Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease

OBJECTIVE—To make a quantitative assessment of the relation between disarray, fibrosis, and small vessel disease in hypertrophic cardiomyopathy.
DESIGN—Detailed macroscopic and histological examination at 19 segments of the left and right ventricle and the left atrial free wall.
PATIENTS—72 patients with hypertrophic cardiomyopathy who had suffered sudden death or progression to end stage cardiac failure (resulting in death or heart transplantation).
MAIN OUTCOME MEASURES—The presence of scarring, atrial dilatation, and a mitral valve impact lesion were noted, and heart weight, wall thickness, per cent disarray, per cent fibrosis, and per cent small vessel disease quantitated for each heart.
RESULTS—Within an individual heart the magnitude of hypertrophy correlated with the severity of fibrosis (p = 0.006) and disarray (p = 0.0002). Overall, however, total heart weight related weakly but significantly to fibrosis (r = 0.4, p = 0.0001) and small vessel disease (r = 0.3, p = 0.03), but not to disarray. Disarray was greater in hearts with mild left ventricular hypertrophy (maximum wall thickness < 20 mm) and preserved systolic function (60.9 (26)% v 43 (20.4)% respectively, p = 0.02) and hearts without a mitral valve impact lesion (26.3% v 18.9%, p = 0.04), but was uninfluenced by sex. Fibrosis was influenced by sex (7% in male patients and 4% in female, p = 0.04), but not by the presence of an impact lesion. No relation was found between disarray, fibrosis, and small vessel disease.
CONCLUSIONS—Myocyte disarray is probably a direct response to functional or structural abnormalities of the mutated sarcomeric protein, while fibrosis and small vessel disease are secondary phenomena unrelated to disarray, but modified by factors such as left ventricular mass, sex, and perhaps local autocrine factors.


Keywords: hypertrophic cardiomyopathy; histopathology; small vessel disease     

Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation

OBJECTIVE—To investigate changes in the alignment of the sarcomeric filaments in hypertrophic cardiomyopathy and the effects of cardiac β myosin heavy chain (β-MHC) mutation on the sarcomeric ultrastructure.
DESIGN—A retrospective analysis.
PATIENTS—Endomyocardial biopsy samples were examined by transmission electron microscopy in seven patients with hypertrophic cardiomyopathy and β-MHC mutation, six with hypertrophic cardiomyopathy but without the mutation, and five controls (with chest pain syndromes).
MAIN OUTCOME MEASURE—Alignment of the sarcomeric filaments and the distance between neighbouring thick myosin filaments.
RESULTS—In controls, cross sections of the sarcomere at the A band showed a highly organised orthohexagonal array with 6 thin actin filaments surrounding one thick myosin filament, whereas in hypertrophic cardiomyopathy the alignment of the sarcomeric filaments was sparse and disrupted. In hypertrophic cardiomyopathy with a mutation, the distance between neighbouring thick myosin filaments was greater than in controls (mean (SD) 45.3 (4.7) v 38.5 (3.5) nm, p < 0.05), and the variance of the distance was greater than in controls (8.0 (0.7) v 4.8 (1.0) nm, p < 0.001) or in patients with hypertrophic cardiomyopathy without a mutation (6.7 (0.6) nm, p < 0.05). In the latter, the variance of the distance was also greater than in the controls (p < 0.01). A significant correlation was found between the grade of the myocyte hypertrophy and the variance of the distance (r = 0.654; p < 0.01).
CONCLUSIONS—The alignment of the sarcomeric filaments is disrupted in hypertrophic cardiomyopathy, particularly when there is β-MHC mutation.


Keywords: hypertrophic cardiomyopathy; β myosin heavy chain; myosin filament; sarcomere     

Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy

Objective—To identify new prognostic indicators in idiopathic dilated cardiomyopathy (DCM) and secondary cardiomyopathy.
Design and patients—Serum concentrations of aminoterminal propeptides of type III procollagen and the 7S domain of type IV collagen (7S collagen)—which have recently been used as indicators of collagen matrix turnover in other diseases—and of cardiac troponin T were measured in 17 consecutive patients with DCM and in four patients with secondary cardiomyopathy (one associated with hyperthyroidism, two with chronic renal failure, one with amyloidosis), confirmed by endomyocardial biopsy. The correlation of these variables with short term prognosis was then assessed prospectively.
Results—11 of the patients were positive for type III procollagen, 7S collagen, or troponin T even though their creatine kinase concentrations were within the normal range. These patients had a poor short term prognosis (p < 0.001).
Conclusions—Within the DCM and secondary cardiomyopathy groups, there was a subgroup of patients with raised concentrations of serum collagen and troponin T, for whom short term prognosis was poor. Although it is unclear whether these serum peptide levels reflect ongoing myocyte degeneration and interstitial fibrosis, they may serve as useful new prognostic indicators for cardiomyopathy.

Keywords: troponin T;  collagen;  dilated cardiomyopathy     

Direct current cardioversion does not cause cardiac damage: evidence from cardiac troponin T estimation

Aim—To determine whether elective direct current (dc) cardioversion of atrial fibrillation/flutter causes myocardial damage.
Methods and results—Cardiac troponin T and creatine kinase were estimated 20-28 hours after dc cardioversion in 51 patients who received dc shocks for elective cardioversion of chronic atrial fibrillation/flutter. Although creatine kinase was raised in 44 patients, cardiac troponin T was undetectable in all patients.
Conclusion—Cardiac damage does not occur as a result of cardioversion.

Keywords: cardioversion;  troponin T;  creatine kinase;  atrial fibrillation     

Sudden death in children and adolescents

OBJECTIVE—To identify the incidence, causes, and characteristics of sudden death at age 1-20 years.
DESIGN—A review of all deaths at age 1-20 years. Death certificates were obtained from the Office for National Statistics, and further information, where appropriate, from coroners, paediatricians, physicians, and pathologists.
SETTING—The resident population of one English health region in 1985-1994.
RESULTS—In a population of 806 500 children and adolescents aged 1-20 years there were 2523 deaths in 10 years. Medical causes accounted for 1017 deaths (40%); 1236 (49%) were unnatural, and 270 (11%) were sudden. These sudden deaths comprised 142 with a previous diagnosis, the commonest being epilepsy 49 (34%), cardiovascular disease 33 (23%), and asthma 30 (21%); 87 attributed to a cause discovered at necropsy, which was respiratory infection in 32 (37%), other infections in 17 (20%), and unsuspected cardiovascular abnormalities in 26 (30%); 41 remained unexplained.
CONCLUSIONS—Half of all sudden deaths in children or adolescents were attributed to an already diagnosed condition. Abnormalities identified at necropsy accounted for one third of sudden deaths. Undiagnosed hypertrophic cardiomyopathy caused less than one death per million person years in the population aged 1-20 years. Unexplained sudden death, which may be caused by primary cardiac arrhythmia, is probably about 10 times more common.


Keywords: sudden death; necropsy; paediatric cardiology     

Can C reactive protein or troponins T and I predict outcome in patients with intractable unstable angina?

Objective—To determine whether a single blood test for the measurement of C reactive protein, or troponin I or T concentrations could be used to stratify patients with intractable unstable angina awaiting transfer for coronary angiography by correlating these values with coronary anatomy and transient myocardial ischaemia.
Design—Prospective study.
Setting—Tertiary cardiac unit.
Patients—All patients admitted to their local hospital with ischaemic chest pain, uncontrolled by medical treatment, in whom acute myocardial infarction had been excluded by serial measurement of creatine kinase and lack of Q waves on ECG.
Intervention—Coronary angiography and ST segment monitoring for 24 hours.
Main outcome measures—Concentrations of C reactive protein, troponins T and I, coronary anatomy, presence of transient myocardial ischaemia.
Results—Median C reactive protein, troponin I, and troponin T concentrations were 17.1 mg/dl (4.8 to 203.9), 0.05 µg/l (0 to 7.8), and 0.0 µg/l (0 to 2.51), respectively. Seven patients (10%) had normal coronaries and 14, 20, and 31 had one, two, or three vessel coronary disease, respectively. Nineteen (26%) had transient myocardial ischaemia, 33 (46%) had complex lesion morphology, and six (8%) had intracoronary thrombus. Of the three markers, troponin T alone was higher in patients with multivessel disease (p < 0.05) and in those with transient myocardial ischaemia (p < 0.05), but there was no significant relation between C reactive protein, troponin T or I and lesion morphology or thrombus.
Conclusions—In patients transferred to a tertiary centre with intractable chest pain, C reactive protein and troponin I are not predictive of transient myocardial ischaemia or lesion morphology, both of which are surrogate markers of outcome. Troponin T is, however, raised in patients with multivessel disease or transient myocardial ischaemia. These serum protein assays cannot be used to stratify the risk of patients with unstable angina who are awaiting transfer to the tertiary centre.

Keywords: C reactive protein;  troponin T;  troponin I;  unstable angina     

Absence of viral nucleic acids in early and late dilated cardiomyopathy

OBJECTIVE—To investigate whether viral infection acts as a trigger factor for the development of dilated cardiomyopathy in genetically predisposed individuals with a family history of disease.
SETTING—Patients attending the cardiomyopathy unit in a cardiac tertiary referral centre.
DESIGN—Nested polymerase chain reaction (nPCR) was used to determine whether enteroviral, adenoviral, or cytomegaloviral nucleic acids were detectable in the myocardium of 19 asymptomatic relatives of patients with dilated cardiomyopathy; all these relatives had echocardiographic abnormalities thought to represent early disease. Explanted hearts from patients with end stage dilated cardiomyopathy were also studied and were compared with 25 controls (ischaemic heart disease (21), valvar heart disease (2), hypertrophic cardiomyopathy (1), restrictive cardiomyopathy (1)). Myocardial tissue from two fatal cases of culture positive coxsackie myocarditis was used as a positive control.
RESULTS—No viral nucleic acid was detected in any group other than in those with myocarditis. Spiking of random wells with purified recombinant viral nucleic acids confirmed the sensitivity and reproducibility of the assays.
CONCLUSIONS—Myocardial viral infection is not detectable in relatives of patients with dilated cardiomyopathy who are suspected of having early disease. There is no evidence that viruses act as a trigger factor for initiating the dilated cardiomyopathy in these patients.


Keywords: viral infection; dilated cardiomyopathy     

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.

Keywords: cardiomyopathy; Friedreich's ataxia; genetics     

A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

Objective—To investigate cardiac function in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and clarify the clinical features of cardiomyopathy in MELAS.
Patients—11 consecutive patients with MELAS (mean age at initial examination 11.3 years, range 4 to 16 years) were enrolled in the study. Six were followed for more than five years.
Results—On echocardiographic examination, three patients showed increased left ventricular end diastolic posterior wall thickness (LVPWTd), exceeding 140% of the normal value. Four patients, including these three, had an ejection fraction of less than 50%, and two also had increased left ventricular end diastolic volume (LVEDV) exceeding 140% of the normal value (%N). The LVPWTd%N was correlated positively with the LVEDV%N (R = 0.669, p < 0.05) and negatively with the ejection fraction (R = −0.6701, p < 0.05). One patient died of heart failure aged 22 years.
Conclusions—The cardiomyopathy in MELAS is characterised by an abnormally thick left ventricular wall with progressive dilatation and poor left ventricular contraction developing over several years, indicating hypertrophic cardiomyopathy advancing to dilated cardiomyopathy.

Keywords: MELAS;  cardiomyopathy     

Increased concentrations of inflammatory mediators in unstable angina: correlation with serum troponin T

OBJECTIVE—To measure plasma interferon γ, monocyte chemotactic protein-1 (MCP-1), and interleukin 6 and to assess their correlation with cardiac troponin T in unstable angina.
DESIGN—Blood sampling in patients undergoing coronary arteriography for known or suspected ischaemic heart disease.
PATIENTS—76 patients divided in three groups: 29 with unstable angina (group 1), 28 with stable angina (group 2), and 19 without ischaemic heart disease and with angiographically normal coronary arteries (group 3).
MAIN OUTCOME MEASURES—Plasma interleukin 6, interferon γ, MCP-1, and troponin T in the three groups of patients.
RESULTS—Interleukin 6 was increased in group 1 (median 2.19 (range 0.53-50.84) pg/ml) compared with the control group (1.62 (0.79-3.98) pg/ml) (p < 0.005), whereas interferon γ was higher in group 1 (range 0-5.51 pg/ml) than in the other two groups (range 0-0.74 pg/ml and 0-0.37 pg/ml; p < 0.005 and p < 0.001, respectively). Patients with unstable angina (group 1) and positive troponin T had higher concentrations of interferon γ than those with negative troponin T (0-5.51 pg/ml v 0-0.60 pg/ml, p < 0.001). Plasma MCP-1 was also higher in group 1 (median 267 (range 6-8670) pg/ml) than in the other two groups (134 (19-890) pg/ml and 84.5 (5-325) pg/ml; p < 0.005 and p < 0.001, respectively), and among group 1 patients with a positive troponin T assay than in those with normal troponin T (531 (14.5-8670) pg/ml v 69 (6-3333) pg/ml; p < 0.01). There was no difference in plasma interleukin 6 in group 1 patients between those with and without raised troponin T.
CONCLUSIONS—The inflammatory cytokines interferon γ and MCP-1 are increased in patients with unstable angina, particularly in those with raised concentrations of troponin T, suggesting that they are probably related to myocardial cell damage or to plaque rupture and thrombus formation.


Keywords: inflammatory cytokines; troponin T; unstable angina     

Cardiac troponin T does not increase after electrical cardioversion for atrial fibrillation or atrial flutter

Objective—To determine whether cardiac troponin T increases after electrical cardioversion in patients with atrial fibrillation or atrial flutter.
Design—Serum creatine kinase (CK), creatine kinase-MB (CKMB), and cardiac troponin T were measured before, 24 hours, and 48 hours after cardioversion in 15 patients with atrial fibrillation or atrial flutter.
Results—12 of the 15 patients (80%) were successfully cardioverted to sinus rhythm. The median number of shocks was three (range one to six), the median cumulative energy 710 J (50 to 1430 J), and the median peak energy 300 J (50 to 360 J). Total CK increased from a baseline median concentration of 92 (45 to 259) to 1324 (96 to 6660) U/l at 24 hours and 1529 (120 to 4774) U/l at 48 hours after cardioversion. There was a small increase in CKMB but the ratio of CKMB to CK did not increase. There was no increase in cardiac troponin T in any patient.
Conclusions—Following electrical cardioversion of atrial fibrillation or atrial flutter, cardiac troponin T remains unchanged despite a large rise in total CK, indicating that the CK is derived from skeletal muscle and that myocardial injury does not occur. If cardiac troponin T is increased after cardioversion for atrial arrhythmias then other causes of myocardial damage should be sought.

Keywords: atrial fibrillation; atrial flutter; cardioversion; troponin T     

Intraoperative release of troponin T in coronary venous and arterial blood and its relation to recovery of left ventricular function and oxidative metabolism following coronary artery surgery

Objective—To investigate the intraoperative release of troponin T during uncomplicated coronary artery surgery and to determine its relation to ischaemic time and to recovery of left ventricular function and oxidative metabolism.
Design—A prospective observational study.
Setting—Cardiac surgical unit in a tertiary referral centre.
Methods—Troponin T, creatine kinase, and lactate were analysed from arterial and coronary sinus samples taken before operation, and 1, 4, 6, 10, 20, 35, and 45 minutes after cross clamp release. Net myocardial troponin T release and lactate extraction were derived from their respective arteriovenous differences. Haemodynamic measurements were made using a thermodilution pulmonary artery catheter.
Patients—45 patients, mean (SD) age 62 (9) years, with two or three vessel coronary artery disease and chronic stable angina undergoing routine coronary artery surgery.
Results—Before operation, troponin T concentrations were not raised, but within one minute of cross clamp release they increased progressively in both coronary sinus and arterial blood for the entire 45 minutes of reperfusion studied. Coronary sinus troponin T concentrations were consistently higher than arterial concentrations at all time points (p < 0.001), indicating net troponin T release by the myocardium. Peak net troponin T release and area under the curve of net troponin T release correlated closely with ischaemic time (r = 0.58 and r = 0.61, p < 0.0001 for both). Area under the curve of arterial troponin T concentration was also significantly correlated with ischaemic time (r = 0.44, p < 0.01). Patients with cross clamp times longer than 72 minutes (upper quartile for ischaemic time) had greater troponin T release, delayed reversion to lactate extraction, and lower left ventricular stroke work index three hours after surgery, compared with patients who had short (< 50 minutes, lower quartile) and intermediate (51-71 minutes, interquartile) cross clamp times. Peak net troponin T release and area under the curve of arterial troponin T concentration were inversely correlated with left ventricular stroke work index three hours after surgery (r = −0.57, r = −0.38, p < 0.01).
Conclusions—Troponin T concentrations increased in every patient after cross clamp release, and were consistently higher in coronary sinus blood than in arterial blood, indicating net myocardial release of troponin T during the period of reperfusion. Intraoperative net troponin T release has functional significance, as it is closely related to ischaemic time and reflects delayed recovery of left ventricular function and oxidative metabolism; therefore, its measurement may contribute to the perioperative assessment of myocardial injury sustained during coronary artery surgery.

Keywords: coronary artery surgery;  troponin T;  intraoperative assessment;  myocardial injury     

Troponin T measurement after myocardial infarction can identify left ventricular ejection of less than 40%

Aim—To determine whether measurement of serum troponin T concentration after first acute myocardial infarction can be used to identify patients with a left ventricular ejection fraction of < 40%, who have an adverse prognosis.
Methods—Troponin T concentration was measured, and coronary and left ventriculography performed in 50 consecutive patients with acute myocardial infarction. Angiographic left ventricular ejection fraction was compared with serum troponin T concentration. Patients with previous myocardial infarction were excluded.
Results—There was a strong negative correlation between left ventricular ejection fraction and troponin T concentration. Spearman's rank correlation coefficient (corrected for ties) was −0.72 (95% confidence intervals (CI) −0.55 to −0.83; p < 0.0001). Analysis by receiver operator characteristic curve produced an area under the curve of 0.9773 (95% CI 0.9409 to 1.0136). A troponin T concentration of > 2.8 µg/l predicted a left ventricular ejection fraction of < 40% with a sensitivity of 100% (CI 84.6 to 100.0) and specificity of 92.9% (CI 76.5 to 99.1). Exclusion of patients who did not receive thrombolytic treatment did not significantly affect the results.
Conclusion—Serum troponin T concentration measured 12-48 hours after admission for first myocardial infarction is a reliable, simple, quick, inexpensive, non-invasive method for identifying patients with a left ventricular ejection fraction of < 40% for whom there is a poor prognosis.

Keywords: troponin T;  acute myocardial infarction;  angiotensin converting enzyme inhibitors;  left ventricular function     

Impaired cardiac adrenergic innervation assessed by MIBG imaging as a predictor of treatment response in childhood dilated cardiomyopathy

OBJECTIVE—To evaluate the prognostic value of metaiodobenzylguanidine (MIBG) imaging in childhood cardiomyopathy.
DESIGN—Prospective cohort study.
SETTING—Tertiary referral centre.
PATIENTS—40 children (21 boys, 19 girls; mean (SD) age, 7.0 (5.6) years) with heart failure resulting from idiopathic dilated cardiomyopathy (n = 23) or various other disorders (n = 17).
METHODS—At the initial examination, cardiac ¹²³I-MIBG uptake and release, circulating noradrenaline (norepinephrine) concentration, x ray cardiothoracic ratio, and echocardiographic variables were recorded. Cardiac MIBG uptake was obtained by measuring the heart to mediastinum activity ratio on the planar image obtained four hours after MIBG injection. MIBG washout rate was evaluated using relative decrease in cardiac activity measured at 20 minutes and four hours. Patients were treated with angiotensin converting enzyme inhibitors, diuretics, and digitalis, and were followed up for 12 (10) months. Fifteen patients did not respond to medical treatment (12 heart transplants; three deaths), and 25 did respond (improved or stable).
RESULTS—Cardiac MIBG uptake was positively correlated with x ray cardiothoracic index (r = 0.55, p = 0.0008) and echocardiographic left ventricular fractional shortening (r = 0.68, p < 0.0001). Among all the clinical and laboratory variables tested, multivariate discriminant analysis showed that the only independent predictor of an unfavourable outcome was a low MIBG uptake (p < 0.001). Survival curves had a mean threshold value of 1.54 for MIBG uptake.
CONCLUSIONS—Impaired cardiac adrenergic innervation is strongly related to adverse outcome in children with dilated cardiomyopathy, independently of the aetiology. MIBG imaging may help to stratify risk in such patients.


Keywords: noradrenaline; MIBG; single photon imaging; children; cardiomyopathy     

Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population

Background—Amiodarone has been reported to reduce the likelihood of sudden death in patients with hypertrophic cardiomyopathy (HCM). However, data regarding the clinical course in HCM have traditionally come from selected referral populations biased toward assessment of high risk patients.
Aims—To evaluate antiarrhythmic treatment for sudden death in an HCM population not subject to tertiary referral bias, closely resembling the true disease state present in the community.
Methods—Cardiovascular mortality was assessed in relation to the occurrence of non-sustained ventricular tachycardia (NSVT) on 24 or 48 hour ambulatory Holter recording, a finding previously regarded as a marker for sudden death, particularly when the arrhythmia was frequent, repetitive or prolonged. 167 consecutive patients were analysed by multiple Holter ECG recordings (mean (SD) 157 (129) hours) and followed for a mean of 10 (5) years. Only patients with multiple repetitive NSVT were treated with amiodarone, and in relatively low doses (220 (44) mg/day).
Results—Nine HCM related deaths occurred: 8 were the consequence of congestive heart failure, but only 1 was sudden and unexpected. Three groups of patients were segregated based on their NSVT profile: group 1 (n = 39), multiple ( 2 runs) and repetitive bursts (on 2 Holters) of NSVT, or prolonged runs of ventricular tachycardia, included 4 deaths due to heart failure; group 2 (n = 38), isolated infrequent bursts of NSVT, included 1 sudden death; group 3 (n = 90), without NSVT, included 4 heart failure deaths. Kaplan-Meier survival analysis showed no significant differences in survival between the three groups throughout follow up.
Conclusions—In an unselected patient population with HCM, isolated, non-repetitive bursts of NSVT were not associated with adverse prognosis and so this arrhythmia does not appear to justify chronic antiarrhythmic treatment. Amiodarone, administered in relatively low doses, did not carry an independent and additive risk for cardiac mortality. Amiodarone may have contributed to the absence of sudden cardiac death in patients believed to be at higher risk because of multiple repetitive NSVT.

Keywords: hypertrophic cardiomyopathy; ventricular tachycardia; amiodarone     

Haemochromatosis gene mutations in idiopathic dilated cardiomyopathy

BACKGROUND—Two common mutations of the haemochromatosis associated gene (HFE) (cys282tyr (C282Y) and his63asp (H63D)) have been implicated in haemochromatosis and as modulators in cardiovascular disease.
OBJECTIVE—To investigate the role of these mutations in the pathogenesis of idiopathic dilated cardiomyopathy.
DESIGN AND SETTING—Case-control and prospective cohort study of patients attending a cardiomyopathy unit in a tertiary referral cardiac centre.
METHODS—207 unrelated white patients with dilated cardiomyopathy, followed up for 259 patient years, and 200 controls were tested for HFE C282Y and H63D mutations by polymerase chain reaction and restriction digestion.
RESULTS—31/207 patients (15%) v 24/200 controls (12%) carried C282Y (adjusted odds ratio (OR) 1.2 (95% confidence interval 0.7 to 2.2)), 74/207 (36%) v 53/200 (27%) carried H63D (OR 1.6 (1.1 to 2.5)), and 10/207 (4.8%) v 4/200 (2%) were compound heterozygotes (OR 2.6 (0.8 to 8.5)). Four patients and six controls were H63D homozygous and one was C282Y homozygous. There was a progressive increase in mean serum iron ([Fe]) and transferrin saturations from patients with no mutation ([Fe] = 16.3 µmol/l, transferrin saturation = 23.7%) through H63D heterozygotes (17.5 µmol/l, 25.8%), C282Y heterozygotes (17.1 µmol/l, 26.6%), H63D homozygotes (20.0 µmol/l, 33.5%), compound heterozygotes (26.8 µmol/l, 41.7%), and C282Y homozygotes (34 µmol/l, 71%). At follow up (median 90 months) the rate of death or cardiac transplantation was 52/207 (25%). C282Y heterozygotes had less ventricular dilatation (mean (SD): 59.9 (1.7) mm v 64.9 (0.9) mm, p < 0.05), better fractional shortening (24 (1.7)% v 18.8 (1.4)%, p < 0.01), and a trend towards improved survival without transplantation. [Fe] and transferrin saturation did not correlate with disease severity and were not associated with reduced survival.
CONCLUSIONS—The frequency of the H63D mutation is significantly increased in patients with idiopathic dilated cardiomyopathy. As H63D has a relatively minor effect on iron status, the mechanism of this association may be unrelated to iron metabolism.


Keywords: dilated cardiomyopathy; genetics; haemochromatosis     

Relaxation in hypertrophic cardiomyopathy and hypertensive heart disease: relations between hypertrophy and diastolic function

AIM—To determine the relation between the extent and distribution of left ventricular hypertrophy and the degree of disturbance of regional relaxation and global left ventricular filling.
METHODS—Regional wall thickness (rWT) was measured in eight myocardial regions in 17 patients with hypertrophic cardiomyopathy, 12 patients with hypertensive heart disease, and 10 age matched normal subjects, and an asymmetry index calculated. Regional relaxation was assessed in these eight regions using regional isovolumetric relaxation time (rIVRT) and early to late peak filling velocity ratio (rE/A) derived from Doppler tissue imaging. Asynchrony of rIVRT was calculated. Doppler left ventricular filling indices were assessed using the isovolumetric relaxation time, the deceleration time of early diastolic filling (E-DT), and the E/A ratio.
RESULTS—There was a correlation between rWT and both rIVRT and rE/A in the two types of heart disease (hypertrophic cardiomyopathy: r = 0.47, p < 0.0001 for rIVRT; r = −0.20, p < 0.05 for rE/A; hypertensive heart disease: r = 0.21, p < 0.05 for rIVRT; r = −0.30, p = 0.003 for rE/A). The degree of left ventricular asymmetry was related to prolonged E-DT (r = 0.50, p = 0.001) and increased asynchrony (r = 0.42, p = 0.002) in all patients combined, but not within individual groups. Asynchrony itself was associated with decreased E/A (r = −0.39, p = 0.01) and protracted E-DT (r = 0.69, p < 0.0001) and isovolumetric relaxation time (r = 0.51, p = 0.001) in all patients. These correlations were still significant for E-DT in hypertrophic cardiomyopathy (r = 0.56, p = 0.02) and hypertensive heart disease (r = 0.59, p < 0.05) and for isovolumetric relaxation time in non-obstructive hypertrophic cardiomyopathy (n = 8, r = 0.87, p = 0.005).
CONCLUSIONS—Non-invasive ultrasonographic examination of the left ventricle shows that in both hypertrophic cardiomyopathy and hypertensive heart disease, the local extent of left ventricular hypertrophy is associated with regional left ventricular relaxation abnormalities. Asymmetrical distribution of left ventricular hypertrophy is indirectly related to global left ventricular early filling abnormalities through regional asynchrony of left ventricular relaxation.


Keywords: hypertrophic cardiomyopathy; hypertensive heart disease; isovolumetric relaxation; diastolic function     

The heart in limb girdle muscular dystrophy

Objective—To assess the frequency, nature, and severity of cardiac abnormalities in limb girdle muscular dystrophy, and its relation to age and weakness in various genotypes.
Design—In 26 autosomal dominant, 38 autosomal recessive, and 33 sporadic strictly defined patients with limb girdle muscular dystrophy, cardiac evaluation included history, physical examination, chest x ray, electrocardiography, 24 hour ECG Holter monitoring, and echocardiography. In 35 of the 71 autosomal recessive and sporadic cases muscle biopsies were available for sarcoglycan analysis.
Main results—Dilated cardiomyopathy was present in one autosomal dominant case and in three advanced autosomal recessive or sporadic patients, of whom two were found to have α sarcoglycan deficiency. Two of these three patients and three other cases showed ECG abnormalities known to be characteristic of the dystrophinopathies. A strong association between the absence of α sarcoglycan and the presence of dilated cardiomyopathy was found (p = 0.04). In six autosomal dominant cases there were atrioventricular (AV) conduction disturbances, increasing in severity with age and in concomitant presence of muscle weakness. Pacemaker implantation was necessary in four.
Conclusions—10% of these patients had clinically relevant cardiac abnormalities. In autosomal dominant limb girdle muscular dystrophy one subtype characterised by muscle weakness and AV conduction disturbances is recognised. In the course of autosomal recessive/sporadic limb girdle muscular dystrophy, dilated cardiomyopathy may develop, probably related to deficiency of dystrophin associated proteins.

Keywords: limb girdle muscular dystrophy;  cardiomyopathy;  AV conduction block;  sarcoglycan     

Cardiopulmonary responses to exercise in patients with hypertrophic cardiomyopathy

Objective—To examine the submaximal and maximal indices of the exercise response of patients with hypertrophic cardiomyopathy.
Design and setting—Prospective examination of cardiopulmonary responses to ramp exercise test of a consecutive group of patients with hypertrophic cardiomyopathy attending a cardiomyopathy outpatient clinic.
Methods—50 patients aged 12 to 76 years (mean (SD) 35 (14)) with diagnosis of hypertrophic cardiomyopathy performed incremental cycle ergometry; 22 sedentary volunteers (seven female, 15 male) aged 14 to 58 years (mean (SD) 31 (12)) served as controls. Respiratory gas was continuously sampled from the mouthpiece, and its concentration profile phase aligned to the respired air flow signals. Following analogue to digital conversion, gas exchange variables were computed breath by breath and the data were averaged every 30 seconds for graphic display. A 12 lead ECG was monitored continuously and recorded every three minutes during the exercise.
Results—Both the peak oxygen uptake attained on the test (O₂ peak) and anaerobic threshold were reduced in patients with hypertrophic cardiomyopathy compared with the control group (p < 0.0001). In 29 patients (59%) the O₂ peak was less than 60% and only two patients achieved a peak above 80% of their predicted values. The anaerobic threshold was below 60% of the predicted value in 31 patients and above 80% in only three patients. The slope of oxygen uptake/work rate relation (ΔO₂/ΔWR) was decreased in 16 patients (32%). The maximum oxygen pulse (O₂/HR) was reduced as a percentage of the predicted value, and became flat at high work rates in 32 patients. There was a significant correlation between anaerobic threshold and O₂ peak (p < 0.0001), work efficiency (p < 0.0001), and maximum oxygen pulse (p < 0.0001). The slope of change in ventilation against change in carbon dioxide output (ΔE/ΔCO₂) for the subanaerobic threshold range was increased in 36 patients (72%) and was inversely correlated with anaerobic threshold (p < 0.0002).
Conclusions—There were severe abnormalities in maximal and submaximal indices of pulmonary gas exchange in a cohort of hypertrophic cardiomyopathy patients attending a referral cardiovascular clinic. The pattern of the abnormalities suggests that a reduced stroke volume response, ventilation/perfusion mismatch, and abnormal peripheral oxygen utilisation are the possible mechanisms of exercise intolerance.

Keywords: exercise tolerance;  work efficiency;  oxygen pulse;  hypertrophic cardiomyopathy     

Luminal narrowing of coronary capillaries in human hypertrophic hearts: an ultrastructural morphometrical study using endomyocardial biopsy specimens

Background—Abnormal microcirculation has been suggested in hearts with pathological conditions, particularly in hypertrophic hearts, even in the presence of normal epicardial coronary arteries. However, the morphology of coronary capillaries has not been well investigated in those hearts.
Methods—Ultrastructural morphometry of the capillaries in 47 endomyocardial biopsy specimens taken from 30 patients was performed.
Patients—Six patients had hypertrophic cardiomyopathy with dilated cardiomyopathy-like features (DCM-like HCM), six had HCM, six had DCM, five had postmyocarditis, and seven were normal subjects.
Results—The short axial diameters of capillaries were similar among the groups. Abnormal stenosis of more than 90% luminal narrowing was found in 31% of capillaries of the DCM-like HCM group, 16% of the HCM group, 13% of the DCM group, 11% of the postmyocarditis group, and 2% of the normal subjects. Mean (SD) stenosis of the lumen was most severe in DCM-like HCM (78(8)%), and more severe in HCM (67(9)%), DCM (66(8)%), and postmyocarditis (68(4)%) than normal subjects (56(8)%). The mean cross sectional areas of capillaries were similar among the groups; however, the endothelial cellular area was significantly (p < 0.05) greater in DCM-like HCM (24.2 (8.2) µm²) than in normal subjects (14.7 (1.8) µm²), indicating that capillary narrowing was due to the increased volume of capillary endothelial cells. The endothelial cells of the stenosed capillaries showed severely oedematous changes of the cytoplasm wholely or partially, but the cytoplasmic organelles and nuclei appeared intact.
Conclusion—Narrowing of the coronary capillaries may be of pathophysiological significance in microcirculatory abnormality in hypertrophic hearts, particularly in patients with DCM-like HCM.

Keywords: capillary;  hypertrophy;  cardiomyopathy;  ultrastructure