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W McKenna

Publications and source records attributed to W McKenna.

At least 19 recordsLinked to original sources
PubMed2005

Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin A/C gene.

Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, give rise to Emery-Dreifuss muscular dystrophy and to limb-girdle muscular dystrophy 1B (EDMD and LGMD1B). With one exception, all the reported EDMD and LGMD1B mutations are confined to the first 10 exons of the gene. We report four separate cases, with mutations in the same codon of LMNA exon 11, characterized by remarkable variability of clinical findings, in addition to features not previously reported. One patient had congenital weakness and died in early childhood. In two other patients, severe cardiac problems arose early and, in one of these, cardiac signs preceded by many years the onset of skeletal muscle weakness. The fourth case had a mild and late-onset LGMD1B phenotype. Our cases further expand the clinical spectrum associated with mutations in the LMNA gene and provide new evidence of the role played by the C-terminal domain of lamin A.

Adult↗
PubMed2003

Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome.

4.1% of sudden cardiac deaths in the 16-64 age-group are unexplained. In this group, cardiac pathological findings are normal and toxicological tests are negative; termed sudden arrhythmic death syndrome (SADS). We searched for evidence of inherited cardiac disease in cases of SADS. Of 147 first-degree relatives of 32 people who died of SADS, 109 (74%) underwent cardiological assessment. Seven (22%) of the 32 families were diagnosed with inherited cardiac disease: four with long QT syndrome; one with non-structural cardiac electrophysiological disease; one with myotonic dystrophy; and one with hypertrophic cardiomyopathy. Families of people who die of SADS should be offered assessment in centres with experience of inherited cardiac disease.

Adolescent↗
PubMed2002

Effect of multisite pacing on ventricular coordination.

OBJECTIVE: To determine the effect of multisite pacing on left ventricular function. DESIGN: Prospective observational study. PATIENTS: 18 patients with heart failure with a dilated poorly functioning left ventricle (LV) and left bundle branch block. INTERVENTIONS: Pacing for 5 minutes in random order at the right ventricle (RV) apex, RV outflow tract, mid posterolateral LV, RV apex and LV simultaneously, and RV outflow tract and LV simultaneously. The best achieved measurements with RV, LV, and biventricular pacing were compared. MAIN OUTCOME MEASURES: LV dimension, filling characteristics, and long axis indices were measured on echocardiography simultaneously with LV pressure. Cycle efficiency (%)--that is, the ratio of the area of the acquired pressure dimension loop to that of the ideal loop for that segment--quantified coordination. RESULTS: The pacing site that gave the best achieved cycle efficiency differed between patients (biventricular in five, LV in two, RV in seven, and no site in four). In patients with baseline incoordination (cycle efficiency < or = 72%, n = 12) cycle efficiency improved significantly with RV pacing (cycle efficiency 76%, p = 0.01) but not with LV (65%) or biventricular (67%) pacing. LV based pacing induced premature short axis contraction in a subset of patients (n = 4), which was associated with a prolonged time from the Q wave on the ECG to the onset of inward movement of the long axis (from apex to mitral ring): biventricular 145 ms, LV 105 ms, RV 85 ms (biventricular v RV, p < 0.05). Excluding patients with baseline incoordination in whom premature activation occurred, pacing at all sites led to a similar increase in cycle efficiency (RV 78%, LV 72%, biventricular 73%). CONCLUSIONS: Ventricular coordination can be improved with pacing in patients with baseline incoordination. Short and long axis fibres may be asynchronised in a subset of patients with LV or biventricular pacing, which may worsen coordination. The clinical significance of these findings remains to be defined.

Aged↗
PubMed2001

Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.

OBJECTIVES: The purpose of this study was to examine the genotype-phenotype relation with respect to penetrance, age and severity of expression, disease progression and prognosis in a recessively inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. METHODS: Twelve families with Naxos disease underwent cardiac and molecular genetic investigation. Serial cardiac assessment with annual resting 12-lead and 24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardiography was performed during 1 to 16 years, median 7 +/- 6 years in all 78 surviving members. RESULTS: Twenty-eight surviving members were homozygous and 40 were heterozygous for the mutation. All adults who were homozygous (n = 26) fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. In eight who were heterozygous, minor ECG or echocardiographic abnormalities were observed. Of the 26 subjects who were affected homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right ventricular structural alterations and 27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmic events and 7 (27%) heart failure. The annual disease-related and sudden death mortality was 3% and 2.3%, respectively. CONCLUSIONS: Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by adolescence. Affected subjects who were homozygous experienced progressive disease with adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/echocardiographic changes, but clinically significant disease did not develop.

Abnormalities, Multiple↗
PubMed2001

Allometric analysis of the association between cardiac dimensions and body size variables in 464 junior athletes.

Empirically derived relationships between body size variables and cardiac dimensions have not been published previously for a large sample of male and female athletes. This process would inform scaling practice and facilitate intra- and inter-group comparisons of cardiac data. Therefore we investigated the relationships of body mass (BM), height and body surface area (BS) with a range of cardiac dimensions derived by echocardiography in 464 male and female elite junior athletes (age range 14-18 years; sporting allocation included rowers, cyclists, footballers, tennis players, swimmers and a miscellaneous group). Initial linearity checks suggested that most of the relationships between the body size variables and cardiac dimensions were non-linear, thus precluding the simple ratio standard approach to scaling. Multiple log-log least-squares linear regression confirmed commonality of slopes (between males and females, across the age range and between sporting groups) for all relationships involving BM and BS. Subsequent analyses of the slope exponent (b) for left ventricular dimensions supported previous data and were dimensionally consistent (LVM-BM, b=0.91+/-0.11; LVM-BS, b=1.44+/-0.19; where LVM is left ventricular mass), except for left ventricular internal dimension in diastole (LVIDd) (LVIDd-BM, b=0.25+/-0.04). Data for the left atria internal dimension (LA) were also dimensionally consistent (LA-BM, b=0.29+/-0.09); however, this was not the case for the right ventricular internal dimension in diastole (RVIDd) (RVIDd-BM, b=0.76+/-0.14). It is possible that these results were due to a study-specific limitation in the data range (LVIDd) and the geometric peculiarities of RVIDd compared with LVIDd. The gender/age/sporting groupxbody size interaction factor for virtually all relationships between height and cardiac dimensions was significant (P<0.05), and thus whole-group b exponents could not be generated. Generally these data support previous small-sample research with athletes, and suggest that allometric scaling, as opposed to simple ratio scaling, should be adopted in studies of cardiac dimensions in athletes. This should allow, with minimal mathematical difficulty, the production of body-size-independent cardiac indices to be evaluated in laboratory or clinical work. Further research is required to develop normative 'allometrically derived' cardiac indices, and care should be taken to determine relationships in specific population groups as well as to confirm commonality of slopes in multiple group comparisons. Caution is expressed regarding the use of height as a scaling variable in future research.

Adolescent↗
PubMed1999

Gender differences in survival in advanced heart failure. Insights from the FIRST study.

BACKGROUND: Previous natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure. METHODS AND RESULTS: The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18+/-4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing was negative (P=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09, P=0.127). CONCLUSIONS: Women with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure.

Aged↗
PubMed1999

Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. PIC study group. Pacing In Cardiomyopathy.

AIMS: Atrioventricular synchronous pacing exerts beneficial effects, including reduction of left ventricular outflow tract gradients, in patients with hypertrophic obstructive cardiomyopathy. The Pacing in Cardiomyopathy study was initiated to explore the effects of pacing in a double-blind randomized crossover fashion. The aims were to ascertain the beneficial effects of pacing in a controlled study and to rule out a placebo effect by pacing. This paper deals with the outcome of pacing on quality of life during 1 year of follow-up. METHODS: Quality of life was evaluated with the Karolinska questionnaire, validated for patients paced for bradyarrhythmias and ischaemic heart disease. Drug-refractory patients with hypertrophic obstructive cardiomyopathy were recruited for the study and after a temporary pacing procedure implanted with permanent pacemakers. Patients were randomized to two study arms defining the sequence of pacemaker programming. In one arm the pacemaker was inactive, in the other active. After 3 months the pacemaker was reprogrammed to the alternate mode and a further 3 months followed. After this period subsequent pacemaker programming corresponded to the mode preferred by the patient. A last assessment was made 1 year after baseline examinations. RESULTS: Eighty patients completed the first crossover period and 75 completed the full 1 year of follow-up. Active pacing induced significant quality of life improvements, in the order of 9-44%, regardless of programming sequence. Discontinuation of pacing after a first active period resulted in the return of symptoms. Fourteen patients requested early reprogramming after having been programmed to inactive pacing after a first period of active pacing. Seventy-six patients preferred active pacing after the crossover period. A further 6 months of pacing induced progressive improvement in symptoms already favourably influenced. CONCLUSION: Atrioventricular synchronous pacing has a profound beneficial effect on most domains of quality of life in patients with hypertrophic obstructive cardiomyopathy refractory to drug treatment.

Adult↗
PubMed1999

Clinical progress after randomized on/off pacemaker treatment for hypertrophic obstructive cardiomyopathy. Pacing in Cardiomyopathy (PIC) Study Group.

BACKGROUND: The therapeutic options for hypertrophic obstructive cardiomyopathy (HOCM) classically include medical treatment with beta-blockers and calcium antagonists or myectomy-myotomy as a surgical possibility for refractory cases. The observation that pacemaker activation of the heart in HOCM reduces the subaortic gradient is well known but less well investigated. METHODS: Eighty-three patients (33 female and 50 male) mean age 53 (18-82) years, with symptoms refractory to drug treatment and a resting gradient above 30 mmHg, who responded favourably to temporary pacing, were included in this prospective study and had a pacemaker (DDD) implanted. After an initial double-blind crossover phase of 6 months, patients were reinvestigated at 12 months and followed for a mean of 36 months. RESULTS: As observed during a screening investigation, the obstruction was significantly reduced from 72 +/- 35 mmHg to 29 +/- 24 mmHg (P < 0.01) when the pacemaker was on, while no major effect was seen during the sham phase. The effect was persistent at 1 year with a remaining resting gradient of 28 +/- 24 mmHg. In parallel, we documented an improvement in functional capacity, according to the NYHA classification and by quality of life analysis, and a significant improvement in dyspnoea and angina. Exercise on treadmill improved only in patients with reduced initial tolerance (< 8 min). During the mean follow-up of 36 months, 65 patients remained on pacing alone, with eight patients having additional AV-node ablation and five patients finally having surgery. CONCLUSION: This controlled multicentre study shows that pacemaker treatment is an option for HOCM patients; it is inoffensive and does not exclude alternative methods, but satisfies 79% of patients beyond 3 years.

Adolescent↗
PubMed1999

Scaling cardiac structural data by body dimensions: a review of theory, practice, and problems.

Robust estimates of the "true" bivariate relationship between body size (X) and heart size (Y) have seldom been determined empirically. The removal of the covariate influence of body size from cardiac dimension variables facilitates both correct inter- or intra-group comparisons, and the construction of reference standards for normality. In the literature to date this "scaling" or normalisation of cardiac dimensions has been performed typically via a per-ratio standards method, (Y/X), with body surface area chosen as the size denominator. This review demonstrates that the per-ratio standards approach may be theoretically, mathematically, and empirically flawed. The most appropriate scaling procedure appears to be a curvilinear, allometric model of the general form Y = aXb. The cardiac dimension variable (Y) may be regressed upon the body size variable (X) to derive a power function ratio (Y/Xb) that is allegedly size-independent. The current consensus is that an estimate of fat-free mass (FFM) provides the most appropriate body size variable. In the scaling literature allometric modelling procedures have generally yielded FFM exponents (b) consistent with the theory of geometric similarity. We suggest that cardiac dimension data should be scaled by appropriate powers of FFM, derived from allometric modelling. However, despite the potential superiority of FFM as a scaling denominator, reference standards for normality based on FFM have not been developed or proposed. Future research should examine the robustness of the FFM-cardiac dimension relationship in large samples.

Body Constitution↗
PubMed1998

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.

BACKGROUND: Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS: DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS: Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS: The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.

Adolescent↗
PubMed1997

Pacing in hypertrophic obstructive cardiomyopathy. A randomized crossover study. PIC Study Group.

BACKGROUND: Uncontrolled studies have shown that short atrioventricular delay dual chamber pacing reduces outflow tract obstruction in hypertrophic obstructive cardiomyopathy. Although the exact mechanism of this beneficial effect is unclear, this seems a promising potential new treatment for hypertrophic obstructive cardiomyopathy. METHOD: In order to evaluate the impact of pacing therapy, were performed a randomized multicentre double-blind cross-over (pacemaker activated vs non activated) study to investigate modification of echocardiography, exercise tolerance, angina, dyspnoea and quality of life in 83 patients with a mean age of 53 (range 22-87) years with symptoms refractory or intolerant to classical drug treatment. RESULTS: After 12 weeks of activated or inactivated pacing, independent of which phase was first, the pressure gradient fell from 59 +/- 36 mmHg to 30 +/- 25 mmHg (P < 0.001) with active pacing. Exercise tolerance improved by 21% in those patients who at baseline tolerated less than 10 min of Bruce protocol; symptoms of dyspnoea and angina also improved significantly from NYHA class 2.4 to 1.4 and 1.0 to 0.4, respectively (P < 0.007). Quality of life assessment with a validated questionnaire objectivated the subjective improvement. CONCLUSION: Pacemaker therapy is of clinical and haemodynamic benefit for patients with hypertrophic obstructive cardiomyopathy, left ventricular outflow gradient at rest over 30 mmHg who are symptomatic despite drug treatment.

Adult↗
PubMed1997

Reduction in heart rate variability in patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether heart rate variability and cardiovascular reflex tests are abnormal in patients with systemic lupus erythematosus (SLE). METHODS: We measured heart rate variability (24 h ambulatory recordings), and used baroreflex sensitivity testing and cardiovascular reflex tests in a cross sectional, case-control study. Those taking drugs with cardiovascular activity were excluded. RESULTS: Determination of heart rate variability was simple to perform, well tolerated, and found to be reduced in the patients with lupus, but not strongly related to disease activity or duration. CONCLUSION: This may reflect underlying autonomic dysfunction; longitudinal studies will determine full clinical relevance.

Adult↗
PubMed1994

Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.

We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2. These findings implicated components of the troponin complex as candidate genes at other FHC loci, particularly cardiac troponin T, which was mapped in this study to chromosome 1q. Missense mutations (Ile79Asn; Arg92Gln) and a mutation in the splice donor sequence of intron 15 of the cardiac troponin T gene are also shown to cause FHC. Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere. Further, because the splice site mutation is predicted to function as a null allele, we suggest that abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy.

Amino Acid Sequence↗
PubMed1993

A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2.

We report that a gene responsible for familial hypertrophic cardiomyopathy (FHC) in a kindred with a mild degree of cardiac hypertrophy maps to chromosome 15q2. The gene encoding cardiac actin, located on chromosome 15q, was analyzed and excluded as a candidate for FHC at this locus. Two additional families with typical FHC were studied and the disorder in one also maps to the chromosome 15q2 locus. The maximum combined multipoint logarithm of odds score in the two linked families is 6.02. Although these two kindreds reside in the same country, we believe that their disorder is caused by independent mutations in the 15q2 locus because of the clinical and genotypic differences between affected individuals. Mutations in at least four loci can cause FHC: chromosomes 14q1 (beta cardiac myosin heavy chain gene), 1q3, and 15q2 and another unidentified locus, suggesting substantial genetic heterogeneity.

Adolescent↗
PubMed1993

Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients.

OBJECTIVES: The purpose of this study was to determine the incidence of cardiologic abnormalities in Noonan syndrome. BACKGROUND: The incidence of cardiac abnormalities in Noonan syndrome remains unknown, largely because of such difficulties as assembling a substantial cohort, ensuring a correct phenotypic diagnosis and providing accurate definitions of the most frequent abnormalities--pulmonary stenosis and left ventricular hypertrophy. METHODS: A cohort of 145 patients was assembled, and before cardiologic assessment two independent geneticists scrutinized the phenotype. The diagnosis was confirmed in 118 patients, and they were studied by two-dimensional and Doppler echocardiography. RESULTS: A dysplastic pulmonary valve was present in eight patients (7%) and was associated with significant stenosis in six (75%) of the eight. Significant stenosis was present in 22 (20%) of 110 patients without dysplasia. Left ventricular hypertrophy was present in 29 patients (25%) without significant pulmonary stenosis. Localized anterior septal hypertrophy was the most common pattern in 12 (41%) of 29 patients. Diffuse hypertrophy involving the entire septum and the free wall was present in nine patients (31%) and was severe (> 1.7 cm) in five. Other abnormalities included secundum atrial septal defects (10%). CONCLUSIONS: The high incidence of cardiac abnormalities suggests that echocardiographic and Doppler evaluation of patients with the Noonan phenotype is important because it will aid in genetic counseling and in the assessment of the natural history of--and, ultimately, identification of the gene(s) responsible for--Noonan syndrome.

Adolescent↗