NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice.

The interleukin-1 family members, IL-1ß and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1ß processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

Manganese-enhanced magnetic resonance imaging in dilated cardiomyopathy and hypertrophic cardiomyopathy.

AIMS: The aim of this study is to quantify altered myocardial calcium handling in non-ischaemic cardiomyopathy using magnetic resonance imaging. METHODS AND RESULTS: Patients with dilated cardiomyopathy (n = 10) or hypertrophic cardiomyopathy (n = 17) underwent both gadolinium and manganese contrast-enhanced magnetic resonance imaging and were compared with healthy volunteers (n = 20). Differential manganese uptake (Ki) was assessed using a two-compartment Patlak model. Compared with healthy volunteers, reduction in T1 with manganese-enhanced magnetic resonance imaging was lower in patients with dilated cardiomyopathy [mean reduction 257 ± 45 (21%) vs. 288 ± 34 (26%) ms, P < 0.001], with higher T1 at 40 min (948 ± 57 vs. 834 ± 28 ms, P < 0.0001). In patients with hypertrophic cardiomyopathy, reductions in T1 were less than healthy volunteers [mean reduction 251 ± 86 (18%) and 277 ± 34 (23%) vs. 288 ± 34 (26%) ms, with and without fibrosis respectively, P < 0.001]. Myocardial manganese uptake was modelled, rate of uptake was reduced in both dilated and hypertrophic cardiomyopathy in comparison with healthy volunteers (mean Ki 19 ± 4, 19 ± 3, and 23 ± 4 mL/100 g/min, respectively; P = 0.0068). In patients with dilated cardiomyopathy, manganese uptake rate correlated with left ventricular ejection fraction (r2 = 0.61, P = 0.009). Rate of myocardial manganese uptake demonstrated stepwise reductions across healthy myocardium, hypertrophic cardiomyopathy without fibrosis and hypertrophic cardiomyopathy with fibrosis providing absolute discrimination between the healthy myocardium and fibrosed myocardium (mean Ki 23 ± 4, 19 ± 3, and 13 ± 4 mL/100 g/min, respectively; P < 0.0001). CONCLUSION: The rate of manganese uptake in both dilated and hypertrophic cardiomyopathy provides a measure of altered myocardial calcium handling. This holds major promise for the detection and monitoring of dysfunctional myocardium, with the potential for early intervention and prognostication.

Association between native T1 mapping of the kidney and renal fibrosis in patients with IgA nephropathy.

INTRODUCTION: IgA nephropathy (IgAN) is the commonest global cause of glomerulonephritis. Extent of fibrosis, tubular atrophy and glomerulosclerosis predict renal function decline. Extent of renal fibrosis is assessed with renal biopsy which is invasive and prone to sampling error. We assessed the utility of non-contrast native T1 mapping of the kidney in patients with IgAN for assessment of renal fibrosis. METHODS: Renal native T1 mapping was undertaken in 20 patients with IgAN and 10 healthy subjects. Ten IgAN patients had a second scan to assess test-retest reproducibility of the technique. Native T1 times were compared to markers of disease severity including degree of fibrosis, eGFR, rate of eGFR decline and proteinuria. RESULTS: All patients tolerated the MRI scan and analysable quality T1 maps were acquired in at least one kidney in all subjects. Cortical T1 times were significantly longer in patients with IgAN than healthy subjects (1540 ms ± 110 ms versus 1446 ± 88 ms, p = 0.038). There was excellent test-retest reproducibility of the technique, with Coefficient-of-variability of axial and coronal T1 mapping analysis being 2.9 and 3.7% respectively. T1 correlated with eGFR and proteinuria (r = - 0.444, p = 0.016; r = 0.533, p = 0.003 respectively). Patients with an eGFR decline > 2 ml/min/year had increased T1 times compared to those with a decline < 2 ml/min/year (1615 ± 135 ms versus 1516 ± 87 ms, p = 0.068), and T1 time was also higher in patients with a histological 'T'-score of > 0, compared to those with a 'T'-score of 0 (1575 ± 106 ms versus 1496 ± 105 ms, p = 0.131), though not to significance. CONCLUSIONS: Cortical native T1 time is significantly increased in patients with IgAN compared to healthy subjects and correlates with markers of renal disease. Reproducibility of renal T1 mapping is excellent. This study highlights the potential utility of native T1 mapping in IgAN and other progressive nephropathies, and larger prospective studies are warranted.

A comparison of the reproducibility of two cine-derived strain software programmes in disease states.

BACKGROUND: Systolic strain and peak-early diastolic strain rate (PEDSR) measure subclinical cardiac dysfunction. These parameters can be derived from cardiovascular magnetic resonance (CMR) cine images using new software packages, but the comparative test-retest reproducibility of these software in disease states is unknown. This study compared the test-retest reproducibility of strain measures derived from two software packages (feature-tracking software (FT) and tissue-tracking (TT)) in disease populations with preserved ejection fractions. METHODS: This was a prospective study of 10 patients with aortic stenosis (AS), 10 haemodialysis patients and 10 diabetic patients at 1.5 and 3-Tesla. 30 subjects underwent test-retest reproducibility scans of global circumferential strain (GCS), global longitudinal strain (GLS), circumferential-PEDSR and longitudinal-PEDSR calculated using TT and FT software. RESULTS: Test-retest reproducibility of GCS and GLS were similar for FT and TT across patient groups. Coefficient of variability (CoV) for FT-derived GCS 8.1%, 5% and 7.9% for AS, diabetic and haemodialysis patients, compared to 3.3%, 9.2% and 5.4% for TT-derived GCS, with CoV for FT-derived GLS 8%, 6.4% and 8.2% for AS, diabetic and haemodialysis patients, compared to 5.3%, 4.8% and 7% for TT-derived GLS). Reproducibility of FT-derived circumferential and longitudinal-PEDSR was worse than TT-derived circumferential and longitudinal-PEDSR (CoV for FT-derived circumferential-PEDSR 18.2%, 18% and 17.4% for AS, diabetic and haemodialysis patients, compared to 6.1%, 11.7% and 11% for TT-derived circumferential-PEDSR with CoV for FT-derived longitudinal PEDSR 18.2%, 18.9%, 18.3% for AS, diabetic and haemodialysis patients, compared to 8.9%, 9.1% and 11.4% for TT-derived longitudinal-PEDSR). Bland-Altman analysis revealed no systematic bias with tighter limits of agreement for TT-derived strain measures. CONCLUSIONS: Reproducibility of GCS and GLS are excellent with FT and TT software across diseases. TT had superior test-retest reproducibility for quantification of longitudinal and circumferential-PEDSR than FT-derived PEDSR across diseases.

Defining myocardial fibrosis in haemodialysis patients with non-contrast cardiac magnetic resonance.

BACKGROUND: Extent of myocardial fibrosis (MF) determined using late gadolinium enhanced (LGE) predicts outcomes, but gadolinium is contraindicated in advanced renal disease. We assessed the ability of native T1-mapping to identify and quantify MF in aortic stenosis patients (AS) as a model for use in haemodialysis patients. METHODS: We compared the ability to identify areas of replacement-MF using native T1-mapping to LGE in 25 AS patients at 3 T. We assessed agreement between extent of MF defined by LGE full-width-half-maximum (FWHM) and the LGE 3-standard-deviations (3SD) in AS patients and nine T1 thresholding-techniques, with thresholds set 2-to-9 standard-deviations above normal-range (1083 ± 33 ms). A further technique was tested that set an individual T1-threshold for each patient (T11SD). The technique that agreed most strongly with FWHM or 3SD in AS patients was used to compare extent of MF between AS (n = 25) and haemodialysis patients (n = 25). RESULTS: Twenty-six areas of enhancement were identified on LGE images, with 25 corresponding areas of discretely increased native T1 signal identified on T1 maps. Global T1 was higher in haemodialysis than AS patients (1279 ms ± 5.8 vs 1143 ms ± 12.49, P < 0.01). No signal-threshold technique derived from standard-deviations above normal-range associated with FWHM or 3SD. T11SD correlated with FWHM in AS patients (r = 0.55) with moderate agreement (ICC = 0.64), (but not with 3SD). Extent of MF defined by T11SD was higher in haemodialysis vs AS patients (21.92% ± 1 vs 18.24% ± 1.4, P = 0.038), as was T1 in regions-of-interest defined as scar (1390 ± 8.7 vs 1276 ms ± 20.5, P < 0.01). There was no difference in the relative difference between remote myocardium and regions defined as scar, between groups (111.4 ms ± 7.6 vs 133.2 ms ± 17.5, P = 0.26). CONCLUSIONS: Areas of MF are identifiable on native T1 maps, but absolute thresholds to define extent of MF could not be determined. Histological studies are needed to assess the ability of native-T1 signal-thresholding techniques to define extent of MF in haemodialysis patients. Data is taken from the PRIMID-AS (NCT01658345) and CYCLE-HD studies (ISRCTN11299707).

Cardiovascular magnetic resonance in the evaluation of heart valve disease.

BACKGROUND: Over the last 25 years, cardiovascular magnetic resonance imaging (CMR) has emerged as an alternative to echocardiography for assessment of valvular heart disease (VHD). Although echo remains the first-line imaging modality for the assessment of patients with VHD, CMR can now provide a comprehensive assessment in many instances. Using a combination of techniques, CMR provides information on valve anatomy and enables quantitative analysis of the severity of the valve lesion. MAIN TEXT: In this review, the fundamentals of CMR in assessment of VHD are described, together with its strengths and weaknesses. We detail the utility of CMR for studying all aspects of VHD, including valve anatomy, flow quantification as well as ventricular volumes and function. The optimisation of CMR for evaluating the commonest valve lesions (aortic stenosis, aortic regurgitation, mitral regurgitation, mitral stenosis) as well as in right-sided VHD and prosthetic valves is summarised. The focus of this review is to enable the reader to optimise the use of CMR in his or her own evaluation of heart valve lesions in clinical practice. CONCLUSIONS: CMR can be used for the comprehensive evaluation of VHD. This exciting, non-invasive imaging modality is likely to have increasing utility in the clinical evaluation of patients with VHD.

Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities.

Cardiovascular disease in patients with end-stage renal disease (ESRD) is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials.

Rationale and design of the randomised controlled trial to assess the impact of liraglutide on cardiac function and structure in young adults with type 2 diabetes (the LYDIA study).

BACKGROUND: The prevalence of type 2 diabetes (T2DM) in younger adults is growing. Compared to the late onset T2DM, it is well recognized that the disease tends to behave more aggressively in the younger age group with evidence of premature micro and macrovasular diseases and shorter life span. This increased mortality is largely attributed to cardiovascular complications. In a recent pilot study, young adults with T2DM were found to have significantly lower peak diastolic strain rate (PEDSR) on cardiac MRI (CMR), a forerunner of diabetic cardiomyopathy. Liraglutide, a glucagon like peptide-1 (GLP-1) analogue, is one of the new classes of glucose lowering therapies licensed to be used in management of T2DM. In randomised controlled trials, liraglutide improves glycaemic control by 1-1.5 % with an added benefit of weight loss of 2-3 kg. In addition, there is emerging evidence elucidating the cardioprotective effects of GLP-1 analogues independent of glycaemic control. In a small study, liraglutide has also been shown to improve cardiac function in patients with coronary ischaemia or congestive heart failure. METHODS AND AIMS: This is a prospective, randomised, open-label, blind end-point (PROBE) active-comparator trial. A total of 90 obese eligible participants with T2DM (18-50 years) will be randomised to either liraglutide 1.8 mg once daily or sitagliptin 100 mg once daily for 26 weeks. The primary aim is to assess whether liraglutide improves diastolic function compared to sitagliptin as measured by PEDSR using CMR. DISCUSSION: Although newer classes of GLP-1 analogues are made available in recent years, there are very few published studies demonstrating the beneficial effect of GLP-1 analogues on cardiovascular endpoints. In a recently published LEADER study, liraglutide has shown superiority to placebo in a population of type 2 diabetes with high risk of cardiovascular disease. To the best of our knowledge, there are no published studies establishing the effect of liraglutide on cardiac function in younger patients with T2DM on a larger scale. The LYDIA study will comprehensively describe changes in various parameters of cardiac structure and function in patients treated with liraglutide aiming to provide new evidence on effect of liraglutide on diastolic function in young obese people with T2DM. Trial Registration ClinicalTrials.gov identifier: NCT02043054.

Design and methods of CYCLE-HD: improving cardiovascular health in patients with end stage renal disease using a structured programme of exercise: a randomised control trial.

BACKGROUND: There is emerging evidence that exercise training could positively impact several of the cardiovascular risk factors associated with sudden cardiac death amongst patients on haemodialysis. The primary aim of this study is to evaluate the effect of an intradialytic exercise programme on left ventricular mass. METHOD AND DESIGN: Prospective, randomised cluster open-label blinded endpoint clinical trial in 130 patients with end stage renal disease on haemodialysis. Patients will be randomised 1:1 to either 1) minimum of 30 min continuous cycling thrice weekly during dialysis or 2) standard care. The primary outcome is change in left ventricular mass at 6 months, assessed by cardiac MRI (CMR). In order to detect a difference in LV mass of 15 g between groups at 80 % power, a sample size of 65 patients per group is required. Secondary outcome measures include abnormalities of cardiac rhythm, left ventricular volumes and ejection fraction, physical function measures, anthropometric measures, quality of life and markers of inflammation, with interim assessment for some measures at 3 months. DISCUSSION: This study will test the hypothesis that an intradialytic programme of exercise leads to a regression in left ventricular mass, an important non-traditional cardiovascular risk factor in end stage renal disease. For the first time this will be assessed using CMR. We will also evaluate the efficacy, feasibility and safety of an intradialytic exercise programme using a number of secondary end-points. We anticipate that a positive outcome will lead to both an increased patient uptake into established intradialytic programmes and the development of new programmes nationally and internationally. TRIAL REGISTRATION NUMBER: ISRCTN11299707 (registration date 5(th) March 2015).

Type 2 diabetes mellitus and obesity in young adults: the extreme phenotype with early cardiovascular dysfunction.

AIM: A pilot study to phenotype young adults (< 40 years) with Type 2 diabetes mellitus. METHODS: Twenty people with Type 2 diabetes (aged 18-40 years), 10 lean and 10 obese control subjects underwent detailed assessment, including tagged cardiac magnetic resonance imaging, inflammatory proteins, lipids, vitamin D and maximal oxygen uptake. Outcomes were compared between the group with Type 2 diabetes and the control group. RESULTS: Mean (standard deviation) age, Type 2 diabetes duration and BMI in the group with Type 2 diabetes were 31.8 (6.6) years, 4.7 (4.0) years and 33.9 (5.8) kg/m(2) respectively. Compared with lean control subjects, those with Type 2 diabetes had more deleterious profiles of hyperlipidaemia, vitamin D deficiency, inflammation and maximal oxygen uptake relative to body mass. However, there was no difference between the group with Type 2 diabetes and the obese control group. The group with Type 2 diabetes had a higher left ventricular mass and a trend towards concentric remodelling compared with the lean control group (P = 0.002, P = 0.052) but not the obese control group (P > 0.05). Peak early diastolic strain rate was reduced in the group with Type 2 diabetes [1.51 (0.24)/s] compared with the lean control [1.97 (0.34)/s, P = 0.001] and obese control [1.78 (0.39)/s, P = 0.042] group. CONCLUSIONS: Young adults with Type 2 diabetes and those with obesity have similar adverse cardiovascular risk profiles, higher left ventricular mass and a trend towards left ventricular concentric remodelling. In addition, those with Type 2 diabetes demonstrate diastolic dysfunction, a known risk marker for future heart failure and mortality.

SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink.

This study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink, whether DNA could be obtained, and whether previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms could be replicated. Seventy-seven statin-induced myopathy patients (serum creatine phosphokinase (CPK) > 4× upper limit of normal (ULN)) and 372 statin-tolerant controls were identified and recruited. Multiple logistic regression analysis showed the SLCO1B1 c.521T>C single-nucleotide polymorphism to be a significant risk factor (P = 0.009), with an odds ratio (OR) per variant allele of 2.06 (1.32-3.15) for all myopathy and 4.09 (2.06-8.16) for severe myopathy (CPK > 10× ULN, and/or rhabdomyolysis; n = 23). COQ2 rs4693075 was not associated with myopathy. Meta-analysis showed an association between c.521C>T and simvastatin-induced myopathy, although power for other statins was limited. Our data replicate the association of SLCO1B1 variants with statin-induced myopathy. Furthermore, we demonstrate how electronic medical records provide a time- and cost-efficient means of recruiting patients with severe adverse drug reactions for pharmacogenetic studies.

MitroFast® annuloplasty ring for complete posterior mitral leaflet destruction: a novel approach in active endocarditis.

We report the successful use of MitroFast® annuloplasty ring in the setting of active endocarditis to preserve the native valve mechanism despite complete posterior leaflet destruction. This patient remained well at 20 month follow-up after her surgery.

Stress cardiovascular MR in routine clinical practice: referral patterns, accuracy, tolerance, safety and incidental findings.

OBJECTIVE: The use of stress cardiovascular MR (CMR) to evaluate myocardial ischaemia has increased significantly over recent years. We aimed to assess the indications, incidental findings, tolerance, safety and accuracy of stress CMR in routine clinical practice. METHODS: We retrospectively examined all stress CMR studies performed at our tertiary referral centre over a 20-month period. Patients were scanned at 1.5 T, using a standardised protocol with routine imaging for late gadolinium enhancement. Angiograms of patients were assessed by an interventional cardiologist blinded to the CMR data. RESULTS: 654 patients were scanned (mean age 65±29 years; 63 inpatients; 9.6%). 14% of patients had incidental extracardiac findings, the commonest being liver or renal cysts (6%) and pulmonary nodules (4%). 639 patients (97.7%) received intravenous adenosine, 10 received intravenous dobutamine and 5 patients had both. Of the 15 patients who received dobutamine, 12 had no side-effects/complications, 2 experienced nausea and 1 chest tightness. Of the 644 patients who received adenosine, 43% experienced minor symptoms, 1% had transient heart block and 0.2% had severe bronchospasm requiring termination of infusion. There were no cases of hospitalisation or myocardial infarction. 241 patients also had coronary angiography. For detecting at least moderate stenosis of ≥50%, sensitivity was 86%, specificity 98% and accuracy 89%. For detecting severe stenoses of ≥70%, sensitivity was 91%, specificity 86% and overall accuracy 90%. These results compare very favourably with previous smaller research studies and meta-analyses. CONCLUSION: We conclude that stress CMR, with adenosine as the main stress agent, is well tolerated, safe and accurate in routine clinical practice.

Non-invasive imaging in coronary artery disease including anatomical and functional evaluation of ischaemia and viability assessment.

Coronary artery disease has an important impact on the morbidity and mortality statistics and health economics worldwide. Diagnosis of coronary artery disease is important in risk stratification and guides further management. Invasive coronary angiography is the traditional method of imaging the coronary arteries and remains the gold standard. It detects luminal stenosis but provides little information about the vessel wall or plaques. Besides, not all anatomical lesions are functionally significant. This has lent itself to a wide variety of imaging techniques to identify and assess a flow-limiting stenosis. The approach to diagnosis of coronary artery disease is broadly based on anatomical and functional imaging. Coronary CT and MRI of coronary arteries provide an anatomical assessment of coronary stenosis. Coronary calcium score and coronary CT assess subclinical atherosclerosis by assessing the atherosclerotic plaque burden. The haemodynamic significance of a coronary artery stenosis can be assessed by stress radioisotope studies, stress echocardiography and stress MRI. The more recent literature also focuses on plaque assessment and identification of plaques that are likely to give rise to an acute coronary syndrome. There is an explosion of literature on the merits and limitations of the different imaging modalities. This review article will provide an overview of all the imaging modalities in the diagnosis of coronary artery disease.

Unusual extracardiac manifestations of isolated native tricuspid valve endocarditis.

Isolated native tricuspid valve endocarditis (TVE) in non-intravenous drug users is a very rare condition. We describe an unusual presentation of Enterococcus faecalis TVE associated with spondylodiscitis, positive cytoplasmic antineutrophil cytoplasmic antibodies and antiproteinase-3 antibodies vasculitic rash in an otherwise healthy patient with no history of intravenous drug use or underlying cardiac abnormalities. A high index of clinical suspicion is required in patients presenting with unusual features and pyrexia of unknown origin. Simple tests including serial blood cultures and echocardiography may help to establish the correct diagnosis and commence appropriate treatment.

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

BACKGROUND: Overall, approximately 5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. METHODS: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. RESULTS: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). INTERPRETATION: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association.

NT-proBNP reflects right ventricular structure and function in pulmonary hypertension.

The aim of the current study was to investigate whether alterations in N-terminal pro brain natriuretic peptide (NT-proBNP) reflect changes in right ventricular structure and function in pulmonary hypertension patients during treatment. The study consisted of 30 pulmonary hypertension patients; 15 newly diagnosed and 15 on long-term treatment. NT-proBNP, right heart catheterisation and cardiac magnetic resonance imaging measurements were performed, at baseline and follow-up. There were no significant differences between newly diagnosed patients and those on treatment at baseline or follow-up with respect to NT-proBNP, haemodynamics and right ventricular parameters. Relative changes in NT-proBNP during treatment were correlated to the relative changes in right ventricular end-diastolic volume index (r = 0.59), right ventricular mass index (r = 0.62) and right ventricular ejection fraction (r = -0.81). N-terminal pro brain natriuretic peptide measurements reflect changes in magnetic resonance imaging-measured right ventricular structure and function in pulmonary hypertension patients. An increase in N-terminal pro brain natriuretic peptide over time reflects right ventricular dilatation concomitant to hypertrophy and deterioration of systolic function.