive waste materials, NAM accurately measure myocardial blood flow, endocardial/epicardial and ischemic/non-ischemic blood flow distributions over a wide range. We compared myocardial blood flows using paired combinations of neutron activated (NAM) and the 'gold standard' radiolabeled microspheres (RM) co-injected during autoregulation, coronary occlusion and flow-mediated hyperemia in an in situ canine ischemia-reperfusion preparation. A direct relation for blood flow and endo/epicardial blood flow ratios between NAM-RM was observed; intermethod mean differences between NAM-RM were minimal in the low to normal blood flow range but increased at higher blood flow levels. These results indicate that NAM accurately measure myocardial blood flow and its transmural distribution in addition to limiting unnecessary production of radioactive laboratory waste products.

Angiotensin inhibition and coronary autoregulation in a canine model of LV hypertrophy.

In humans with hypertension and LV hypertrophy, beneficial effects of angiotensin inhibition may be associated with preserved autoregulatory capacity. We studied the effect of acute angiotensin converting enzyme (ACE) inhibition on coronary autoregulatory pressure-flow relations and transmural distribution of blood flow in sham and LV hypertrophy dogs. Heart/body weight ratio increased (p = 0.001) from 5.5 +/- 0.7 in sham to 6.9 +/- 0.5 in LV hypertrophy dogs. The lower coronary pressure limit (LPL) on the pressure-flow relation was 47 +/- 2 mmHg in sham and 57 +/- 6 mmHg (p = 0.001) in LV hypertrophy dogs; after acute ACE-inhibition the LPL was reduced to 40 +/- 5 mmHg and 49 +/- 6 mmHg (p = 0.001), respectively. Transmural distribution of blood flow was preserved at the LPL in both groups before and after acute ACE-inhibition. Concomitant blockade of prostaglandin and nitric oxide release and bradykinin catabolism had no additional effects on the LPL and distribution of blood flow. After acute ACE-inhibition in LV hypertrophy dogs, distribution of blood flow across the LV wall was preserved and subendocardial vascular reserve was maintained even though the LPL was significantly lower. Preservation of autoregulatory capacity by ACE inhibitors contributes to beneficial outcome in patients with hypertension and LV hypertrophy.

Myocardial blood flow after chronic cardiac decentralization in anesthetized dogs: effects of ACE-inhibition.

Coronary blood flow regulation was studied in dogs with an intact or chronically decentralized intrinsic cardiac nervous system. We also examined the effect of angiotensin-converting enzyme inhibition (ACEI) on coronary autoregulatory pressure-flow relations and distribution of blood flow since the renin-angiotensin system may play a critical role in vasoregulation. Myocardial oxygen demand was reduced in the chronic decentralized dogs compared to the control dogs. The lower pressure limit of the autoregulatory pressure-flow relation was similar for the control and chronic decentralized dogs (47+/-2 and 44+/-7 mm Hg, respectively; p = NS). After ACEI, the lower pressure limit shifted leftward to 40 mm Hg (p=0.001) in both groups. Concomitant blockade of cyclooxygenase, bradykinin catabolism and nitric oxide synthase had no further effect on the lower pressure limit. Total myocardial blood flow was lower (p=0.001) in the chronic decentralized dogs compared to the control dogs, while transmural distribution of blood flow was preserved in both groups. The results show that even though myocardial oxygen requirements are lower in the chronically decentralized heart compared to controls, coronary autoregulation is maintained at levels observed in normally innervated hearts. The present findings indicate that intrinsic cardiac neurons contribute to coronary autoregulatory control and myocardial blood flow distribution even in the absence of cardiac connections to the central nervous system. In addition, in the chronic decentralized dog, ACEI allows the heart to work at lower coronary perfusion pressures while myocardial blood flow distribution is preserved.

Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction.

OBJECTIVES: The aim of this study was to determine the prognostic value of right ventricular (RV) function in patients after a myocardial infarction (MI). BACKGROUND: Right ventricular function has been shown to predict exercise capacity, autonomic imbalance and survival in patients with advanced heart failure (HF). METHODS: Two-dimensional echocardiograms were obtained in 416 patients with left ventricular (LV) dysfunction (ejection fraction [LVEF] < or = 40%) from the Survival And Ventricular Enlargement (SAVE) echocardiographic substudy (mean 11.1 +/- 3.2 days post infarction). Right ventricular function from the apical four-chamber view, assessed as the percent change in the cavity area from end diastole to end systole (fractional area change [FAC]), was related to clinical outcome. RESULTS: Right ventricular function correlated only weakly with the LVEF (r = 0.12, p = 0.013). On univariate analyses, the RV FAC was a predictor of mortality, cardiovascular mortality and HF (p < 0.0001 for all) but not recurrent MI. After adjusting for age, gender, diabetes mellitus, hypertension, previous MI, LVEF, infarct size, cigarette smoking and treatment assignment, RV function remained an independent predictor of total mortality, cardiovascular mortality and HF. Each 5% decrease in the RV FAC was associated with a 16% increased odds of cardiovascular mortality (95% confidence interval 4.3% to 29.2%; p = 0.006). CONCLUSIONS: Right ventricular function is an independent predictor of death and the development of HF in patients with LV dysfunction after MI.