Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation.

INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.

Predictors and Mechanisms of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

Growth Hormone Improves Cardiopulmonary Capacity and Body Composition in Children With Growth Hormone Deficiency.

Context: Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking. Objectives: Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents. Design: Prospective, case-control study. Patients and Methods: Twenty-one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual-energy x-ray absorptiometry, before and after 12 months of GH therapy. Twenty-one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year. Results: At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function. Conclusion: Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short-term GH replacement therapy.

Nitric oxide-sensitive pulmonary hypertension in congenital rubella syndrome.

Persistent pulmonary hypertension is a very rare presentation of congenital virus infection. We discuss the case of complete congenital rubella syndrome presenting at echocardiography with pulmonary hypertension that worsened after ductus ligation. Cardiac catheterization showed a normal pulmonary valve and vascular tree but a PAP = 40 mmHg. The infant promptly responded to inhaled nitric oxide while on mechanical ventilation and was later shifted to oral sildenafil. It is not clear whether our observation may be due to direct viral damage to the endothelium or to the rubella virus increasing the vascular tone via a metabolic derangement.

ß1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy.

BACKGROUND: The sphingosine-1-phosphate receptor 1 (S1PR1) and ß1-adrenergic receptor (ß1AR) are G-protein-coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein-coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of ß1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein-coupled receptor kinase-2. METHODS AND RESULTS: In HEK (human embryonic kidney) 293 cells overexpressing both ß1AR and S1PR1, we demonstrated that ß1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a ß-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein-coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic ß-adrenergic receptor stimulation and in a rat model of postischemic heart failure. CONCLUSIONS: We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious ß1AR overstimulation in heart failure.

Prognostic value of cardiovascular magnetic resonance in patients with suspected arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Early recognition and accurate risk stratification are important in the management of arrhythmogenic right ventricular cardiomyopathy (ARVC). Identification of predictors of outcome by cardiovascular magnetic resonance (CMR) in patients undergoing evaluation for ARVC is limited. We investigated the predictive value of morphological abnormalities detected by CMR for major clinical events in patients with suspected ARVC. METHODS: We performed a longitudinal study on 369 consecutive patients with at least one criterion for ARVC. Abnormal CMR was defined by the presence of one of the following: increased right ventricular (RV) volumes, reduced RV ejection fraction, RV regional wall motion abnormalities, myocardial fatty infiltration, and myocardial fibrosis. The end-point was a composite of cardiac death, sustained ventricular tachycardia, ventricular fibrillation, and appropriate ICD discharge. RESULTS: Twenty patients met the composite end-point over a mean follow-up of 4.3±1.5 years. An abnormal CMR was an independent predictor of outcomes (p<0.001). The presence of multiple abnormalities heralded a particular high risk of events (HR 23.0, 95% CI 5.7-93.2, p<0.001 for 2 abnormalities; HR 35.8, 95% CI 9.7-132.6, p<0.001 for 3 or more abnormalities). The positive predictive value of an abnormal CMR study was 21.0% for an adverse event, whilst the negative predictive value of a normal CMR study was 98.8% over the follow-up period. CONCLUSIONS: CMR provides important prognostic information in patients under evaluation for ARVC. A normal study portends a good prognosis. Conversely, the presence of multiple abnormalities identifies a high risk group of patients who may benefit from ICD implantation.

Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy.

IMPORTANCE: Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for implantable cardioverter-defibrillators (ICDs) and other management decisions. OBJECTIVE: To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance [LGE-CMR] imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy. DESIGN, SETTING, AND PATIENTS: Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011. MAIN OUTCOME MEASURES: Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation. RESULTS: Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio [HR], 2.96 [95% CI, 1.87-4.69]; absolute risk difference, 16.2% [95% CI, 8.2%-24.2%]; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 [95% CI, 3.15-8.72]; absolute risk difference, 22.6% [95% CI, 14.6%-30.6%]; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 [95% CI, 1.50-3.92]; P < .001) and the extent (HR, 1.11 [95% CI, 1.06-1.16]; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 [95% CI, 1.95-5.31], P < .001; and by fibrosis extent: HR, 1.15 [95% CI, 1.10-1.20], P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 [95% CI, 2.75-7.74], P < .001; and by fibrosis extent: HR, 1.10 [95% CI, 1.05-1.16], P < .001), and the HF composite (by fibrosis presence: HR, 1.62 [95% CI, 1.00-2.61], P = .049; and by fibrosis extent: HR, 1.08 [95% CI, 1.04-1.13], P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 [95% CI, 0.11-0.41]; P = .001 and 0.29 [95% CI, 0.11-0.48]; P = .002, respectively). CONCLUSIONS AND RELEVANCE: Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.

Prognostic role of CMR in patients presenting with ventricular arrhythmias.

OBJECTIVES: The goal of this study was to explore whether fibrosis detected by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is an independent predictor of hard cardiovascular events in patients presenting with ventricular arrhythmia. BACKGROUND: In patients at risk of sudden cardiac death, risk stratification for device therapy remains challenging. METHODS: A total of 373 consecutive patients with sustained ventricular tachycardia (VT) (n = 204) or nonsustained ventricular tachycardia (NSVT) (n = 169) underwent LGE-CMR. The group was prospectively followed up for a median of 2.6 years (range 11 months to 11 years). The predetermined endpoint was a composite of cardiac death/arrest, new episode of sustained VT, or appropriate implantable cardioverter-defibrillator discharge. RESULTS: Mean left ventricular (LV) ejection fraction (EF) was 60 ± 13%. The presence of fibrosis was a strong and independent predictor of the primary outcome for the whole group (hazard ratio [HR]: 3.3, 95% confidence interval [CI]: 1.8 to 5.8, p < 0.001). In the sustained VT subset, both LV fibrosis and severely impaired systolic function (LVEF <35%) were significant independent predictors in the multivariate model (HR: 3.0, 95% CI: 1.4 to 6.2, p = 0.001; and HR: 2.5, 95% CI: 1.1 to 6.2, p = 0.038, respectively). In the NSVT subset, the presence of fibrosis was the only independent predictor of the endpoint (HR: 4.2, 95% CI: 1.7 to 10.1, p = 0.006). CONCLUSIONS: LGE-CMR-detected fibrosis is an independent predictor of adverse outcomes in patients with ventricular arrhythmia and may have an important role in risk stratification. (The Prognostic Significance of Fibrosis Detection in Ischemic and Non-Ischemic Cardiomyopathy; NCT00930735).

Percutaneous treatment of a aorto-caval fistula in a old high risk patient.

BACKGROUND: To remark the feasibility of endovascular treatment of an aorto-caval fistula in a old high risk patient with "hostile" abdomen for previous surgeries. METHODS: In September 2009 a 81-years-old patient was admitted in emergency at our department because of abdominal pain and massive oedema of the lower extremities associated to dyspnoea (New York Heart Association (NYHA) functional class III). A CT scan showed an aorto-caval fistula involving the abdominal aorta below the renal arteries. This abnormal communication was likely due to the previous abdominal surgeries, was complicated by occlusion of the inferior vena cava at the diaphragm and was responsible for the massive oedema of the lower extremities. Because of unstable conditions and hostile abdomen the patient was considered unfit for conventional surgery and an endovascular approach was planned. After unsuccessful attempt by positioning of an Amplatzer vascular ring into the fistula, a Medtronic covered stent-grafts were implanted from the renal arteries to the both common iliac arteries. The patient had an impressive improvement characterized by a 18 Kg weight loss and a complete restoration of the functional capacity (from NYHA class III to NYHA class I) associated to a complete resolution of the lower extremities oedema as confirmed at the a month-CT-scan. CONCLUSION: Endovascular surgery of aorto-caval fistula represents a good option in alternative to conventional surgery mostly in old high risk patient.

Multiple MGuard stent implantation to treat massive right coronary artery dissection during primary coronary angioplasty.

Here we report a case of a 79-year-old woman with inferior myocardial infarction, transferred to our cath lab to perform a primary percutaneous coronary intervention (PPCI). During the procedure, a massive dissection complicated the thrombotic lesion of the right coronary artery (RCA). In this case, we decided to use the MGuard stent to treat both the large dissection and the thrombotic lesion. MGuard stent is a combination of a coronary stent merged with an embolic protection device. After multiple MGuard stent implantation we obtained a complete resolution of the coronary dissection obtaining a patent RCA with normal antegrade flow.

Infantile facial haemangioma and subclinical left ventricular dysfunction: the importance of z score in the diagnostic and therapeutic process.

Large facial haemangiomas have a high rate of complications and can be associated with neurological, ophthalmological and cardiac abnormalities (PHACE syndrome; Posterior fossa malformations, Haemangiomas, Arterial anomalies, Coarctation of the aorta and cardiac defects, and Eye abnormalities). However, a thorough clinical examination is absolutely necessary. In fact, even in the absence of a PHACE syndrome, large haemangiomas can induce important complications. In the present brief report we describe a case of left ventricular dilatation in a 6-month-old girl due to a giant facial haemangioma. Left ventricular dilatation has been evaluated by two-dimensional echocardiography. Studies to identify other major arteriovenous malformations were negative. Medical therapy with diuretics, angiotensin-converting enzyme (ACE) inhibitors and steroids was able to halt the progression towards left ventricular dysfunction, avoiding an early surgical approach for a disease that very often is self-limiting.

Induction of mitogen-activated protein kinases is proportional to the amount of pressure overload.

Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal-regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal-regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.

Recurrent pulmonary and cerebral thromboembolism in an adult patients following incomplete removal of ventriculoatrial shunt for congenital hydrocephalus.

A 34-year-old man was admitted to our hospital's department of neurology because he had experienced a cryptogenic stroke followed by a transient ischaemic attack. The patient suffered from congenital hydrocephalus which was treated by ventriculoatrial shunt at 8 months of age. Twelve months later, because of recurrent infections, the catheter was partially removed and the distal segment was left in place. At admission, the transoesophageal echocardiogram showed severe pulmonary hypertension (80 mm Hg confirmed by invasive measurement). The distal tip of the catheter had migrated into the left atrium through a patent foramen ovale inducing a massive right-to-left shunt. We surgically removed the catheter and closed the interatrial defect. At 1 and 6 months follow-up the patient was asymptomatic with a reduced pulmonary hypertension (50 mm Hg). Since there was no other clinical finding responsible for the recurrent thromboembolic events, both at the pulmonary and cerebral level, the catheter was removed to prevent further complications.

Ab initio molecular dynamics study of the hydrolysis reaction of diborane.

The hydrolysis reaction of the diborane molecule in aqueous solution has been studied by a series of Car-Parrinello Molecular Dynamics simulations in the Blue Moon Ensemble. The total reaction has been divided into two parts: one dealing with the breaking of B(2)H(6) molecule and the formation of a BH(4)(-) ion, a H(2)BOH molecule and a H(+) ion; the second leads to the formation of two hydrogen molecules and another H(2)BOH molecule, starting from BH(4)(-), two water molecules and a H(+) ion. The total reaction studied in this work has been B(2)H(6) + 2H(2)O --> 2H(2)BOH + 2H(2). We have described both structurally and electronically the reagents and the products through the radial distribution functions and the Wannier Function Center positions calculations, with attention to the solvent effects on the compounds. The free energy barrier value for the first part of the reaction and a detailed mechanisms for both parts have been reported. An interesting behavior of BH(3) and H(2) molecules in solution has been observed. They form a quite stable three center bond between the electron pair of the hydrogen molecule and the empty orbital of the boron atom in BH(3), which has been described from both a structural and electronic point of view.

Solid-state phase transition induced by pressure in LiOH x H2O.

When the free energy surface of the lithium hydroxide monohydrate crystal was explored, the high-pressure solid-state phase transition was determined. The high-pressure phase has been obtained through ab initio Car-Parrinello molecular dynamics simulation in the isothermic-isobaric ensemble. The recent metadynamics method has been applied to overcome the high activation energy barriers typical of rare events, like solid-state phase transition at high pressures. In the LiOH x H2O system, there are two kinds of H bonds: water-water and hydroxyl-water. The effect of the pressure has been investigated, to give further insight into the high-pressure phase. The strengthening of the H bonds of the system produces modifications in the water and the hydroxyl ion dipole electronic environment. The infrared spectra of both phases have been calculated and compared with experiments, and the assignment of the external modes has been discussed.