9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Heart rate and blood pressure effects during caloric vestibular testing.

OBJECTIVES: To determine whether the caloric vestibular test causes significant changes in heart rate and mean arterial blood pressure. MATERIALS AND METHODS: Changes in heart rate and mean arterial blood pressure before and after caloric irrigation were compared with the degree of nystagmus (as measured by maximum slow phase velocity) and the patient's subjective dizziness (scored from 0 to 10). A cardiologist reviewed each patient's heart rate and mean arterial blood pressure changes. Patients' anxiety levels were also assessed. RESULTS: Eighteen patients were recruited. There were no adverse events in any patient. There were no overall significant differences between the heart rate and mean arterial pressure before and after each irrigation. There was a significant correlation between the maximum slow phase velocity and patients' subjective dizziness scores. CONCLUSION: Heart rate and mean arterial blood pressure are not significantly influenced by the caloric vestibular test. This preliminary study will enable patients with stable cardiovascular disease to be recruited for further risk determination.

Perioperative myocardial injury after elective open abdominal aortic aneurysm repair predicts outcome.

OBJECTIVE: Myocardial injury, detected by rises in cardiac troponin I (TnI), is common and associated with decreased survival following open AAA surgery. We examined the relationship between perioperative myocardial injury and postoperative outcome. DESIGN: Observational Cohort Study. METHODS: Forty-three consecutive patients who underwent elective open AAA repair were screened for perioperative myocardial injury or infarction using serial TnI measurements (taken on days 1, 3, and 7), ECG and clinical assessment. The primary outcome was survival free of cardiac failure, or myocardial infarction (MI) at follow-up. RESULTS: Twenty (47%) of the 43 patients had a TnI elevation. Of these, 11 (26%) patients met the criteria for MI. At a mean (+/-SD) follow-up of 1.5+/-0.8 years, 12 (28%) subjects had experienced at least one endpoint event. Survival free of cardiac failure or MI was 55% in patients who had TnI rises compared to 87% in those without (P=0.02). Logistic regression revealed that TnI elevation was an independent predictor of outcome with an odds ratio of 5.4 (95% CI 1.2-2.4, P=0.03). CONCLUSION: Perioperative myocardial injury after elective open AAA repair predicts outcome after surgery. Routine TnI measurement should be considered in all patients, especially in those with high cardiovascular risk.

Cardioprotection by remote ischaemic preconditioning.

Perioperative myocardial infarction is a leading cause of morbidity and mortality after major non-cardiac surgery. Pharmacological agents such as beta-blockers may reduce the risk but are associated with side-effects and may be contra-indicated in some patients. Basic scientific experiments and preliminary clinical trials in humans suggest that remote ischaemic preconditioning (RIPC), where brief ischaemia in one tissue confers resistance to subsequent sustained ischaemic insults in another tissue, may provide a simple, cost-effective means of reducing the risk of perioperative myocardial ischaemia. The Medline and Pubmed databases were searched for articles concerning RIPC. The mechanism may be humoral, neural, or a combination of both, and involves adenosine, opioids, bradykinins, protein kinase C, and K-ATP channels, although the precise end-effector remains unclear. Small randomized trials in humans undergoing major surgery suggest that RIPC induced by brief lower limb ischaemia significantly reduces myocardial injury. It may also reduce other ischaemic complications of surgery and anaesthesia. Small studies provide some evidence that RIPC could reduce myocardial injury and other ischaemic complications of surgery. However, large-scale clinical trials to assess the effect of RIPC on mortality and morbidity are required before RIPC can be recommended for routine clinical use.

The contribution of positron emission tomography to the study of ischemic heart failure.

Cardiac imaging with positron emission tomography offers unrivaled sensitivity and specificity to probe cardiovascular physiology in health and disease. The use of positron emission tomography to noninvasively measure regional myocardial blood flow and assess myocardial viability in patients with ventricular dysfunction and coronary artery disease has contributed greatly to our understanding of the pathophysiology of ischemic heart failure. The advances and the need for further studies to establish both the natural history of such ventricular dysfunction and the role of coronary revascularization are discussed.

Echocardiographic characterization of cardiomyopathy in Friedreich's ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients.

BACKGROUND: Conventional and tissue Doppler echocardiographically derived myocardial velocity gradients (MVGs) were used to characterize the myocardium in patients with Friedreich's ataxia (FRDA), and the relationship between MVGs and the mutation in the FRDA gene, a GAA triplet repeat expansion, was investigated. METHODS AND RESULTS: We studied 29 patients with FRDA (10 men, mean age 31+/-9 years) who were homozygous for the GAA expansion in the FRDA gene and were without cardiac symptoms. A comparison was made with a group of 30 age-matched control subjects. In patients with FRDA, interventricular septal thickness (1.17+/-0.26 versus 0.85+/-0.13 cm, P:<0.005), posterior left ventricular wall thickness (1.00+/-0.24 versus 0.88+/-0.15 cm, P:<0.01), and left atrial diameter (3.3+/-0.5 versus 2.9+/-0.3 cm, P:=0.01) were increased compared with control subjects. MVGs were reduced in FRDA during systole (3.1+/-1.2 versus 4.5+/-0.5 s(-1), P:<0.0001) and in early diastole (4.9+/-2.7 versus 8.8+/-1.8 s(-1), P:<0.0001) but increased in late diastole (2.0+/-1. 3 versus 1.1+/-0.9 s(-1), P:<0.01). The strongest relationship was seen between age-corrected early diastolic MVGs and the GAA expansion in the smaller allele of the FRDA gene (r=-0.68, P:<0. 0001). CONCLUSIONS: MVGs offer a means of further characterizing the myocardial abnormalities in patients with FRDA. Early diastolic MVGs appear to relate most closely to the genetic abnormality and the consequential reduction in frataxin protein.

Prolonged left ventricular dysfunction occurs in patients with coronary artery disease after both dobutamine and exercise induced myocardial ischaemia.

OBJECTIVE: To determine whether pharmacological stress leads to prolonged but reversible left ventricular dysfunction in patients with coronary artery disease, similar to that seen after exercise. DESIGN: A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and dobutamine induced ischaemia. SUBJECTS: 10 patients with stable angina, angiographically proven coronary artery disease, and normal left ventricular function. INTERVENTIONS: Treadmill exercise and dobutamine stress were performed on different days. Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test. RESULTS: Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction. There was no difference in the maximum double product (p = 0.53) or ST depression (p = 0.63) with either form of stress. After exercise, ejection fraction was reduced at 15 and 30 minutes compared with baseline (mean (SEM), -5.6 (1.5)%, p < 0.05; and -6.1 (2.2)%, p < 0. 01), and at 30 and 45 minutes after dobutamine (-10.8 (1.8)% and -5. 5 (1.8)%, both p < 0.01). Regional analysis showed a reduction in the worst affected segment 15 and 30 minutes after exercise (-27.9 (7.2)% and -28.6 (5.7)%, both p < 0.01), and at 30 minutes after dobutamine (-32 (5.3)%, p < 0.01). The isovolumic relaxation period was prolonged 45 minutes after each form of stress (p < 0.05). CONCLUSIONS: In patients with coronary artery disease, dobutamine induced ischaemia results in prolonged reversible left ventricular dysfunction, presumed to be myocardial stunning, similar to that seen after exercise. Dobutamine induced ischaemia could therefore be used to study the pathophysiology of this phenomenon further in patients with coronary artery disease.

Acute saline infusion reduces alveolar-capillary membrane conductance and increases airflow obstruction in patients with left ventricular dysfunction.

BACKGROUND: Impaired alveolar-capillary membrane conductance is the major cause for the reduction in pulmonary diffusing capacity for carbon monoxide (DLCO) in heart failure. Whether this reduction is fixed, reflecting pulmonary microvascular damage, or is variable is unknown. The aim of this study was to assess whether DLCO and its subdivisions, alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (Vc), were sensitive to changes in intravascular volume. In addition, we examined the effects of volume loading on airflow rates. METHODS AND RESULTS: Ten patients with left ventricular dysfunction (LVD) and 8 healthy volunteers were studied. DM and Vc were determined by the Roughton and Forster method. The forced expiratory volume in 1 second (FEV1), vital capacity, and peak expiratory flow rates (PEFR) were also recorded. In patients with LVD, infusion of 10 mL. kg-1 body wt of 0.9% saline acutely reduced DM (12.0+/-3.3 versus 10.4+/-3.5 mmol. min-1. kPa-1, P<0.005), FEV1 (2.3+/-0.4 versus 2.1+/-0.4 L, P<0.0005), and PEFR (446+/-55 versus 414+/-56 L. min-1, P<0.005). All pulmonary function tests had returned to baseline values 24 hours later. In normal subjects, saline infusion had no measurable effect on lung function. CONCLUSIONS: Acute intravascular volume expansion impairs alveolar-capillary membrane function and increases airflow obstruction in patients with LVD but not in normal subjects. Thus, the abnormalities of pulmonary diffusion in heart failure, which were believed to be fixed, also have a variable component that could be amenable to therapeutic intervention.

Marked variation in the cardiomyopathy associated with Friedreich's ataxia.

OBJECTIVE: To document the cardiac phenotype associated with Friedreich's ataxia, a recessively inherited disorder characterised by spinocerebellar degeneration. SETTING: Individuals with Friedreich's ataxia who accepted the invitation to participate in the study. HYPOTHESIS: The cardiomyopathy associated with Friedreich's ataxia may offer a human model for the study of factors modulating cardiac hypertrophy. METHODS: 55 patients (mean (SD) age 30 (9) years) with a clinical diagnosis of Friedreich's ataxia were studied by clinical examination, electrocardiography, cross sectional and Doppler echocardiography, and analysis of the GAA repeat in the first intron of the frataxin gene. RESULTS: A wide variety of cardiac morphology was documented. Subjects with normal frataxin alleles had no evidence of cardiomyopathy. In homozygous subjects, a relation was found between the thickness of the interventricular septum (r = 0.53, p < 0.005), left ventricular mass (r = 0.48, p < 0.01), and the number of GAA repeats on the smaller allele of the frataxin gene. No relation was shown between the presence of electrocardiographic abnormalities (mainly repolarisation changes) and either the pattern of ventricular hypertrophy (if present) and degree of neurological disability or the length of time since diagnosis. No tendency to ventricular thinning or dilatation with age was found. Although ventricular systolic function appeared impaired in some cases, Doppler studies of ventricular filling were within the normal range for age. CONCLUSIONS: The cardiomyopathy associated with Friedreich's ataxia shows a variable phenotype which is not concordant with the presence of ECG abnormalities or the neurological features of the condition. As the genetic basis for Friedreich's ataxia has been established, further studies will help to clarify the molecular mechanisms of the cardiac hypertrophy.

Disruption of the relationship between renin and atrial natriuretic peptide early in the course of ventricular dysfunction.

BACKGROUND: Plasma renin activity is normal in left ventricular dysfunction in the absence of diuretic therapy. In health there is a reciprocal relationship between renin and atrial natriuretic peptide (ANP) but a positive correlation in advanced heart failure. The relationship between renin and ANP in mild left ventricular dysfunction is unknown. METHODS AND RESULTS: Patients with left ventricular dysfunction (n = 35, 18 without diuretic therapy) were compared to 20 age-matched healthy subjects. Plasma concentrations of active renin (PARC), ANP and norepinephrine were measured after 20 min rest and 45 min after an infusion of normal saline (10 ml/kg body wt.). Basal plasma ANP was increased in patients with left ventricular dysfunction compared to healthy subjects, whether or not they were receiving diuretics. PARC was similar in healthy controls and patients untreated with diuretics but was increased in diuretic treated patients. After saline loading in healthy subjects PARC fell while ANP rose. Patients with left ventricular dysfunction had a smaller decline in PARC, that did not achieve statistical significance, but had a greater increase in plasma ANP compared to healthy subjects (P<0.05). The close reciprocal relationship between PARC and ANP observed in healthy subjects before and after saline loading (r = 0.8, P<0.001 and r = 0.6, P<0.01) was weakened in those not receiving diuretics (r = 0.4, P<0.05 and r = 0.24, ns) and lost in those receiving diuretics (r = 0.1 and r = 0.08). CONCLUSIONS: Patients with left ventricular dysfunction have a disturbance of the normal reciprocal relationship between PARC and ANP which antedates diuretic treatment. This should be taken into account when interpreting plasma neuroendocrine measurements in patients with ventricular dysfunction.

Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension.

OBJECTIVES: We sought to compare the myocardial velocity gradient (MVG) measured across the left ventricular (LV) posterior wall during the cardiac cycle between patients with hypertrophic cardiomyopathy (HCM), athletes and patients with LV hypertrophy due to systemic hypertension and to determine whether it might be used to discriminate these groups. BACKGROUND: The MVG is a new ultrasound variable, based on the color Doppler technique, that quantifies the spatial distribution of transmyocardial velocities. METHODS: A cohort of 158 subjects was subdivided by age into two groups: Group I (mean [+/-SD] 30 +/- 7 years) and Group II (58 +/- 8 years). Within each group there were three categories of subjects: Group Ia consisted of patients with HCM (n = 25), Group Ib consisted of athletes (n = 21), and Group Ic consisted of normal subjects; Group IIa consisted of patients with HCM (n = 19), Group IIb consisted of hypertensive patients (n = 27), and Group IIc consisted of normal subjects (n = 33). RESULTS: The MVG (mean [+/-SD] s-1) measured in systole was lower (p < 0.01) in patients with HCM (Group Ia 3.2 +/- 1.1; Group IIa 2.9 +/- 1.2) compared with athletes (Group Ib 4.6 +/- 1.1), hypertensive patients (Group IIb 4.2 +/- 1.8) and normal subjects (Group Ic 4.4 +/- 0.8; Group IIc 4.8 +/- 0.8). In early diastole, the MVG was lower (p < 0.05) in patients with HCM (Group Ia 3.7 +/- 1.5; Group IIa 2.6 +/- 0.9) than in athletes (Group Ib 9.9 +/- 1.9) and normal subjects (Group Ic 9.2 +/- 2.0; Group IIc 3.6 +/- 1.5), but not hypertensive patients (Group IIb 3.3 +/- 1.3). In late diastole, the MVG in patients with HCM (Group Ia 1.3 +/- 0.8; Group IIa 1.4 +/- 0.8) was lower (p < 0.01) than that in hypertensive patients (Group IIb 4.3 +/- 1.7) and normal subjects (Group IIc 3.8 +/- 0.9). An MVG < or = 7 s-1, as a single diagnostic approach, differentiated accurately (0.96 positive and 0.94 negative predictive value) between patients with HCM and athletes when the measurements were taken during early diastole. CONCLUSIONS: In both age groups, the MVG was lower in both systole and diastole in patients with HCM than in athletes, hypertensive patients or normal subjects. The MVG measured in early diastole in a group of subjects 18 to 45 years old would appear to be an accurate variable used to discriminate between HCM and hypertrophy in athletes.

Effects of aging on neuroendocrine activation in subjects and patients in the presence and absence of heart failure with left ventricular systolic dysfunction.

The neuroendocrine profile and echocardiographic features of 40 patients (81 +/- 1 years, means +/- standard error) with heart failure and impaired left ventricular systolic function were compared with those of an age-matched group of healthy subjects, 20 younger patients with heart failure (aged 58 +/- 1 years) and 15 younger healthy subjects. Normal elderly subjects had a neuroendocrine profile similar to that of healthy younger subjects apart from elevated plasma norepinephrine (958 +/- 84 vs 302 +/- 118 pg/ml; p< 0.001) and atrial natriuretic peptide ( 40 +/- 6 vs 28 +/- 5 pg/ml; p<0.05). Despite a similar severity of heart failure, elderly patients had smaller ventricular dimensions (left ventricular internal dimension in diastole 51 +/- 2 vs 69 +/- 3 mm;p<0.0001 and greater impairment of ventricular compliance using Doppler indexes. Plasma norepinephrine was higher (1,191 +/- 80 vs 620 +/- 67 ppg/ml; p<0.01), and plasma atrial natriuretic peptide, plasma active renin, and angiotensin II were lower in elderly patients than in the younger patients with heart failure. As functional capacity declines with age, elderly patients may have less severe cardiac dysfunction for any given level of functional impairment, and this may account for most of the differences in neuroendocrine activity with age. Age appears to be an important determinant of plasma norepinephrine and may be a confounding factor in interpreting the prognostic significance of this hormone.

Plasma neuro-endocrine activity in very elderly subjects and patients with and without heart failure.

Marked neuro-endocrine activation in patients with heart failure indicates a worse prognosis and a greater prognostic benefit from the use of ACE inhibitors. However, although the incidence of heart failure rises rapidly with age, relatively little is known about activation of the renin-angiotensin and sympathetic nervous system in patients with heart failure over the age of 75 years. This study was undertaken to investigate plasma concentrations of neurohormonal variables in elderly patients referred to the cardiac clinic with a presumptive, but unconfirmed, diagnosis of heart failure, and to compare these values to plasma concentrations found in age-matched normal subjects. Fifty patients referred with a diagnosis of heart failure were studied. All were receiving a diuretic but not an ACE inhibitor. Patients with renal, haematological and valve disease were excluded. Routine biochemistry and neurohormonal measurements were performed at their first visit, together with an electrocardiogram, chest X-ray and a full clinical examination by an experienced cardiologist. An echocardiogram and Doppler study was also performed and the diagnosis of heart failure either confirmed or refuted. Plasma concentrations of neuro-endocrine variables in healthy elderly subjects were similar to our normal laboratory range in younger subjects with the exception of atrial natriuretic peptide (ANP) (40 +/- 6 pg.ml-1, normal range < 40) and noradrenaline (5.7 +/- 0.7 nmol.l-1, normal range < 2.8). Impairment of left ventricular systolic function was confirmed in 38 of the 50 symptomatic patients (76%) and was associated with increases in plasma concentrations of active renin (58 +/- 8 IU.mol-1, P < 0.001 compared to healthy elderly subjects), angiotensin II (23 +/- 5 pg.ml-1, P < 0.008), noradrenaline (7.7 +/- 1.2 nmol.l-1, P < 0.01) and atrial natriuretic peptide (121 +/- 18 pg.ml-1, P < 0.002). Plasma concentrations were similar in normal subjects and those receiving treatment for heart failure but in whom the diagnosis was not confirmed. A weak relationship between plasma atrial natriuretic peptide (ANP) and left ventricular fractional shortening was demonstrated (r = -0.5, P < 0.001). Using an upper limit of ANP in the healthy elderly subjects of 62 pmol.ml-1 (mean + SD), plasma concentrations of ANP in the population with suspected heart failure had a sensitivity of 74% and specificity of 66% for the diagnosis of heart failure among elderly patients in the community or where access to echocardiography is limited. Left ventricular diastolic filling (assessed by Doppler) was abnormal in healthy elderly subjects and patients with heart failure, and appeared of limited value in the diagnosis of heart failure secondary to diastolic dysfunction. This study confirms that the renin-angiotensin system is activated in elderly patients with heart failure treated with diuretics. ANP may be helpful in diagnosing heart failure where it appears to have a complimentary role to echocardiography.

Effect of arterial cannulation and contrast agents on blood coagulation.

RATIONALE AND OBJECTIVES: Nonionic contrast media have been considered by some to have thrombogenic properties. We prospectively assessed the effect of femoral artery catheterization and both nonionic and ionic contrast media on the coagulation parameters--fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FpA)--during clinical angiography. METHODS: Seventeen patients undergoing aortography were included. Blood samples were obtained before and after arterial puncture and before and up to 30 min after contrast administration. RESULTS: An increase in FpA was observed after arterial puncture (range = 8.4 +/- 1.9 to 13.6 +/- 2.3 ng/ml, p < .004; data are written as mean +/- standard error of the mean). There was an observed increase in F1 + 2 after arterial puncture that was not statistically significant (2.0 +/- 0.4 to 2.3 +/- 0.4 nmol/l). No further increase was observed in either FpA or F1 + 2 levels after nonionic or ionic contrast media administration. CONCLUSION: The increased activity of the coagulation system during angiography is related to the arterial puncture, and nonionic and ionic contrast media have no thrombogenic potential in vivo.

Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance.

BACKGROUND: The pulmonary diffusing capacity for carbon monoxide (DLCO) is reduced in chronic heart failure (CHF) and is an independent predictor of peak exercise oxygen uptake. The pathophysiological basis for this remains unknown. The aim of this study was to partition DLCO into its membrane conductance (DM) and capillary blood volume components (Vc) and to assess if alveolar-capillary membrane function correlated with functional status, exercise capacity, and pulmonary vascular resistance. METHODS AND RESULTS: The classic Roughton and Forster method of measuring single-breath DLCO at varying alveolar oxygen concentrations was used to determine DM and Vc in 15 normal subjects and 50 patients with CHF. All performed symptom-limited maximal bicycle exercise tests with respiratory gas analysis; 15 CHF patients underwent right heart catheterization. DLCO was significantly reduced in CHF patients compared with normal subjects, predominantly because of a reduction in DM (7.0 +/- 2.6 versus 12.9 +/- 3.8 versus 20.0 +/- 6.1 mmol.min-1.kPa-1 in New York Heart Association class III, class II, and normal subjects, respectively, P < .0001), even when the reduction in lung volumes was accounted for by the division of DM by the effective alveolar volume. The Vc component of DLCO was not impaired. DM significantly correlated with maximal exercise oxygen uptake (r = .72, P < .0001) and inversely correlated with pulmonary vascular resistance (r = .65, P < .01) in CHF. CONCLUSIONS: Reduced alveolar-capillary membrane diffusing capacity is the major component of impaired pulmonary gas transfer in CHF, correlating with maximal exercise capacity and functional status. DM may be a useful marker for the alveolar-capillary barrier damage induced by raised pulmonary capillary pressure.

Optimising heart failure pharmacotherapy: the ideal combination.

Good management of all patients with heart failure is complex. Fortunately most patients fall into only one or two categories, making management less daunting. Most patients with heart failure need treatment with loop diuretics and ACE inhibitors and for many these drugs, possibly combined with antithrombotic measures, are all that is needed for optimal treatment, but optimal treatment can only follow adequate diagnosis. This needs a partnership between the specialist and the family doctor, with ease of access to non-invasive investigations such as echocardiography.