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Background Transcatheter aortic valve implantation (TAVI) has proven efficacy in the treatment of aortic stenosis (AS). Understandably, there is increasing enthusiasm for its use to treat aortic regurgitation (AR). However, there are significant anatomical differences between AS and AR which make TAVI for AR more complex. Case summary We present the case of technically challenging TAVI for severe AR, which was complicated by a traumatic ventricular septal defect (VSD) that required percutaneous closure. To our knowledge, this is the first published case of VSD post-TAVI for AR. Discussion This unanticipated complication highlights anatomical differences between TAVI use in AS and AR. Lack of aortic valve calcification and excessive annular compliance made stable deployment of a self-expanding valve extremely challenging. Despite device oversizing, repeated embolization of the prosthesis into the left ventricular outflow tract traumatized the interventricular septum.

Background Infective endocarditis (IE) is a potentially life-threatening infection of the heart’s endocardial surface. Despite advances in the diagnosis and management of IE, morbidity and mortality remain high. Aim To characterize the demographics, bacteriology and outcomes of IE cases presenting to an Irish tertiary referral centre. Design Retrospective cohort study. Methods Patients were identified using Hospital Inpatient Enquiry and Clinical Microbiology inpatient consult data, from January 2005 to January 2014. Patients were diagnosed with IE using Modified Duke Criteria. Standard Bayesian statistics were employed for analysis and cases were compared to contemporary international registries. Results Two hundred and two patients were diagnosed with IE during this period. Mean age 54 years. Of these, 136 (67%) were native valve endocarditis (NVE), 50 (25%) were prosthetic valve endocarditis (PVE) and 22 (11%) were cardiovascular implantable electronic device-associated endocarditis. Culprit organism was identified in 176 (87.1%) cases and Staphylococcal species were the most common (57.5%). Fifty-nine per cent of NVE required surgery compared to 66% of PVE. Mean mortality rate was 17.3%, with NVE being the lowest (12.5%) and PVE the highest (32%). Increasing age was also associated with increased mortality. Fifty-three (26.2%) patients had embolic complications. Conclusions This Irish cohort exhibited first-world demographic patterns comparable to those published in contemporary international literature. PVE required surgery more often and was associated with higher rates of mortality than NVE. Embolic complications were relatively common and represent important sequelae, especially in the intravenous drug user population. It is also pertinent to aggressively treat older cohorts as they were associated with increased mortality.

Background Spontaneous coronary artery dissection (SCAD) is a recognized cause of acute coronary syndrome (ACS). Pregnancy, the postpartum period, and illicit drug use have all been reported as potential triggers. Case summary We describe the case of a 41-year-old patient who presented to the emergency department with chest pain in the setting of recent cocaine and amphetamine use. The patient was 4 months postpartum following an uncomplicated pregnancy. Past medical history was non-contributory, with no known risk factors for ischaemic heart disease. Electrocardiogram was normal but high-sensitivity troponin T was significantly elevated. Coronary angiography revealed multi-vessel SCAD. This was managed conservatively as the patient remained clinically stable and pain free without high-risk anatomy (left main stem or proximal two-vessel coronary artery dissection). Discussion Spontaneous coronary artery dissection must be considered in a postpartum patient presenting with ACS, particularly in the context of environmental stressors such as illicit drug use. Coronary angiography is key to determine diagnosis and guide management. Conservative therapy is favoured, except for patients with ongoing ischaemia, haemodynamic instability, and left main stem involvement. In this case, we suspect SCAD occurred due to the haemodynamic effects of cocaine and amphetamines in the context of structural arterial changes of the postpartum state.

ObjectivesCT coronary angiography (CTCA) is a well-validated clinical tool in the evaluation of chest pain. In our institution, CTCA availability was increased in January 2020, and subsequently, expanded further to replace all exercise testing during the COVID-19 pandemic. Our objective was to assess the impact of increased utilisation of CTCA on length of stay in patients presenting with chest pain in the prepandemic era and during the COVID-19 pandemic.MethodsStudy design was retrospective. Patients referred for cardiology review between October 2019 and May 2020 with chest pain and/or dyspnoea were broken into three cohorts: a baseline cohort, a cohort with increased CTCA availability and a cohort with increased CTCA availability, but after the national lockdown due to COVID-19. Coronary angiography and revascularisation, length of stay and 30-day adverse outcomes were assessed.Results513 patients (35.3% female) presented over cohorts 1 (n=179), 2 (n=182), and 3 (n=153). CTCA use increased from 7.8% overall in cohort 1% to 20.4% in cohort 3. Overall length of stay for the patients undergoing CTCA decreased from a median of 4.2 days in cohort 1 to 2.5 days in cohort 3, with no increase in 30 days adverse outcomes. Invasive coronary angiogram rates were 45.8%, 39% and 34.2% across the cohorts. 29.6% underwent revascularisation in cohort 1, 15.9% in cohort 2 and to 16.4% in cohort 3.ConclusionsIncreased CTCA availability was associated with a significantly reduced length of stay both pre-COVID-19 and post-COVID-19 lockdown, without any increase in 30-day adverse outcomes.

BackgroundStudying variability in the care provided to secondary prevention coronary heart disease (CHD) outpatients can identify interventions to improve their outcomes.MethodsWe studied outpatients who had an index CHD event in the preceding 6–24 months. Eligible CHD events included acute coronary syndrome (ACS) and coronary revascularisation for stable chronic coronary syndrome (CCS). Site training was provided by a core team and data were collected using standardised methods.ResultsBetween 2017 and 2019, we enrolled 721 outpatients at nine Irish study sites; 81% were men and mean age was 63.9 (SD ±8.9) years. The study examination occurred a median of 1.16 years after the index CHD event, which was ACS in 399 participants (55%) and stable-CCS in 322. On examination, 42.5% had blood pressure (BP) >140/90 mm Hg, 63.7% had low-density lipoprotein cholesterol (LDL-C) >1.8 mmol/L and 44.1% of known diabetics had an HbA1c >7%. There was marked variability in risk factor control, both by study site and, in particular, by index presentation type. For example, 82% of outpatients with prior-ACS had attended cardiac rehabilitation versus 59% outpatients with prior-CCS (pConclusionsDespite international secondary prevention guidelines broadly recommending the same risk factor targets for all adults with CHD, we found marked differences in outpatient risk factor control and management on the basis of hospital location and index CHD presentation type (acute vs chronic). These findings highlight the need to reduce hospital-level and patient-level variability in preventive care to improve outcomes; a lesson that should inform CHD prevention programmes in Ireland and around the world.

Background: TAVI is a percutaneous approach to aortic valve replacement in high surgical risk patients deemed inoperable. Aim: To evaluate the early and mid-term outcomes for an Irish TAVI cohort over a six-year period at St James's Hospital and Blackrock Clinic, Dublin, Ireland. Results: In total 147 patients, 56% male with an average age of 82 underwent TAVI between December 2008 and December 2014. Thirty day, one year and two year survival was 90.5%, 83% and 71% respectively. Major vascular complications and renal failure were the biggest predictors of mortality at 30 days (p = 0.02). We observed a pacing rate of 13.5%, the majority in patients who had Medtronic Corevalve implants (p

Objectives Four variants (K60N, Q128R, G202R, and A592E) in the nebulette gene were identified in patients with dilated cardiomyopathy (DCM) and endocardial fibroelastosis. We sought to determine if these mutations are cardiomyopathy causing. Background Nebulette aligns thin filaments and connects them with the myocardial Z-disk, playing a role in mechanosensation. Methods We generated transgenic mice with cardiac-restricted overexpression of human wild-type or mutant nebulette. Chimera and transgenic mice were examined at 4, 6, and 12 months of age by echocardiography and cardiac magnetic resonance imaging. The hearts from embryos and adult mice were assessed by histopathologic, immunohistochemical, ultrastructural, and protein analyses. Rat H9C2 cardiomyoblasts with transient expression of nebulette underwent cyclic mechanical strain. Results We identified lethal cardiac structural abnormalities in mutant embryonic hearts (K60N and Q128R). Founders of the mutant mouse lines developed DCM with severe heart failure. An irregular localization pattern for nebulette and impaired desmin expression were noted in the proband and chimeric Q128R mice. Mutant G202R and A592E mice exhibited left ventricular dilation and impaired function with specific changes in I-band and Z-disk proteins by 6 months of age. The mutations modulated distribution of nebulette in the sarcomere and Z-disk during stretch of H9C2 cells. Conclusions Nebulette is a new susceptibility gene for endocardial fibroelastosis and DCM. Different mutations in nebulette trigger specific mechanisms, converging to a common pathological cascade leading to endocardial fibroelastosis and DCM.

BACKGROUND A standard 12-lead electrocardiogram (ECG) is performed in all hypertensive patients, primarily to detect left ventricular hypertrophy. Echocardiographic assessment of hypertensive subjects reveals that abnormalities in diastolic function occur more commonly and earlier than increased left ventricular mass. However, ECG changes associated with diastolic dysfunction (DD) remain poorly defined; we assessed the ventricular activation time (VAT) (i.e., the time for the ventricle to depolarize) as a potential marker for DD in early hypertension. METHODS Ninety subjects (aged 46 +/- 1.3 years; 43 men) with newly diagnosed, untreated hypertension underwent ECG and comprehensive two-dimensional echocardiography. Left ventricular DD was echocardiographically assessed using Canadian Consensus Guidelines. We compared VAT, which corresponds to the QR interval in the 12-lead ECG, with echocardiographic parameters of DD. RESULTS VAT was prolonged in subjects with DD (46.3 +/- 0.4 vs. 39.6 +/- 0.3 ms, P < 0.01). There was a significant correlation between VAT and tissue Doppler imaging (TDI) (early diastolic velocity) e' (r = -0.53, P < 0.0001), (ratio of early and late diastolic velocities) e'/a' (r = -0.53, P < 0.0001), transmitral Doppler (TMD) (early peak filling rate, and early deceleration peak) E/A (r = -0.32, P = 0.001), and (ratio of early diastolic mitral inflow and early diastolic velocities) E/e' (r = 0.44, P < 0.0001). CONCLUSION Prolongation of the VAT is associated with DD in patients with newly diagnosed untreated hypertension.

Background— In autoimmune disorders, circulating autoantibodies identify healthy relatives at risk years before clinical presentation. Healthy relatives of patients with dilated cardiomyopathy (DCM) who have echocardiographic changes, including left ventricular enlargement or depressed fractional shortening at baseline, have increased medium-term risk for DCM development. Approximately one third of relatives have serum anti-heart autoantibodies (AHAs) at baseline; we intended to assess their potential role in predicting DCM development. Methods and Results— Baseline evaluation, including electrocardiography, echocardiography, and AHA, was performed in 592 asymptomatic relatives of 169 consecutive DCM patients (291 males and 301 females; mean age 36±16 years). Relatives were classified in accordance with published echocardiographic criteria; those who did not have DCM were followed up (median of 58 months). DCM among relatives was diagnosed by echocardiography at follow-up. Of the 592 individuals evaluated, 77% were assessed as normal, 4.4% as having DCM, and 19% as possibly affected on the basis of depressed fractional shortening without ventricular dilatation in 17 and left ventricular enlargement without systolic dysfunction in 94. Five-year follow-up of 311 relatives revealed that 26 had progressed (13 to DCM, 11 to left ventricular enlargement, and 2 to depressed fractional shortening). Relatives who developed DCM were more frequently AHA-positive than those who did not (69% versus 37%, P =0.02). Five-year probability of progression to DCM, among normal or possibly affected relatives, was higher in AHA-positive cases ( P =0.03). By Cox regression, positive AHAs at baseline were independent predictors of progression (RR 2.26, CI 1 to 5.1, P =0.03). Conclusions— Among healthy relatives of DCM patients, AHAs are independent predictors of disease development within 5 years.

OBJECTIVES The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM). BACKGROUND Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease. METHODS Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM. RESULTS Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years. CONCLUSIONS The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.

Aims Non-compaction of the left ventricle (LVNC) is a disorder of endomyocardial morphogenesis that results in multiple trabeculations in the left ventricular myocardium. The current literature suggests that LVNC in adults is rare and associated with a poor prognosis. Given that the disorder is present at birth and that several studies have reported asymptomatic familial disease in some patients, we hypothesized that there is a long pre-clinical phase of the disease. The aim of this study was to define the prognosis and familial incidence of LVNC. Methods and results This study cohort comprised 45 patients (mean age at diagnosis 37 years) consecutively identified at a referral centre for cardiomyopathy over a 10-year period. Twenty-eight patients (62%) had dyspnoea at presentation; 41 (91%) an abnormal ECG; and 30 (66%) left ventricular dilatation and impaired systolic function. Nine patients (20%) had non-sustained ventricular tachycardia on 24 h Holter monitoring. Mean survival from death or transplantation was 97% at 46 months. There were three thromboembolic events in two patients (4%). On systematic family screening, 8 of 32 (25%) asymptomatic relatives had a range of echocardiographic abnormalities, including LVNC, LVNC with impaired systolic function, and left ventricular enlargement without LVNC. Conclusion This study demonstrates that LVNC is associated with a better prognosis than previously reported. In patients with familial disease, relatives may have features consistent with dilated cardiomyopathy rather than LVNC.

Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterised by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic mechanisms are a source of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.

Background In elite athletes left ventricular morphologic changes are predicted to alter passive pressure/volume characteristics by reducing myocardial stiffness and increasing compliance. Aim We investigated the utility of a new Doppler tissue index based on the pressure volume relation ((E/Ea)/LVEDD), which provides a measure of myocardial stiffness, and assessed its usefulness in detecting cardiac adaptation in elite rowers. Methods Thirty-six international rowers (mean age 27±7 years,) who had trained intensively for 15-20 hours per week for more than 5 years and a control group of 30 sedentary but otherwise normal subjects (mean age 26±8 years,) were consented and enrolled into the study. The groups were similar in age and gender. Left ventricular (LV) septal and posterior wall thickness, mass, chamber size, transmitral Doppler peak early (E) and late (A) diastolic filling velocities and isovolumic relaxation times were measured. Early diastolic myocardial velocities (Ea) were averaged from 4 sites at the mitral annulus; Diastolic stiffness was assessed with the use of three indices E, Ea, and the left ventricular end diastolic diameter in diastole (LVEDD). The ratio, [(E/Ea)/LVEDD], represents a pressure/volume relationship and provides a novel index of diastolic stiffness. Rowers were further divided into 2 groups based on the presence or absence of left ventricular hypertrophy (LVH), ≤ 12mm and > 12mm. Results There was no significant difference in Ea (4 site average) between the two groups, but there was a difference in the stiffness index, with rowers having significantly more compliant ventricles (p=0.0003). When compared with controls and adjusted for body surface area (BSA) and heart rate this difference remained statistically significant (p= 0.016). When the rowers were divided into 2 groups based on the presence or absence of LVH there was no difference in the stiffness index (p = 0.68) Conclusions The key distinguishing feature of intense training is a reduction of myocardial stiffness despite the development of left ventricular hypertrophy.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

BACKGROUND Diastolic dysfunction is common in early hypertension. We hypothesized that improvement in diastolic dysfunction is blood pressure (BP) dependent and may occur early with treatment in newly diagnosed untreated hypertensive patients. METHODS Forty untreated hypertensive subjects (age 52 +/- 1.4 years, mean +/- s.e.m.) with diastolic dysfunction based on Canadian Consensus Guidelines, received either bendroflumethiazide 2.5 mg (1.25 mg for the first month), or candesartan 16 mg (8 mg for the first month). Left ventricular (LV) structure and function, early diastolic velocity (E') and systolic velocity, and systolic myocardial velocity (Sm) were assessed echocardiographically using M-mode, 2-dimensional, and tissue Doppler imaging (TDI) before and at 1 and 3 months following treatment. RESULTS Antihypertensive treatment reduced BP significantly at 3 months (168 +/- 2/97 +/- 1-143 +/- 2/86 +/- 1 mm Hg, P < 0.0001). Both drugs had similar and significant effects on TDI E' which increased from 7.8 +/- 0.2 to 10 +/- 0.3 cm/s (P < 0.001). The improvement in TDI E' was independent of LV mass index (LVMI) regression but was significantly related to the improvement in Sm (r = 0.73, P < 0.0001) and the fall in systolic BP (R = 0.51, P < 0.001). Normalization of diastolic function was associated with better control of BP (130 +/- 4/81 +/- 2 mm Hg vs. 149 +/- 2/88 +/- 1 mm Hg, P < 0.05). In a stepwise regression model, reduction in systolic BP (P < 0.001) and TDI Sm (P < 0.0001) emerged as independent determinants of improvement in TDI E' with no contribution from age, gender or change in relative wall thickness (RWT) (R(2) = 0.68, P < 0.0001). CONCLUSIONS Achieving good BP control and enhancement in systolic function determines the improvement in diastolic function in early hypertension.

A 58-year-old female with a medical history of ≈2 years of chronic atrial fibrillation (on warfarin treatment), previous right mastectomy for invasive ductal carcinoma, and hypertension presented with a hypertensive emergency and mental status changes. Her symptoms resolved with appropriate antihypertensive treatment. The international normalized ratio on presentation was 2.9. During an additional work-up for transient neurological symptoms, transesophageal echocardiography was performed, revealing a 2×2-cm, well-circumscribed, spherical, mobile echodensity within the ostium of the left atrial appendage (LAA), …

Objective The primary role of the patient bedside observation chart is to make clinicians aware of the deteriorating patient. Despite this, its performance has not been scrutinised. Many versions exist with different styles of data entry but the optimal format remains elusive. This paper hypothesised that chart design measurably influences function and that redesign and standardisation would improve the detection of physiological decline by clinical staff. Design Objective evaluation of existing charts (n = 5), evidence based redesign, and re-evaluation of new chart. Setting 250 bed district general hospital. Results Design of existing observation charts had a significant effect on the ability of clinical staff to detect patient deterioration, with detection rates of parameters indicating physiological decline ranging from 0% to 100%. Graphical plots portrayed information better than written values for all parameters being measured except tachypnoea. No single existing chart was best for all variables. A new chart was designed, implemented with training in its use, and re-evaluated. The new chart also incorporated an early warning scoring system. There were significant improvements in the average detection rates of parameters poorly identified on existing charts: detection rates of tachypnoea and hypoxia increased by 41% (p Conclusion Evidence based redesign of the patient bedside observation chart coupled with specific training in its use significantly improves the detection of patient physiological deterioration.

Many cases of cardiomyopathy have a genetic component: 90% of cases of hypertrophic cardiomyopathy are familial, and genetic factors may be responsible for 30% to 50% of cases of dilated cardiomyopathy. Clinical genetic testing for hypertrophic cardiomyopathy is becoming available, with significant implications for the clinician. This article gives an overview of how these genetic discoveries were made and how these new insights from genetics will affect clinical practice.

To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM).1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS)or = 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported.26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p = 0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p = 0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p = 0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p = 0.001). Patients with SI had greater wall thinning (p = 0.001), left ventricular cavity enlargement (p0.0005), and deterioration in New York Heart Association functional class (p = 0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function.SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.

The aim of this study was to investigate the clinical expression of adenosine monophosphate-activated protein kinase (AMPK) gene mutations (PRKAG2) in adenosine monophosphate (AMP) kinase disease based on 12 years follow-up of known mutation carriers and to define the prevalence of PRKAG2 mutations in hypertrophic cardiomyopathy (HCM).Adenosine monophosphate-activated protein kinase gene mutations cause HCM with Wolff-Parkinson-White syndrome and conduction disease.Clinical evaluation of 44 patients with known AMP kinase disease was analyzed. Mutation analysis of PRKAG2 was performed by fluorescent single-strand confirmation polymorphism analysis and direct sequencing of abnormal conformers in 200 patients with HCM.Only one additional mutation was identified. The mean age at clinical diagnosis in the 45 gene carriers was 24 years (median 20 years, range 9 to 55 years). Symptoms of palpitation, dypspnea, chest pain, or syncope were present in 31 (69%) gene carriers; 7 (15%) complained of myalgia and had clinical evidence of proximal myopathy. Skeletal muscle biopsy showed excess mitochondria and ragged red fibers with minimal glycogen accumulation. Disease penetrance defined by typical electrocardiogram abnormalities was 100% by age 18 years. Thirty-two of 41 adults (78%) had left ventricular hypertrophy (LVH) on echocardiography, and progressive LVH was documented during follow-up. Survival was 91% at a mean follow-up of 12.2 years. Progressive conduction disease required pacemaker implantation in 17 of 45 (38%) at a mean age of 38 years.The AMP kinase disease is uncommon in HCM and is characterized by progressive conduction disease and cardiac hypertrophy and includes extracardiac manifestations such as a skeletal myopathy, consistent with a systemic metabolic storage disease. Defects in adenosine triphosphate utilization or in specific cellular substrates, rather than mere passive deposition of amylopectin, may account for these clinical features.

Numerous studies have shown that biventricular pacing (BVP) improves symptoms and exercise capacity in patients with congestive cardiac failure (CCF) and left bundle branch block (LBBB). The mechanism of symptomatic improvement has been attributed to changes in ventricular synchrony. However, the degree of asynchrony is not a good predictor of response.1,2 The aim of this study was to assess whether the presence of a restrictive mitral filling pattern, previously shown to be a marker for diastolic ventricular interaction (DVI) in patients with CCF,3 might identify a cohort of patients more likely to respond to BVP.

OBJECTIVES The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] greater than or equal to30 mm) and whether changes in cardiac morphology influence the course of the disease.BACKGROUND Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning.METHODS A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (greater than or equal to1 year) assessment.RESULTS Of the 106 patients, the majority (78 [71.6%]) were

Objectives: To determine whether pregnancy is well tolerated in hypertrophic cardiomyopathy. Setting: Referral clinic. Design: The study cohort comprised 127 consecutively referred women with hypertrophic cardiomyopathy. Forty (31.5%) underwent clinical evaluation before pregnancy. The remaining 87 (68.5%) were referred after their first pregnancy. All underwent history, examination, electrocardiography, and echocardiography. Pregnancy related symptoms and complications were determined by questionnaire and review of medical and obstetric records where available. Results: There were 271 pregnancies in total. Thirty six (28.3%) women reported cardiac symptoms in pregnancy. Over 90% of these women had been symptomatic before pregnancy. Symptoms deteriorated during pregnancy in fewer than 10%. Of the 36 women with symptoms during pregnancy, 30 had further pregnancies. Symptoms reoccurred in 18 (60%); symptomatic deterioration was not reported. Heart failure occurred postnatally in two women (1.6%). No complications were reported in 19 (15%) women who underwent general anaesthesia and in 22 (17.4%) women who received epidural anaesthesia, three of whom had a significant left ventricular outflow tract gradient at diagnosis after pregnancy. Three unexplained intrauterine deaths occurred in women taking cardiac medication throughout pregnancy. No echocardiographic or clinical feature was a useful indicator of pregnancy related complications. Conclusions: Most women with hypertrophic cardiomyopathy tolerate pregnancy well. However, rare complications can occur and therefore planned delivery and fetal monitoring are still required for some patients.

OBJECTIVES We evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy (DCM) with or without isolated non-compaction of the left ventricular myocardium (INLVM). BACKGROUND Dilated cardiomyopathy, characterized by left ventricular dilation and systolic dysfunction with signs of heart failure, is genetically transmitted in 30% to 40% of cases. Genetic heterogeneity has been identified with mutations in multiple cytoskeletal and sarcomeric genes causing the phenotype. In addition, INLVM with a hypertrophic dilated left ventricle, ventricular dysfunction, and deep trabeculations, is also inherited, and the genes identified to date differ from those causing DCM. Cypher/ZASP is a newly identified gene encoding a protein that is a component of the Z-line in both skeletal and cardiac muscle. METHODS Diagnosis of DCM was performed by echocardiogram, electrocardiogram, and physical examination. In addition, levels of the muscular isoform of creatine kinase were measured to evaluate for skeletal muscle involvement. Cypher/ZASP was screened by denaturing high performance liquid chromatography (DHPLC) and direct deoxyribonucleic acid sequencing. RESULTS We identified and screened 100 probands with left ventricular dysfunction. Five mutations in six probands (6% of cases) were identified in patients with familial or sporadic DCM or INLVM. In vitro studies showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP. CONCLUSIONS These data suggest that mutated Cypher/ZASP can cause DCM and INLVM and identify a mechanistic basis.

OBJECTIVE—To assess prospectively the prognostic value of soluble cellular adhesion molecules (CAMs) in patients with unstable angina and non-Q wave myocardial infarction and to compare their prognostic accuracy with that of C reactive protein (CRP). DESIGN AND SETTING—Prospective observational study of patients presenting acutely with unstable angina and non-Q wave myocardial infarction to a single south Dublin hospital. METHODS—Patients with Braunwald IIIA unstable angina and non-Q wave myocardial infarction had serum samples taken at presentation before initiation of antithrombotic treatment and were followed for six months. The primary end point was the occurrence of major adverse cardiovascular events (recurrent unstable angina, non-fatal myocardial infarction, and cardiovascular death) at six months. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin, and soluble platelet selectin were measured using an enzyme linked immunosorbent assay technique. CRP was measured with an immunophelometric assay. RESULTS—91 patients (73 men and 18 women, mean (SD) age 61 (11) years) were studied; 27 patients (30%) had major adverse cardiac events during the six months of follow up. Concentration of CRP were significantly raised in patients who had an ischaemic event (mean (SEM) 11.5 (6.4) mg/l v 5.4 (2.5) mg/l, p 3 mg/l and sVCAM-1 > 780 ng/ml for predicting future events was > 90%. There was no difference in concentrations of sICAM-1, soluble endothelin selectin, or soluble platelet selectin between event and non-event groups. CONCLUSION—Raised concentrations of sVCAM-1 and CRP are predictive of an increased risk of major adverse cardiovascular events six months after presentation with unstable angina and non-Q wave myocardial infarction. These findings suggest that the intensity of the vascular inflammatory process at the time of presentation is a determinant of clinical outcome in unstable coronary artery disease. Keywords: cell adhesion molecules; risk stratification; unstable angina

OBJECTIVES This study was designed to document the inflammatory response up to one year after acute presentation with unstable angina (UA) and non–Q wave infarction (NQMI) as reflected by the expression of soluble cell adhesion molecules (CAMs). BACKGROUND Coronary plaque inflammation is a key component in the pathogenesis of acute coronary syndromes. Cell adhesion molecules are critical mediators of the inflammatory process. Soluble forms of these molecules are detectable in serum and are elevated acutely in patients with UA and NQMI. METHODS Patients presenting with UA and NQMI had serum samples taken at presentation and then after three, six and 12 months. A control group of similar age and gender distribution was used for comparison. Levels of soluble inter-cellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial-selectin and platelet-selectin were measured using an ELISA technique. RESULTS We studied 91 patients (M/F = 73/18, mean age 62 ± 11 years, 56 UA and 35 NQMI) and 24 controls (M/F = 18/6, mean age 56 ± 12 years). Levels of all four soluble CAMs were significantly elevated in both UA and NQMI patients at presentation, three and six months in comparison with controls. Levels in UA and NQMI groups fell between six and 12 months after initial presentation. CONCLUSIONS The results suggest that the inflammatory stimulus triggering expression of CAMs is sustained for up to six months after presentation with either UA or NQMI and then returns toward control values over the following six months.

For over four decades, the scientific community has struggled to characterise and understand the nature of the disease, or group of diseases, known as hypertrophic cardiomyopathy (HCM). A cursory look at the change in nomenclature over time (“acquired subaortic stenosis, in-stent stenosis, hypertrophic obstructive cardiomyopathy”, etc) suggests a constant development in the understanding of the disorder, as each generation of researchers isolates a novel feature that contradicts previously held dogma. Clarification of the underlying genetic background and the prognostic implications of the disease have been advanced by intense study of referral centre populations, but features of the pathophysiology of HCM can still surprise us, and novel findings, based on meticulous clinical observation, are still to be made. Two recent papers substantially alter our understanding of an important characteristic of HCM—namely, the prevalence of left ventricular outflow tract obstruction (LVOTO), and raise further questions as to the prognostic importance of such obstruction. LVOTO was initially thought to be a fixed entity, defined by geometric abnormalities created by the asymmetric growth in the interventricular septum.1 Gradually, the refinement of two-dimensional echocardiography clarified the role of systolic anterior motion (SAM) of the mitral valve into the …

Background Functional and intrinsic mitral valve (MV) abnormalities are common in hypertrophic cardiomyopathy (HCM); however, morphologic characteristics constituting indications for surgical intervention are incompletely defined. This study was conducted to define the echocardiographic features of MV pathology in patients with HCM and relate these to repairability of the MV, MV procedures performed, durability of repair, and survival. Methods From 1986 to 2003, 851 patients with HCM underwent operation, and 115 had a concomitant MV procedure. Detailed analysis of their 784 transthoracic and transesophageal echocardiograms, performed intraoperatively and postoperatively, was conducted. Outcomes were assessed by cross-sectional follow-up. Results Sixty-seven patients (58%) underwent MV repair, and 48 (42%) had MV replacement. The mean left ventricular outflow tract peak gradient was 70 ± 50 mm Hg. Systolic anterior motion was present in 95%. Valve abnormalities were degenerative in 36 (31%), myxomatous in 23 (20%), papillary muscle in 23 (20%), restrictive chordal in 22 (19%), restrictive leaflet in 80 (70%), and long leaflet in 64 (56%). Patients undergoing MV repair had higher prevalence of long leaflets and degenerative MV pathology. The anterior mitral leaflet was 3.0 ± 0.49 cm in the repair group vs 2.5 ± 0.40 cm in the replacement group ( p = 0.0001). MV replacement patients were older, more symptomatic, and had more renal dysfunction and lower hematocrits. By 3 years, 91% of patients with a repair were free of reoperation. Conclusions Intrinsic MV pathology is frequently observed in HCM patients with symptomatic obstruction who undergo myectomy. Echocardiography can identify MV features predictive of successful valve repair. Repair, although durable, is feasible in only about half of patients.

OBJECTIVES: We performed genetic investigations of cardiac troponin T (TNNT2) and troponin C (TNNC1) in 235 consecutive patients with idiopathic dilated cardiomyopathy (DCM) to evaluate prevalence of mutations and associated disease expression in affected families. BACKGROUND: Recently, mutations in sarcomeric genes have been reported in DCM. However, the prevalence, penetrance, and clinical significance of sarcomere gene mutations in large consecutive cohorts of DCM patients are poorly defined. METHODS: Mutation detection was performed by fluorescent SSCP/DHPLC analysis and direct sequencing. The functional effects of mutations on interactions within the troponin complex were assessed by a two-hybrid luciferase assay. RESULTS: A total of 43% (102 of 235) of the study cohort had familial DCM. One TNNC1 and four TNNT2 (three novel) mutations were identified in one and four families, respectively. The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a penetrance of 100%. A total of 21 mutation carriers were identified; 6 underwent cardiac transplantation, 5 died of heart failure, and 4 died suddenly at a mean age of 29 years, while 6 remained stable on medication. Functional studies showed significant impairment of mutated troponin interaction compared with wild-type control, indicating an altered regulation of myocardial contractility. CONCLUSIONS: Cardiac troponin C was identified as a novel DCM gene. The disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance. The data suggest that mutation analysis of the troponin complex in DCM patients may prove valuable in early identification of individuals with an adverse prognosis and a high risk of premature death. This may lead to improved management and survival.

OBJECTIVES The aim of this study was to evaluate the potential utility of genetic diagnosis in clinical management of families with hypertrophic cardiomyopathy (HCM) caused by mutations in the gene for cardiac troponin I (TNNI3). BACKGROUND Knowledge about the clinical disease expression of sarcomeric gene mutations in HCM has predominantly been obtained by investigations of single individuals (probands) or selected families. To establish the role of genetic diagnosis in HCM families, systematic investigations of probands and their relatives are needed. METHODS Cardiac troponin I was investigated by direct sequencing and fluorescent (F)-SSCP analysis in 748 consecutive HCM families. Relatives of HCM probands with TNNI3 mutations were invited for cardiovascular and genetic assessment. RESULTS The prevalence of TNNI3 mutations was 3.1%. Mutations appeared to cluster in exons 7 and 8. A total of 100 mutation carriers were identified in 23 families with 13 different mutations (6 novel). Disease penetrance was 48%. Patients were diagnosed from the second to eighth decade of life. The morphologic spectrum observed represented a wide range of HCM. Two offspring of clinically unaffected mutation carriers were resuscitated from cardiac arrest, and an additional four individuals died suddenly as their initial presentation. Six individuals experienced other disease-related deaths. CONCLUSIONS The clinical expression of TNNI3 mutations was very heterogeneous and varied both within and between families with no apparent mutation- or gene-specific disease pattern. The data suggest that disease development may be monitored by regular assessment of cardiac symptoms and electrocardiographic abnormalities. Genetic diagnosis of TNNI3 is valuable in identifying clinically unaffected mutation carriers at risk of disease development and facilitates accurate management and counseling.

Dilated cardiomyopathy (DCM), a primary disorder of the cardiac muscle characterized by ventricular chamber dilation and diminished cardiac contractility (1), is the most common cause of chronic heart failure (CHF) in the young and the most common indication for cardiac transplantation (2). The underlying etiologies are varied and include genetic, viral (myocarditis), toxins like alcohol, mitochondrial, and metabolic disorders (3–6). Familial inheritance is seen in ≈30% to 40% of DCM patients (5). Autosomal dominant mode of inheritance is the most common (≈90%), followed by X-linked (5% to 10%), autosomal recessive, and mitochondrial inheritance patterns (