Search PubMed⌕ Search

Biomedical subjects

Tomas G Neilan

Publications and source records attributed to Tomas G Neilan.

At least 19 recordsLinked to original sources
PubMed2025

Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.

IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n&#x2009;=&#x2009;42&#x202f;137, 2008-2025), with replication in the UK Biobank (n&#x2009;=&#x2009;295&#x202f;160, 2005-2010), FinnGen (n&#x2009;=&#x2009;417&#x202f;950, 2017-2025), and the Veterans Affairs Million Veteran Program (n&#x2009;=&#x2009;516&#x202f;066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24&#x202f;551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P&#x2009;<&#x2009;.001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.

Humans↗
PubMed2006

Cardiomyocyte-specific overexpression of nitric oxide synthase 3 prevents myocardial dysfunction in murine models of septic shock.

Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca(2+) transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+) in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N(G)-nitro-l-arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+), thereby reducing myocardial dysfunction and mortality in murine models of septic shock.

Actin Cytoskeleton↗
PubMed2006

Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon.

BACKGROUND: Multiple studies have individually documented cardiac dysfunction and biochemical evidence of cardiac injury after endurance sports; however, convincing associations between the two are lacking. We aimed to determine the associations between the observed transient cardiac dysfunction and biochemical evidence of cardiac injury in amateur participants in endurance sports and to elicit the risk factors for the observed injury and dysfunction. METHODS AND RESULTS: We screened 60 nonelite participants, before and after the 2004 and 2005 Boston Marathons, with echocardiography and serum biomarkers. Echocardiography included conventional measures as well as tissue Doppler-derived strain and strain rate imaging. Biomarkers included cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP). All subjects completed the race. Echocardiographic abnormalities after the race included altered diastolic filling, increased pulmonary pressures and right ventricular dimensions, and decreased right ventricular systolic function. At baseline, all had unmeasurable troponin. After the race, > 60% of participants had increased cTnT > 99th percentile of normal (> 0.01 ng/mL), whereas 40% had a cTnT level at or above the decision limit for acute myocardial necrosis (> or = 0.03 ng/mL). After the race, NT-proBNP concentrations increased from 63 (interquartile range [IQR] 21 to 81) pg/mL to 131 (IQR 82 to 193) pg/mL (P<0.001). The increase in biomarkers correlated with post-race diastolic dysfunction, increased pulmonary pressures, and right ventricular dysfunction (right ventricular mid strain, r=-0.70, P<0.001) and inversely with training mileage (r=-0.71, P<0.001). Compared with athletes training > 45 miles/wk, athletes who trained < or = 35 miles/wk demonstrated increased pulmonary pressures, right ventricular dysfunction (mid strain 16+/-5% versus 25+/-4%, P<0.001), myocyte injury (cTnT 0.09 versus < 0.01 ng/mL, P<0.001), and stress (NT-proBNP 182 versus 106 pg/mL, P<0.001). CONCLUSIONS: Completion of a marathon is associated with correlative biochemical and echocardiographic evidence of cardiac dysfunction and injury, and this risk is increased in those participants with less training.

Athletic Injuries↗
PubMed2006

The impact of spontaneous echocardiographic contrast in patients with left atrial enlargement undergoing cardiac valvular surgery.

OBJECTIVE: The aim of this study was to evaluate the impact of either left atrial or aortic spontaneous echocardiographic contrast (SEC), as identified on intraoperative transesophageal echocardiography, on short-term morbidity and mortality in patients with left atrial enlargement undergoing cardiac valvular surgery. DESIGN: Retrospective and observational. SETTING: Single-center, university teaching hospital. PARTICIPANTS: The authors identified 197 patients (105 males and 92 females; mean age, 68 +/- 14 years) with left atrial enlargement who underwent surgical intervention for valvular heart disease from January 1, 2004 to January 1, 2005. MAIN RESULTS: Of the total population, 40 patients (20.3%) showed left atrial SEC, and 10 patients (5.1%) showed aortic SEC. On multivariate analysis, increasing left atrial size and the absence of mitral regurgitation were independent predictors for the presence of left atrial SEC. On multivariate analysis, the presence of atrial fibrillation and a dilated descending aorta were predictive of aortic SEC. Although the identification of left atrial SEC was an echocardiographic marker of an increased risk for thromboembolic events postoperatively, this finding did not hold true for the presence of aortic SEC. CONCLUSIONS: Intraoperative identification of left atrial dilatation or aortic dilatation is predictive of SEC in the left atrium or descending aorta, respectively. The identification of left atrial SEC is an echocardiographic marker of an increased risk for thromboembolic events in this high-risk population.

Academic Medical Centers↗
PubMed2006

Sustained improvement in left ventricular diastolic function after alcohol septal ablation for hypertrophic obstructive cardiomyopathy.

AIMS: Impaired diastolic function is responsible for many of the clinical features of hypertrophic cardiomyopathy. In patients with hypertrophic obstructive cardiomyopathy (HOCM) whose symptoms are refractory to medical therapy, alcohol septal ablation (ASA) reduces left ventricular (LV) outflow tract gradient, with short-term improvement in LV diastolic function. Little is known about the longer term impact of ASA on diastolic function. METHODS AND RESULTS: We evaluated LV diastolic function at baseline and 1- and 2-year follow-up after successful ASA. In 30 patients (58+/-15 years, 22 men) who underwent successful ASA, New York Heart Association class was lower at 1-year follow-up compared with baseline (3.0+/-0.5 to 1.5+/-0.7; P<0.0001). LV outflow tract gradient (76+/-37 to 19+/-12; P<0.0001), interventricular septal thickness (19+/-2 to 14+/-2; P<0.0001), and left atrial volume (26+/-5 to 20+/-4; P<0.0001) were decreased. Significant improvement in E-wave deceleration time, isovolumic relaxation time, early diastolic mitral lateral annular velocity (E'), mitral inflow propagation velocity (V(p)), ratio of transmitral early LV filling velocity (E) to early diastolic Doppler tissue imaging of the mitral annulus (E/E'), and E/V(p) were observed at 1 year following successful ASA. These changes persisted in the subset cohort (n=21) for whom 2-year data were available. CONCLUSION: Successful ASA for HOCM leads to significant and sustained improvement in echocardiographic measures of diastolic function, which may contribute to improved functional status after successful ASA.

Adult↗
PubMed2006

Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury.

AIMS: Currently available non-invasive imaging methods frequently fail to detect alterations in left ventricular (LV) function despite histological evidence of injury. Tissue Doppler imaging (TDI) can detect subtle LV dysfunction. The aim of this study was to investigate whether TDI indices can predict LV systolic dysfunction and mortality following exposure to doxorubicin (DOX) in mice. METHODS AND RESULTS: TDI-derived peak endocardial systolic velocity (V(ENDO)) and strain rate (SR), as well as M-mode and two-dimensional indices of LV systolic function, were measured serially in mice after receiving DOX as a single dose (20 mg/kg). Haemodynamic measurements were obtained invasively before and at 1, 2, 4, and 5 days after the single DOX dose. Cardiac apoptosis was measured before and at 1 day after DOX. V(ENDO) and SR decreased after 1 and 2 days, respectively, whereas changes in fractional shortening (FS) and LV ejection fraction (LVEF) were not detected before 5 days. The reduction in both V(ENDO) and SR correlated with the decrease in dP/dt(MAX), and the change in V(ENDO) correlated with the early increase in cardiac cell apoptosis. In a subsequent experiment, DOX was administered at 4 mg/kg/week for 5 weeks, and LV function was followed serially for 16 weeks. In this chronic experiment, TDI indices decreased before FS and LVEF, correlated with late LV dysfunction, and predicted DOX-induced mortality. CONCLUSION: In a murine model of DOX-induced cardiac injury, TDI detects LV dysfunction prior to alterations in conventional echocardiographic indices and predicts mortality. This study suggests that TDI may be a reliable tool to detect early subtle changes in DOX-induced cardiac dysfunction.

Animals↗
PubMed2006

Mitral valve ring dehiscence with an aorta-left atrial fistula.

In an era with the increasing use of various imaging modalities including echocardiography, ventriculography and cardiac magnetic resonance (CMR) imaging, one must be aware of the limitations of each discipline. We report a case of an individual who presented with both a partial dehiscence of a mitral valve annuloplasty ring and an aorta-left atrium fistula following surgical management of infective endocarditis that was correctly identified using transesophageal echocardiographic imaging.

Aorta↗
PubMed2006

Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression.

AIMS: The use of doxorubicin (DOX) as a chemotherapeutic agent is limited by cardiac injury. Iloprost, a stable synthetic analogue of prostacyclin, has previously been shown to protect against DOX-induced cardiomyocyte injury in vitro. Here, we addressed whether iloprost is cardioprotective in vivo and whether it compromises the anti-tumour efficacy of DOX. METHODS AND RESULTS: Lewis Lung Carcinoma cells were implanted subcutaneously in the flank of C57BL/6 mice. DOX treatment was commenced from when tumours became visible. Iloprost was administered from prior to DOX treatment until sacrifice. Echocardiography and invasive haemodynamic measurements were performed immediately before sacrifice. As expected, DOX induced cardiac cell apoptosis and cardiac dysfunction, both of which were attenuated by iloprost. Also, iloprost alone had no effect on tumor growth and indeed, did not alter the DOX-induced suppression of this growth. CONCLUSION: In a murine model, iloprost attenuated the acute cardiac injury and dysfunction induced by DOX therapy without compromising its chemotherapeutic effect.

Animals↗
PubMed2006

Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin.

To determine the role of cyclooxygenase (COX)-2 in anthracycline-induced cardiac toxicity, we administered doxorubicin (Dox) to mice with genetic disruption of COX-2 (COX-2-/-). After treatment with Dox, COX-2-/- mice had increased cardiac dysfunction and cardiac cell apoptosis compared with Dox-treated wild-type mice. The expression of the death-associated protein kinase-related apoptosis-inducing protein kinase-2 was also increased in Dox-treated COX-2-/- animals. The altered gene expression, cardiac injury, and dysfunction after Dox treatment in COX-2-/- mice was attenuated by a stable prostacyclin analog, iloprost. Wild-type mice treated with Dox developed cardiac fibrosis that was absent in COX-2-/- mice and unaffected by iloprost. These results suggest that genetic disruption of COX-2 increases the cardiac dysfunction after treatment with Dox by an increase in cardiac cell apoptosis. This Dox-induced cardiotoxicity in COX-2-/- mice was attenuated by a prostacyclin analog, suggesting a protective role for prostaglandins in this setting.

Animals↗
PubMed2006

Persistent and reversible cardiac dysfunction among amateur marathon runners.

AIMS: Transient systolic and diastolic abnormalities in ventricular function have previously been documented during endurance sports. However, these described alterations may be limited by the techniques applied. We sought, using less load-dependent methods, to characterize both the extent and the chronology of the cardiac changes associated with endurance events. METHODS AND RESULTS: Transthoracic echocardiography (TTE) was performed prior to, immediately after, and approximately 1 month after completion of the 2003 Boston Marathon in 20 amateur athletes. TTE included two-dimensional, spectral and tissue Doppler (TD) and flow propagation velocity (V(p)). After completion of the marathon, global measures of left ventricular (LV) systolic function were unchanged (EF 59 +/- 6 vs. 61 +/- 4% post, P = 0.14), whereas TD-derived measures of LV systolic function [septal strain -23 +/- 5 vs. -17 +/- 4%, P = 0.007; septal strain rate (SR) -1.5 +/- 0.3 vs. -1.1+/- 0.2 s(-1), P = 0.007] and right ventricular (RV) systolic function (RV apical strain -33 +/- 4 vs. -27 +/- 5%, P = 0.001; RV apical SR -2.4 +/- 0.7 vs. -1.8 +/- 0.5, P = 0.002) were reduced. Significant changes in transmitral velocity (E/A ratio 2.0 +/- 0.5 vs.1.3 +/- 0.3, P = 0.005) and TD indices of LV and RV diastolic function (E(a) septal 9.5 +/- 1.8 vs. 8.1 +/- 1.2 cm/s post-marathon, P = 0.01) were also observed, indicating an inherent alteration in LV relaxation. Although all indices of LV and RV systolic function had returned to normal on follow-up, there were persistent diastolic abnormalities (RV E(a), 11.5 +/- 1.5 cm/s pre-marathon vs. 10.0 +/- 1.6 cm/s follow-up, P = 0.01). CONCLUSION: Marathon running leads to transient systolic and more persistent diastolic dysfunction of both the LV and the RV.

Adult↗
PubMed2006

Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury.

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.

Administration, Inhalation↗
PubMed2006

Surgical management of infective endocarditis: early predictors of short-term morbidity and mortality.

BACKGROUND: Infective endocarditis is a diagnostic and therapeutic challenge that ultimately requires surgical intervention in 20% of all cases. Early determinants of morbidity and mortality in this high risk population are not well described. METHODS: The aim of this study was to determine preoperative clinical, microbiological, electrocardiographic, and echocardiographic variables that predicted the need for permanent pacemaker implantation and in-hospital death in a surgical cohort of patients with active infective endocarditis. RESULTS: We identified 91 patients (61 males and 30 females, mean age 58 +/- 16 years) who underwent surgical intervention for active culture-positive infective endocarditis as defined by the Duke criteria. Native valve infective endocarditis was present in 78 (85.7%) and prosthetic valve endocarditis in 13 (14.3%) of cases. The aortic valve was infected in 61 (67.0%), the mitral in 35 (38.5%), and multiple valves in 8 patients (8.8%). The most common indication for surgical intervention was intractable heart failure. Twenty-two patients (24.2%) required pacemakers, while there were 14 (15.4%) in-hospital deaths. In age-adjusted and gender-adjusted analyses, the presence of left bundle branch block on preoperative electrocardiogram (ECG) and presence of depressed left ventricular systolic function (ejection fraction [EF] < 50%) predicted the need for a permanent pacemaker implantation, while the presence of depressed left ventricular function predicted in-hospital mortality. CONCLUSIONS: Preoperative ECG findings of left bundle branch block and reduced left ventricular function may allow for early risk stratification of this high risk population.

Adult↗
PubMed2006

Myocardial adaptation to short-term high-intensity exercise in highly trained athletes.

We aimed to clarify the myocardial adaptation to short-term high-intensity exercise among trained athletes. We screened 17 participants in the 2004 World Indoor Rowing Championships before and after a 2000-m sprint. Echocardiography included standard measurements and tissue Doppler-derived strain (epsilon), strain rate, and 2-dimensionally derived speckle-tracking imaging for left ventricular (LV) torsion. LV volumes and ejection fraction were unchanged after exercise. There was a reduction in early and an increase in late diastolic filling velocities and a decrease in the flow propagation velocity. Annular systolic velocities, slope of the systolic acceleration, septal and lateral epsilon, and speckle tracking-derived torsion were increased. The increased LV torsion was a result of increased basal and apical rotation. Right ventricular apical epsilon decreased. In conclusion, maximal intensity short-duration exercise was associated with attenuation of LV diastolic function, augmentation of LV systolic function, and a reduction in apical right ventricular contractility.

Adaptation, Physiological↗
PubMed2006

A case report of a round cystic tumor in the left ventricular outflow tract.

We report a case of a patient who was admitted to our hospital complaining of angina pectoris. On auscultation, a systolic ejection murmur was heard at the right upper sternal border. Transthoracic echocardiography displayed regional wall motion abnormalities and detected a mobile mass in the left ventricular outflow tract, causing mild obstruction during systole. The mass appeared as an unilocular cystic tumor. Coronary angiography showed a significant lesion in the left anterior descending artery. Surgical treatment was indicated for coronary artery disease and for the unpredictable behaviour of the neoplasm. The mass was identified as arising from the top of the anterior papillary muscle. Histopathological examination revealed that the tumor was a cavernous hemangioma. Cardiac hemangiomas are rare, benign vascular tumors of the heart. This is an unusual case of left ventricular hemangioma incidentally discovered, which raised an interesting differential diagnosis.

Aged↗