John G. Kingma

Use of Valsalva Maneuver to Unmask Left Ventricular Diastolic Function Abnormalities by Doppler Echocardiography in Patients with Coronary Artery Disease or Systemic Hypertension

It has been suggested that changes in left atrial pressure may mask or mimic left ventricular diastolic function abnormalities detected by Doppler echocardiography. The effect of the Valsalva maneuver on the transmitral flow velocity profile was therefore studied in 28 patients without evidence of coronary artery disease (group 1, mean age +/- standard deviation 50 +/- 8 years) and in 94 patients with evidence of coronary artery disease or systemic hypertension (group 2, mean age 54 +/- 10 years). At baseline, group 2 patients had higher peak late diastolic filling velocity (A), lower peak early (E) to late diastolic filling velocity (E/A) ratio and longer isovolumic relaxation time than group 1, whereas heart rate, E velocity and E deceleration time were similar in both groups. During Valsalva, both groups had similar increases in heart rate and similar decreases in E velocity but E/A ratio decreased significantly only in group 2 because of a lesser decrease in A velocity. The E/A ratio was greater than or equal to 1.0 both before and during Valsalva in all but 1 patient in group 1, whereas in group 2, 32 patients had E/A greater than or equal to 1.0 at rest and during Valsalva, 33 patients had E/A greater than or equal to 1.0 at rest but less than 1.0 both at rest and during Valsalva. Using group 1 as controls, prevalence, specificity and positive predictive value of E/A less than 1.0 in group 2 were 31, 100 and 100% at rest and 66, 96 and 98% during Valsalva.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischaemic hearts

Electrical excitation of the dorsal aspect of the rostral thoracic spinal cord imparts long-term therapeutic benefits to patients with angina pectoris. Such spinal cord stimulation also induces short-term suppressor effects on the intrinsic cardiac nervous system. The purpose of this study was to determine whether spinal cord stimulation (SCS) induces long-term effects on the intrinsic nervous system, particularly in the presence of myocardial ischaemia. The activity generated by right atrial neurons was recorded in 10 anesthetized dogs during basal states, during prolonged (15 min) occlusion of the left anterior descending coronary artery, and during the subsequent reperfusion phase. Neuronal activity and cardiovascular indices were also monitored when the dorsal T1-T4 segments of the spinal cord were stimulated electrically (50 Hz; 0.2 ms) at an intensity 90% of motor threshold (mean 0.32 mA) for 17 min. SCS was performed before, during and after 15-min periods of regional ventricular ischaemia. Occlusion of a major coronary artery, one that did not perfuse investigated neurons, resulted in their excitation. Ischaemia-induced neuronal excitatory effects were suppressed (-76% from baseline) by SCS. SCS suppression of intrinsic cardiac neuronal activity persisted during the subsequent reperfusion period; after terminating 17 min of SCS, at least 20 min elapsed before intrinsic cardiac neuronal activity returned to baseline values. It is concluded that populations of intrinsic cardiac neurons are activated by inputs arising from the ischaemic myocardium. Ischaemia-induced activation of these neurons is nullified by SCS. The neuronal suppressor effects that SCS induces persist not only during reperfusion, but also for an extended period of time thereafter. These long-term effects may account, in part, for the fact that SCS imparts clinical benefit to patients with angina of cardiac origin not only during its application, but also for a time thereafter.

Long-term impact of diabetes and its comorbidities in patients undergoing isolated primary coronary artery bypass graft surgery.

Background— The objective of this study was to identify the impact of diabetes and related comorbidities, namely chronic renal failure, peripheral vascular disease, and low ejection fraction (<35%), on long-term survival of patients undergoing coronary artery bypass graft surgery. Methods and Results— A unicenter study was conducted on 9125 survivors of isolated coronary artery bypass graft surgery between 1992 and 2002. There were 6581 nondiabetic patients and 2544 diabetics, including 1809 patients with noninsulin-dependent diabetes mellitus and 735 patients with insulin-dependent diabetes mellitus. Cardiac-specific survival at 5 and 10 years was lower in insulin-dependent diabetes mellitus compared with both nondiabetic mellitus patients and patients with noninsulin-dependent diabetes mellitus (P<0.0001). However, freedom from cardiac-related death was similar for patients with noninsulin-dependent diabetes mellitus and nondiabetes mellitus patients up to 6 years (P=0 0.08) after surgery and was significantly lower thereafter (P=0.004). Cardiac-specific survival after coronary artery bypass graft surgery in patients with one or more comorbidities was comparable (P=0.4) for both nondiabetes mellitus patients and patients with noninsulin-dependent diabetes mellitus, but was significantly lower for those requiring insulin therapy (P<0.0001). Noninsulin-dependent diabetes mellitus was not an independent predictor of long-term cardiac death (hazard ratio: 1.09, P=0.41); however, insulin-dependent diabetes mellitus, chronic renal failure, peripheral vascular disease, and low ejection fraction were all independent risk factors for late cardiac death (all P<0.0001). The impact of comorbidities on the long-term risk of cardiac death was similar for the 3 groups. Conclusions— Noninsulin-dependent diabetes is not an independent predictor of late cardiac death after coronary artery bypass graft surgery, because cardiac-related survival is similar to that of nondiabetic patients for 6 years after surgery. In diabetic and nondiabetic patients, cardiac survival is adversely affected by the need for insulin therapy and/or the presence and number of comorbidities such as chronic renal failure, peripheral vascular disease, and low ejection fraction.

The heart reinnervates after transplantation

BACKGROUND Whether cardiac reinnervation occurs after transplantation remains controversial. If reinnervation does occur, how sympathetic and parasympathetic efferent neurons do this remains unknown. METHODS Power spectral analysis of heart rate variability was assessed for 1 year after cardiac autotransplantation in 9 dogs. After induction of anesthesia 13 months after transplantation, cardiac and intrinsic cardiac neuronal responses elicited by both electrical stimulation of parasympathetic or sympathetic efferent neurons and systemic or local coronary artery administration of nicotine (5 microg/kg), angiotensin II (0.75 microg/kg), and tyramine (1.2 microg/kg) were studied. The transmembrane electrical properties of intrinsic cardiac neurons were studied in vitro. Ventricular tissue catecholamine content, alpha-tubulin expression, and beta-adrenergic receptor density and affinity were studied. The presence of axons crossing suture lines was sought histologically. RESULTS Nerves were identified crossing suture lines. Electrical or chemical (ie, nicotine or angiotensin II) activation of sympathetic efferent neurons enhanced cardiodynamics, as did tyramine. Stimulating vagal efferent preganglionic axons induced bradycardia in half of the dogs. Functional reinnervation did not correlate with specific power spectra derived from rate variability in the conscious state. Responding to nicotine and angiotensin II in situ, transplanted intrinsic cardiac neurons generated spontaneous activity. These neurons displayed nicotine-dependent synaptic inputs in vitro. Ventricular tissue had normal beta-adrenergic receptor affinity and density but reduced catecholamine and alpha-tubulin contents. CONCLUSIONS The intrinsic cardiac nervous system receives reduced input from extracardiac sympathetic efferent neurons after transplantation and inconsistent input from parasympathetic efferent preganglionic neurons. These heterogeneous neuronal inputs are not reflected in heart rate variability or ventricular beta-adrenergic receptor function. Transplanted angiotensin II-sensitive intrinsic cardiac neurons exert greater cardiac control than do nicotine-sensitive ones. The intrinsic cardiac nervous system remodels itself after cardiac transplantation, and this indicates that direct assessment of extracardiac and intrinsic cardiac neuronal behavior is required to fully understand cardiac control after transplantation.

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.

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.

Myocardial perfusion imaging findings and the role of adenosine in the warm-up angina phenomenon

OBJECTIVES This study examined the roles of myocardial perfusion and adenosine in warm-up angina. BACKGROUND In warm-up angina, neither the role of an adenosine-mediated mechanism, as is found in experimental ischemic preconditioning, nor of increased myocardial perfusion is well defined. METHODS In substudy A, a single-photon emission computed tomography (SPECT)-thallium-201 exercise test was performed by 12 subjects with ischemic heart disease on three occasions one week apart. The third test was preceded by a warm-up test. The extent of the thallium deficit and its intensity on the third test were compared with the baseline tests controlling for the heart rate-systolic blood pressure product (RPP) at thallium injection. In substudy B, 12 similar subjects did two successive exercise tests at two separate sessions and received the adenosine antagonist, aminophylline (intravenous 5 mg/kg bolus and 0.9 mg/kg/h infusion) at one session, and equivalent saline at the other session. Change in ischemic threshold (RPP at 1 mm ST segment depression) and in maximum ST depression adjusted for RPP were analyzed. RESULTS In substudy A, despite a significant attenuation of electrocardiogram indexes of myocardial ischemia between the baseline and third (warmed-up) tests, the thallium extent deficits (20.8 +/- 15.1% and 16.8 +/- 12.4%) and intensity deficits (41.2 +/- 12.6% and 39.3 +/- 12.6%) did not differ significantly. In substudy B, the increase in ischemic threshold on re-exercise was unaffected by aminophylline. Adjusted maximum ST depression even decreased to a greater extent on re-exercise with aminophylline (by 51 +/- 21%) than with saline (by 32 +/- 19%) (p = 0.012). CONCLUSIONS While warm-up angina is associated with a significant attenuation of exercise electrocardiogram indexes of ischemia, it is unaccompanied by significant changes in SPECT perfusion and does not appear to be mediated by an adenosine-dependent mechanism since it is not blocked by aminophylline. Thus, its mechanism, which appears distinct from experimental ischemic preconditioning, remains unidentified.

Failure of AICA riboside to limit infarct size during acute myocardial infarction in rabbits

This study examined whether the adenosine potentiator, 5-aminoimidazole-4-carboxamide riboside (AICAr), could limit tissue necrosis during acute myocardial infarction in rabbit hearts with minimal coronary collateral flow. Forty-four rabbits underwent 45 min of ischemia with or without coronary reperfusion for 180 min. Five groups were studied. Saline or AICAr (20 mg/kg, i.v.) was administered as a bolus either 10 min before coronary occlusion or 10 min before the onset of coronary reperfusion. The anatomic risk zone size was assessed by radiolabeled microsphere autoradiography and the area of tissue necrosis was defined using the tetrazolium staining method. Coronary collateral flow in the central ischemic zone was assessed using the radiolabeled microsphere technique. No differences were observed for tissue necrosis (normalized to risk zone size) for saline- and AICAr-treated rabbits (66.2 +/- 10.9% vs. 70.8 +/- 19.9%, p = NS) subjected to 45 min of coronary occlusion without reperfusion. Similarly, tissue necrosis in rabbit hearts with 45 min of coronary occlusion followed by 180 min of reperfusion was not significantly reduced when AICAr was administered either 10 min before ischemia or 10 min before reperfusion (79.8 +/- 17.5 and 76.4 +/- 8.1%, respectively) compared to saline-treated controls (68.1 +/- 22.7%). Coronary collateral flow in these hearts was almost nonexistent. The risk zone size and cardiac hemodynamics were similar between the treatment groups. These results demonstrate that AICAr was unable to limit myocyte necrosis when administered either before ischemia or before coronary reperfusion in this experimental preparation of acute myocardial infarction.

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.

Effects of perfluorochemical hemodilution on coronary blood flow distribution in dogs.

To determine the effect of perfluorocarbon (PFC) hemodilution on myocardial vessel capacity to autoregulate, circumflex coronary artery pressure-flow relations were studied in anesthetized dogs under three conditions: maximal vasodilatation before and after PFC; autoregulation before and after PFC with 100% oxygen supplemented with room air ventilation, and autoregulation with PFC hemodilution during either room air or 100% oxygen supplemented with room air ventilation. During coronary vasodilatation, PFC did not modify coronary conductance or zero-flow pressure. During autoregulation after PFC, the lower pressure limit of the autoregulatory pressure-flow relation was shifted leftward. This leftward shift occurred because endocardial blood flow was maintained at a lower coronary perfusion pressure with PFC while epicardial blood flow was unchanged. Endocardial blood flow was also preserved at 50% of control blood flow levels as evidenced by the higher endocardial-epicardial blood flow ratio with PFC. After PFC with 100% oxygen supplemented with room air ventilation, oxygen transport increased significantly when coronary perfusion pressure was below the lower pressure limit; the effect was most prominent in the endocardial tissue layer. Thus, PFC shifts the lower pressure limit to the left because of the increased ability of the endocardial vessel to autoregulate. Consequently, PFC can be considered a useful intervention for improving endocardial oxygen transport at low coronary perfusion pressures.