Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.

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.

Reduced right ventricular myocardial strain in the elite athlete may not be a consequence of myocardial damage. "Cream masquerades as skimmed milk".

BACKGROUND: Latest research shows that the lower resting values of right ventricular (RV) myocardial % strain may represent a physiologic change rather than subclinical myocardial damage. Therefore, we assessed load-independent changes to the RV as a consequence of high intensity training by measuring the Isovolumic acceleration (IVA) of the free wall of the RV in conjunction with NT pro-BNP measured by an electrochemiluminescence assay. METHODS: Seventeen controls (mean age 27 ± 4), 24 soccer footballers (mean age 24 ± 4), and 18 elite rowers (mean age 22 ± 4) were studied. Left ventricular (LV) and RV % strain were measured using two-dimensional (2D) speckle based automated functional imaging (AFI) software. RV free wall IVA was measured using pulsed-wave tissue Doppler at the lateral tricuspid annulus. Standard 2D echo were used to measured RV parameters including the Tei index (systolic and diastolic function) and the total annular plane systolic excursion (TAPSE) of the RV annulus. NT pro-BNP was measured by an electrochemiluminescence assay. RESULTS: The RV diameter was increased in the footballers and elite rowers compared with controls (P < 0.001). RV wall size was greater in the elite rowers compared with controls and footballers (P = 0.002). The peak IVA of the RV was higher in the rowers, compared with the footballers and to controls (P < 0.001). The mean LV and RV % myocardial strain were lower in the elite athletes and the footballers compared with controls (P < 0.001). There was no difference in RV Tei index, levels of BNP, and TAPSE across all subjects. CONCLUSIONS: This study showed a significant increase in IVA of the RV of athletes despite reduced myocardial % strain and normal levels in NT-proBNP. This suggests that the decrease in % strain is not a consequence of myocardial damage, but may represents a part of the physiological response to endurance exercise. Therefore, a reduced IVA in a remodeled RV could herald a pathological response.

Myocardial strain: a clinical review.

BACKGROUND: Myocardial strain-change in myocardial fibre length over the cardiac cycle-is a measure of cardiac muscle function. It is obtained using conventional techniques such as echocardiography and magnetic resonance imaging, adding additional clinical information to augment the current techniques. METHODS: A narrative review of the current relevant literature with respect to myocardial strain, with a focus on strain measured by echocardiography. RESULTS: Myocardial strain identifies global and regional abnormalities in myocardial function and differentiates types of cardiomyopathy. It is an earlier marker of myocardial disease than ejection fraction and is predictive of cardiovascular adverse events. Accurate measurement requires high-quality images and experienced practitioners. CONCLUSION: This review explains advantages and disadvantages of myocardial strain imaging and explains why, through adding increased precision without additional burden, it should be a standard part of cardiac assessment.

Long-term Outcomes for Drug-eluting Balloons versus Drug-eluting Stents in the Treatment of Small Vessel Coronary Artery Disease: A Systematic Review and Meta-analysis.

Background: This systematic review and meta-analysis compares long-term outcomes follow-up data comparing drug-eluting balloons (DEBs) and drug-eluting stents (DESs) in interventional treatment of small coronary artery disease (<3 mm). Methods: A systematic review was undertaken along with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was 1-3-year performance of DEB versus DES in major adverse cardiac events. Secondary outcomes include all-cause mortality, MI, cardiac death, vessel thrombosis, major bleeding, target vessel revascularisation and target lesion revascularisation. Two independent reviewers extracted data. All outcomes used the Mantel-Haenszel and random effects models. ORs are presented with a 95% CI. Results: Of 4,661 articles, four randomised control trials were included (1,414 patients). DEBs demonstrated reduced rates of non-fatal MI at 1 year (OR 0.44; 95% CI [0.2-0.94]), and BASKET-SMALL 2 reported a significant reduction in 2-year bleeding rates (OR 0.3; 95% CI [0.1-0.91]). There was no significant difference in all other outcomes. Conclusion: Long-term follow-up of DEB and DES use in small coronary arteries demonstrates DEBs be comparable with DESs in all outcomes at 1, 2 and 3 years of follow-up. A significant reduction was found in rates of non-fatal MI at 1 year in the DEB arm, and a reduction in major bleeding episodes at 2 years in the BASKET-SMALL 2 trial. These data highlight the potential long-term utility of novel DEBs in small coronary artery disease revascularisation.

Predictive value of high-sensitivity troponin for significant coronary artery disease in new-onset atrial fibrillation with rapid ventricular response.

BACKGROUND: High-sensitivity troponin-T (HS-cTnT) levels are often measured in patients presenting with atrial fibrillation (AF), with many subjected to unnecessary invasive assessments. The significance of a normal or mildly raised HS-cTnT in this context is poorly understood. This study aimed to determine the predictive value of HS-cTnT for significant coronary artery disease (CAD) in new AF with rapid ventricular response. We also compared the discriminative ability of HS-cTnT to suspected angina for significant CAD. METHODS: We examined patients presenting with new AF to two tertiary Irish centers in a defined period. Those included had HS-cTnT taken at presentation and subsequent ischemic evaluation. RESULTS: Of 5350 cases screened for inclusion, 281 were deemed eligible. Of these, 148 and 133 patients had a positive and negative index HS-cTnT, respectively. Of those with negative HS-cTnT, 13 (9.8%) had significant CAD versus 51 (34.5%) with positive HS-cTnT (P < 0.001). Positive Hs-cTnT status remained significant upon multivariate analysis (OR, 2.9; 95% CI, 1.37-6.14; P = 0.005). A similar model where HS-cTnT was replaced with suspected angina produced an OR of 1.64 (95% CI, 0.75-3.59; P = 0.213). A logistic model determined optimal cutoff value for HS-cTnT to be less than 30 ng/l, producing a negative predictive value of 91.8% and area under the receiver operative curve of 83.36. CONCLUSION: HS-cTnT exhibits potential as an effective screening biomarker to predict nonsignificant CAD in new rapid AF, allowing more targeted and rationalized ischemic testing. HS-cTnT may also be a more accurate predictor of significant CAD than clinically suspected stable angina.Graphical abstract: http://links.lww.com/MCA/A540.

The use of deformation imaging in the assessment of patients pre and post transcatheter aortic valve implantation.

BACKGROUND: Deformation imaging represents a method of measuring myocardial function, including global longitudinal strain (GLS), peak atrial longitudinal strain (PALS) and radial strain. This study aimed to assess subclinical improvements in left ventricular function in patients undergoing transcatheter aortic valve implantation (TAVI) by comparing GLS, PALS and radial strain pre and post procedure. METHODS: We conducted a single site prospective observational study of 25 patients undergoing TAVI, comparing baseline and post-TAVI echocardiograms. Individual participants were assessed for differences in GLS, PALS and radial strain in addition to changes in left ventricular ejection fraction (LVEF) (%). RESULTS: Our results revealed a significant improvement in GLS (mean change pre-post of 2.14% [95% CI 1.08, 3.20] p = 0.0003) with no significant change in LVEF (0.96% [95% CI - 2.30, 4.22], p = 0.55). There was a statistically significant improvement in radial strain pre and post TAVI (mean 9.68% [95% CI 3.10, 16.25] p = 0.0058). There was positive trend towards improvements in PALS pre and post TAVI (mean change of 2.30% [95% CI - 0.19, 4.80] p = 0.068). CONCLUSION: In patients undergoing TAVI, measuring GLS and radial strain provided statistically significant information regarding subclinical improvements in LV function, which may have prognostic implications. The incorporation of deformation imaging in addition to standard echocardiographic measurements may have an important role in guiding future management in patients undergoing TAVI and assessing response.

Cardiac Magnetic Resonance at 3.0 T in Patients With C282Y Homozygous Hereditary Hemochromatosis: Superiority of Radial and Circumferential Strain Over Cardiac T2* Measurements at Baseline and at Post Venesection Follow-up.

BACKGROUND: Iron-overload cardiomyopathy initially manifests with diastolic dysfunction and can progress to dilated cardiomyopathy if untreated. Previous studies have shown that patients with primary and secondary hemochromatosis can have subclinical left ventricle dysfunction with abnormalities on strain imaging. This study aimed to evaluate the relationship between cardiac T2* values and myocardial-wall strain in patients with hereditary hemochromatosis (HH) at the time of diagnosis and after a course of venesection treatment. MATERIALS AND METHODS: Baseline cardiac magnetic resonance (CMR) at 3 T was performed in 19 patients with newly diagnosed HH with elevated serum ferritin levels and repeated after a course of treatment with venesection. Quantitative T2* mapping and strain analysis were performed offline using dedicated relaxometry fitting and feature-tracking software. RESULTS: The majority (84%) of patients had normal baseline myocardial T2* values (mean 19.3 ms, range 8.9 to 31.2 ms), which improved significantly after venesection (mean 24.1 ms, range 11 to 38.1 ms) ( P =0.021). Mean global radial strain significantly improved from 25.0 (range: 15.6 to 32.9) to 28.3 (range: 19.8 to 35.8) ( P =0.001) and mean global circumferential strain improved, decreasing from -15.7 (range: -11.1 to -19.2) to -17.1 (range: -13.0 to -20.1) ( P =0.001). CONCLUSION: Patients with HH may have normal T2* values in the presence of subclinical left ventricle dysfunction, which can be detected by abnormal radial and circumferential strain. As strain imaging improves following venesection in HH, it may serve as a useful biomarker to guide treatment.

Two-stage percutaneous closure of mitral periprosthetic valvular leak.

Periprosthetic valve leak can develop as a complication of valve replacement surgery and may manifest as symptomatic valvular regurgitation, heart failure, or haemolysis. We report a case of severe mitral periprosthetic valve leak requiring a two-stage percutaneous closure technique with multiple Amplatzer® III vascular plugs.

A case report of ventricular septal defect complicating transcatheter aortic valve implant for aortic regurgitation: novel complication and technical considerations.

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.

CT coronary angiography and COVID-19: inpatient use in acute chest pain service.

OBJECTIVES: CT 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. METHODS: Study 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. RESULTS: 513 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. CONCLUSIONS: Increased 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.

Interhospital and interindividual variability in secondary prevention: a comparison of outpatients with a history of chronic coronary syndrome versus outpatients with a history of acute coronary syndrome (the iASPIRE Study).

BACKGROUND: Studying variability in the care provided to secondary prevention coronary heart disease (CHD) outpatients can identify interventions to improve their outcomes. METHODS: We 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. RESULTS: Between 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 (p<0.001) and there were also large differences in control of traditional risk factors like LDL-C (p=0.002) and systolic BP (p<0.001) among outpatients with prior-ACS versus prior-CCS as the index presentation. CONCLUSIONS: Despite 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.

Current status of vulnerable plaque detection.

Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high-risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high-risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high-risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow-limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high-risk but non flow-limiting plaque to establish patient-specific targeted therapy and to refine plaque stabilizing strategies in the future.

Improvements in cardiac function detected using echocardiography in patients with hereditary haemochromatosis.

BACKGROUND: Hereditary haemochromatosis is often not diagnosed until adulthood. Iron overload cardiomyopathy initially results in diastolic dysfunction and can result in arrhythmias and irreversible cardiac failure if untreated. The aim of this study was to investigate whether patients with newly diagnosed hereditary haemochromatosis without signs of heart failure exhibit subclinical alterations of cardiac function and to determine if cardiac function improved after 1 year of venesection. METHODS: Baseline echocardiography was performed on 25 patients with newly diagnosed hereditary haemochromatosis with elevated serum ferritin levels. The test was repeated after 1 year of treatment with venesection. Tissue Doppler imaging (TDI) and deformation (strain) imaging using speckle tracking were performed. Left atrial force was measured according to the Newtonian principle, in which force (dynes) = mass × acceleration. Left atrial force was calculated by the Manning method expressed as ρ × 0.53 × mitral annular orifice area × (peak A velocity)2. RESULTS: Radial strain showed a significant improvement after 1 year of venesection (increase from 38.8 to 52.6). The LAF showed a significant decrease after 1 year of venesection (median decrease = 0.6 (IQR 0, 1.60), p = 0.0004). Iso-volumetric relaxation time (IVRT) decreased significantly in patients after 1 year of venesection (decrease from 107.4 ± 16.2 to 97.68 ± 15.4 ms, p (0.0187)). CONCLUSION: Among all measurements, radial strain, IVRT and left atrial force were shown to significantly improve following a 1-year course of venesection, suggesting that these parameters could be used to identify subclinical cardiac dysfunction in patients with iron overload secondary to hereditary haemochromatosis and to guide intensification of venesection therapy.

Prospective familial assessment in dilated cardiomyopathy: cardiac autoantibodies predict disease development in asymptomatic relatives.

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.

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy.

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.

Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history.

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.

Tissue synchronization imaging and optimal left ventricular pacing site in cardiac resynchronization therapy.

The optimal pacing site in cardiac resynchronization therapy (CRT) remains controversial. Tissue synchronization imaging is a novel echocardiographic technique that color-codes for areas of maximal delay in myocardial velocities. This study aimed to identify whether the left ventricular (LV) pacing lead position in CRT should be guided by a patient's area of maximal mechanical delay. Fifty-four patients with advanced heart failure were assessed echocardiographically before and 6 months after CRT. Response was analyzed according to the relation between the LV lead position and the area of maximal delay to peak velocity by tissue synchronization imaging in the first half of the ejection phase: group 1 (n = 22) had lead placement corresponding to the segment of maximal delay; group 2 (n = 13) had lead placement 1 segment adjacent; and group 3 (n = 19) had lead placement remote from this site. Evidence of LV reverse remodeling and improved systolic function was documented in group 1 (mean percentage decrease in end-systolic volume 23%) more than in group 2 (mean decrease 15%), and more than in group 3 (mean increase 8.9%, p <0.0001 compared with groups 1 and 2). In group 1, 16 of 22 patients had reverse remodeling (>15% decrease in end-systolic volume); reverse remodeling was seen in 7 of 13 patients in group 2 and 1 of 19 in group 3. The placing of the lead position proximal to the site of maximal delay by tissue synchronization imaging was correlated with reverse remodeling (r = 0.449, p = 001). Of 7 patients with delay confined to the septum and anterior wall only, none had evidence of reverse remodeling after CRT. In conclusion, pacing at the site of maximal mechanical delay was associated with reverse remodeling. Individually tailored LV lead positioning should be considered before CRT.

Use of tissue Doppler imaging to guide tube current modulation in cardiac multidetector computed tomographic angiography.

In multidetector computed tomographic coronary angiography, strategies to minimize effective radiation dose (ERD) are urgently needed. Prospective tube current modulation (TCM) allows a decrease in ERD, although it may limit reconstruction options. We sought to determine if tissue Doppler imaging (TDI) by echocardiography could predict an optimal phase for multidetector computed tomography and be used to guide TCM. Echocardiographic studies were performed in 94 patients immediately before multidetector computed tomography (83% men; mean 60 +/- 11 years of age, mean body mass index 27.7+/-4.1 kg/m2) and identified the most quiescent phase of the cardiac cycle within the atrioventricular groove. In 40 patients, prospective TCM was programmed according to TDI (TCM(TDI) group); 54 patients underwent multidetector computed tomography without TCM (no-TCM). In 25 patients assigned to the TCM(TDI) group, multidetector computed tomograms were correlated with invasive quantitative coronary angiograms to ensure maintenance of diagnostic accuracy. Optimal phase determined by TDI was 71 +/- 11%, with a distinct bi-modal distribution. Compared with no-TCM, effective radiation dose was decreased by 42% in the TCM(TDI) group (6.6 +/- 1.2 vs 11.4 +/- 2.2 mSv, p < 0.0001). Only 8 segments (3%) were unevaluable due to motion artifact. In 296 segments, sensitivity, specificity, and positive and negative predictive values to detect lesions > 50% by multidetector computed tomography were 92%, 94%, 65%, and 99%, respectively. There was good correlation between quantitative coronary angiography and multidetector computed tomography for absolute degree of stenosis (r = 0.70, p < 0.0001). In conclusion, TDI is a useful tool to guide prospective TCM in multidetector computed tomography. ERD in multidetector computed tomography may be significantly decreased using this technique while maintaining excellent image quality.

Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease.

BACKGROUND: Idiopathic dilated cardiomyopathy is often familial, and apparently healthy relatives may have latent, early, or undiagnosed established disease. OBJECTIVE: To determine the prevalence and natural history of asymptomatic cardiac abnormalities among sampled relatives of unselected patients referred for management of dilated cardio-myopathy. DESIGN: Prospective cohort study. PATIENTS: 767 asymptomatic relatives of 189 consecutive unselected patients with dilated cardiomyopathy. MEASUREMENTS: Clinical evaluation, including history, physical examination, electrocardiography, and echocardiography, was performed. Participants were classified in accordance with published echocardiographic criteria. Sampled relatives who did not have evidence of dilated cardiomyopathy at the initial evaluation were followed for a median of 57 months (range, 1 to 133 months). RESULTS: Of the 767 patients evaluated, 592 (77.2%) were assessed as healthy, 35 (4.6% [95% CI, 3.7% to 7.6%]) had dilated cardiomyopathy, 119 (15.5% [CI, 12.5% to 18.8%]) had left ventricular enlargement without systolic dysfunction, and 21 (2.7% [CI, 1.9% to 4.9%]) had depressed fractional shortening without ventricular dilatation. At follow-up, progression to dilated cardiomyopathy occurred in 13 (10%) relatives with left ventricular enlargement or depressed fractional shortening versus 3 (1.3%) healthy relatives. In a multivariate model, only left ventricular enlargement or depressed fractional shortening independently predicted progression to dilated cardiomyopathy (hazard ratio, 10.0 [CI, 2.8 to 35.5]; P < 0.001). LIMITATIONS: Because relatives had to be willing to participate and be available geographically, selection bias may have occurred. CONCLUSION: Treatable asymptomatic dilated cardiomyopathy was identified in 4.6% of asymptomatic relatives. In addition, left ventricular enlargement and depressed fractional shortening were common in asymptomatic relatives of patients with dilated cardiomyopathy and were associated with a statistically significant medium-term risk for disease progression. Evaluation of relatives of patients with cardiomyopathy is recommended.

Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.