C. M. Oakley

Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy

BACKGROUND Two important features of dilated cardiomyopathy (DCM) are low myocardial contractility and risk of thromboembolism. Nitric oxide (NO) exerts a negative inotropic effect on the myocardium and is produced by NO-synthase, an inducible form of which (iNOS) is stimulated by tumour necrosis factor (TNF-alpha). Accordingly, we hypothesized that locally produced TNF-alpha might contribute to the pathogenesis and complications of DCM by inducing iNOS in the heart. METHODS iNOS and TNF-alpha were quantified by histochemistry and computerised image analysis in explanted heart tissues or myocardial biopsy material from patients with DCM (n = 21) or ischaemic heart disease (HD; n = 10) and from normal donor hearts (n = 9). FINDINGS Immunoreactivity for iNOS was strong in myocytes of DCM hearts, particularly in areas adjacent to the endocardium, and moderately intense in blood vessels of DCM and IHD hearts. The median optical density of the immunostaining for iNOS was greater in cardiac myocytes of patients with DCM (0.86, range 0.21 to 1.29) than in those from patients with IHD (0.20, range 0.095 to 0.26) (p < 0.01) or controls (0.01, range 0.001 to 0.02) (p < 0.001). Staining for TNF-alpha was observed in the vascular endothelium and smooth muscle cells of patients with DCM but not in IHD or control tissues. INTERPRETATION The localisation of iNOS and TNF-alpha within cardiac tissues in DCM suggests that TNF-alpha contributes to both the low contractility and the tendency to thromboembolism in these patients.

Improved survival with amiodarone in patients with hypertrophic cardiomyopathy and ventricular tachycardia.

The effect of amiodarone on survival was assessed in patients with hypertrophic cardiomyopathy and ventricular tachycardia in a drug trial with historical controls. During 1976 and 1977, 24 hour (seven) or 48 hour (79) electrocardiographic monitoring was performed in 86 consecutive patients; 24 had ventricular tachycardia and received conventional antiarrhythmic agents. Nineteen clinical, echocardiographic, and haemodynamic features were assessed. Seven patients died suddenly during follow up of three years; of these, five had continued to have ventricular tachycardia and two had no documented ventricular tachycardia. During 1978 and 1979, ventricular tachycardia was detected during 48 hour electrocardiographic monitoring in 21 of the next 82 consecutive patients with hypertrophic cardiomyopathy. They received amiodarone (150-400 mg/day, median 300); ventricular tachycardia was suppressed in all during repeat 48 hour electrocardiographic examination. Two patients died suddenly during a three year follow up, but neither belonged to the amiodarone treated group with ventricular tachycardia. The clinical and haemodynamic variables were similar in patients taking amiodarone and conventional agents. The fact that control of ventricular arrhythmia with amiodarone is significantly associated with improved survival suggests that amiodarone may prevent sudden death in patients with hypertrophic cardiomyopathy and ventricular tachycardia.

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.

Enhanced basal nitric oxide production in heart failure: another failed counter-regulatory vasodilator mechanism?

Endothelial dysfunction in heart failure could impair nitric oxide production and lead to increased vascular resistance. If endogenous production of nitric oxide is reduced, NG-monomethyl-L-arginine (L-NMMA), an inhibitor of such production, should have a diminished vasoconstrictor effect. We administered L-NMMA to 12 patients being investigated for heart failure. L-NMMA increased median pulmonary and systemic vascular resistances by 61 (range -3 to 240) and 430 (63 to 1609) dynes s cm-5, respectively (p < 0.03 and p < 0.005). Arterial pressures also increased. Median cardiac output fell by 0.6 (0 to -2.3) L per min (p < 0.005). These data suggest that vascular nitric oxide may be another example of a failed counter-regulatory vasodilator system in heart failure.

Natural history of secundum atrial septal defect in adults after medical or surgical treatment: a historical prospective study

Objective—To compare outcome in patients with medically treated secundum atrial septal defect (ASD) first diagnosed after the age of 25 with the long-term outcome in a similar group of patients after surgical closure. Design—A historical, prospective, unrandomised study. Setting—A tertiary referral centre. Patients—All patients with ASD followed up since 1955 who fulfilled the entry criteria and had reached a current age of over 45 years—that is, 34 medical and 48 surgical patients with a mean follow up of 25 years. Main outcome measures—Survival, symptoms, and complications. Results—There was no difference in survival or symptoms between the two groups and no difference in the incidence of new arrhythmias, stroke or other embolic phenomena, or cardiac failure. No patient in either group developed progressive pulmonary vascular disease. Conclusion—Outcome in adults with ASD was not improved by surgical closure. Because progressive pulmonary vascular disease did not develop in any of these patients its prevention is not a reason for advising closure of ASD in adults.

Percutaneous catheter fragmentation and distal dispersion of proximal pulmonary embolus

Rapid restoration of pulmonary blood flow is important in preventing death due to a massive pulmonary embolus. Devices developed specifically for percutaneous transvenous removal of pulmonary emboli are bulky and their insertion through a cut down or by the use of a large venous sheath can lead to bleeding at the entry site. In 3 patients with acute massive pulmonary embolism, conventional cardiac catheters were used to break up the embolus and disperse the fragments distally. Cardiac output was rapidly restored in all patients. There were no serious complications. This technique requires no more specialist equipment or skill than those needed for temporary cardiac pacing and could be important for the emergency management of patients with acute severe pulmonary embolism.

Effects of increased inspired oxygen concentrations on exercise performance in chronic heart failure

Exercise capacity in patients with stable heart failure may be influenced by prolonged drug treatment or exercise training, but acute interventions are generally thought to have little effect. Cardiorespiratory responses to exercise were studied in 12 consecutive patients with chronic congestive heart failure who underwent serial submaximal and maximal exercise tests at inspired oxygen concentrations of 21% (room air), 30%, and 50%. Mean (SD) exercise duration during progressive testing to maximum exercise capacity was prolonged from 548 (276) s on room air to 632 (285) s on 50% oxygen (p = 0.012). During steady-state exercise at 45 W, oxygen enrichment to 50% was associated with significantly increased arterial oxygen saturation (94.6 [1.9]% to 97.5 [1.3]%), and significantly reduced minute ventilation (36.1 [8.6] l/min to 28.1 [5.9] l/min), cardiac output (7.5 [2.3] l/min to 6.5 [1.9] l/min), and subjective scores for fatigue and breathlessness (13.9 [3.1] to 11.5 [3.5]) compared with room air intermediate changes were observed with 30% inspired oxygen. Increased inspired oxygen concentrations can improve exercise performance acutely and modify the ventilatory response to exercise in patients with heart failure. Hyperoxia reduces ventilatory response and circulatory demand while maintaining oxygen delivery at a given workload. The potential benefits of increased inspired oxygen concentrations in the treatment of chronic heart failure merit further assessment.

Right ventricular dilated cardiomyopathy.

Fourteen patients with predominantly right sided dilated cardiomyopathy were studied, of whom five died suddenly. The condition is characterised by male preponderance, syncope, ventricular tachycardia, which typically has a left bundle branch block pattern on the surface electrocardiogram, and right heart failure. The diagnosis should be considered in patients presenting with otherwise unexplained ventricular tachycardia or syncope; the diagnosis may be readily missed because of the nonspecific nature or absence of signs.

Sarcoidosis: a pattern of clinical and morphological presentation.

The diagnosis of cardiac sarcoidosis, particularly when there is no overt systemic involvement, is frequently delayed because of its varied manifestations. Focal left ventricular wall motion abnormalities were recognised in five patients with sarcoidosis. Three patients showed abnormal regional wall motion in the basal portion of the ventricular septum and free wall with sparing of the apex. The angiographic appearances supported the echocardiographic findings which were atypical of ischaemic heart disease. The remaining two patients both had diffuse left ventricular hypokinesia, with a focal abnormality that was most pronounced in the anteroapical region; this pattern is often seen with coronary disease. The recognition by echocardiography or angiography of focal abnormalities of wall motion affecting the basal portion of the ventricular septum should suggest the possibility of myocardial sarcoidosis even in the absence of recognised systemic manifestations.

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.