Improved prediction of knee osteoarthritis progression by genetic polymorphisms: the Arthrotest Study.

OBJECTIVE: The aim of this study was to develop a genetic prognostic tool to predict radiographic progression towards severe disease in primary knee OA (KOA) patients. METHODS: This investigation was a cross-sectional, retrospective, multicentric association study in 595 Spanish KOA patients. Caucasian patients aged ≥40 years at the time of diagnosis of primary KOA of Kellgren-Lawrence grade 2 or 3 were included. Patients who progressed to Kellgren-Lawrence score 4 or who were referred for total knee replacement within 8 years after diagnosis were classified as progressors to severe disease. Clinical variables of the initial stages of the disease (gender, BMI, age at diagnosis, OA in the contralateral knee, and OA in other joints) were registered as potential predictors. Single nucleotide polymorphisms and clinical variables with an association of P < 0.05 were included in the multivariate analysis using forward logistic regression. RESULTS: A total of 23 single nucleotide polymorphisms and the time of primary KOA diagnosis were significantly associated with KOA severe progression in the exploratory cohort (n = 220; P < 0.05). The predictive accuracy of the clinical variables was limited: area under the curve (AUC) = 0.66. When genetic variables were added to the clinical model (full model), the prediction of KOA progression was significantly improved (AUC = 0.82). Combining only genetic variables (rs2073508, rs10845493, rs2206593, rs10519263, rs874692, rs7342880, rs780094 and rs12009), a predictive model with good accuracy was also obtained (AUC = 0.78). The predictive ability for KOA progression of the full model was confirmed on the replication cohort (two-sample Z-test; n = 62; P = 0.190). CONCLUSION: An accurate prognostic tool to predict primary KOA progression has been developed based on genetic and clinical information from OA patients.

Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance.

BACKGROUND: Myocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the left ventricle (LV). Recent reports suggest a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and also within small samples of genotype positive but phenotype negative relatives. The presence of a crypt has been suggested to be a predictor of gene carrier status. However, the prevalence and clinical significance of crypts in the general population is unclear. We aimed to determine the prevalence of myocardial crypts in a large cohort of subjects using clinical cardiovascular magnetic resonance (CMR). METHODS: Consecutive subjects referred for clinical CMR during a 12-month period (n = 1020, age 52.6 ± 17, males: 61%) were included. Crypts were defined as >50% invagination into normal myocardium and their overall prevalence, location and shape was investigated and compared between different patient groups. RESULTS: The overall prevalence of crypts was 64/1020 (6.3%). In a predefined 'normal' control group the prevalence was lower (11/306, 3.6%, p = 0.031), but were equally prevalent in ischemic heart disease (12/236, 5.1%, p = n/s) and the combined non-ischemic cardiomyopathy (NICM) groups (24/373; 6.4%, p = n/s). Within the NICM group, crypts were significantly more common in HCM (9/76, 11.7%, p = 0.04) and hypertensive CM subjects (3/11, 27%, p = 0.03). In patients referred for CMR for family screening of inherited forms of CM, crypts were significantly more prevalent (10/41, 23%, p < 0.001), including a smaller group with a first degree relative with HCM (3/9, 33%, p = 0.01). CONCLUSION: Myocardial crypts are relatively common in the normal population, and increasingly common in HCM and hypertensive cardiomyopathy. Crypts are also more frequently seen in normal phenotype subjects referred because of a family history of an inherited cardiomyopathy and HCM specifically. It is uncertain what the significance of crypts are in this group, and because of variability in the imaging protocols used and their relative frequency within the normal population, should not be used to clinically stratify these patients. Prospective studies are required to confirm the clinical significance of myocardial crypts, as their significance remains unclear.

Global left ventricular longitudinal strain is associated with decreased melatonin levels in patients with acute myocardial infarction: a two-dimensional speckle tracking study.

Low circulating melatonin levels predict poor outcome in patients with ST-segment elevation myocardial infarction (STEMI). In the present study, we investigated whether a relationship between myocardial deformation in parameters measured by echocardiography and circulating melatonin level exists. We prospectively included 112 patients with STEMI who performed echocardiography and simultaneous measurement of serum melatonin, during the light period within 72 h of admission. We found a negative correlation between circulating melatonin levels and global longitudinal strain (p = 0.006, r = -0.33). In conclusion, melatonin levels have a correlation with two-dimensional speckle tracking in patients with STEMI.

Usefulness of serum neopterin levels in acute decompensated heart failure to predict renal dysfunction.

CONTEXT: Neopterin serum concentration increases in the presence of renal dysfunction. OBJECTIVE: We sought to determine the relationship between admission serum neopterin levels and worsening renal function (WRF) in patients with heart failure (HF). METHODS: We prospectively measured serum neopterin levels in patients with HF and the patients were subdivided into two groups: with and without WRF during hospital admission. RESULTS: Logistic regression analysis showed that high serum neopterin levels at admission were associated with a greater likelihood of developing WRF. CONCLUSIONS: Patients admitted to hospital with HF, elevated serum neopterin levels are associated with an increased risk of developing WRF.

Decreased level of melatonin in serum predicts left ventricular remodelling after acute myocardial infarction.

As experimental studies suggest that melatonin is cardioprotective after myocardial infarction (MI), this study sought to investigate the relationships between circulating levels of melatonin and left ventricular (LV) remodelling in patients after acute MI. This prospective study included 161 patients (age 61±3yr; 78% men) undergoing primary percutaneous coronary intervention who were assessed echocardiographically at hospital discharge (day 3-7) and at 12 months. LV remodelling was defined as >20% increase in LV end-diastolic volume at 12-month follow-up compared with baseline. Serum melatonin concentrations were measured at admission, during the light period. Twenty-four patients showed LV remodelling, and 137 had no evidence of LV remodelling. Patients with LV remodelling had lower levels of melatonin at study entry [9.96 (8.28-11.03) versus 16.74 (13.77-19.59) pg/mL, respectively; P <0.0001]. Multivariate analysis showed that melatonin levels (OR=2.10, CI 95% 1.547-2.870, P<0.001) were an independent predictor of LV remodelling at 12-month follow-up. Receiver operating characteristic (ROC) analysis showed an area under the curve of 0.959 (CI 95% 0.93-0.98; P<0.0001). To our knowledge, this is the first study to show the relationship between melatonin and LV remodelling during the chronic phase post-MI.

Prospective application of a bleeding and ischemic risks-adjusted antithrombotic protocol in elderly patients revascularized with everolimus-eluting stents: EPIC05-Sierra75 study.

OBJECTIVES: Elderly patients show a higher incidence of ischemic and bleeding events after percutaneous transluminal coronary intervention (PCI). We sought to investigate outcomes in elderly patients treated with antithrombotic strategy guided by bleeding and ischemic risks after revascularization with last generation everolimus-eluting stent (EES). METHODS: Prospective multicenter registry including patients over 75 years revascularized with EES and antithrombotic therapy guided by clinical presentation, PCI complexity and PRECISE DAPT score. Co-primary safety endpoints were: (1) composite of cardiac death, myocardial infarction and stent thrombosis and; (2) bleeding (BARC 2-5). Primary efficacy endpoint was target lesion revascularization. A matched group of patients revascularized with current drug-eluting stents and no such tailored antithrombotic therapy was used as control. RESULTS: Finally, 1064 patients were included in SIERRA-75 cohort, 80.8 ± 4.2 years, 36.6% women, 71% acute coronary syndromes (ACS) and 53.6% complex PCI. Co-primary safety endpoint of major adverse cardiovascular events was met in 6.2%, co-primary safety endpoint of bleeding in 7.8% and primary efficacy endpoint of TKLR in 1.5%. The multivariable adjusted model showed no significant association of the prescribed short/long dual antiplatelet therapy (DAPT) durations with any endpoint suggesting a well tailored therapy. No stent thrombosis reported in the subgroup with 1-3 months DAPT duration. As compared to control group, bleeding BARC 2-5 was significantly lower in SIERRA-75 group (7.4% vs. 10.2%, P = 0.04) as well as the net safety-efficacy endpoint (14.3% vs. 18.5%, P = 0.02). CONCLUSIONS: In elderly population, the application of this risks-adjusted antithrombotic protocol after revascularization with last generation EES seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes.

Impact of operators experience on peri-procedural outcomes with Watchman FLX: Insights from the FLX-SPA registry.

BACKGROUND: The Watchman FLX is a device upgrade of the Watchman 2.5 that incorporates several design enhancements intended to simplify left atrial appendage occlusion (LAAO) and improve procedural outcomes. This study compares peri-procedural results of LAAO with Watchman FLX (Boston Scientific, Marlborough, Massachusetts) in centers with varying degrees of experience with the Watchman 2.5 and Watchman FLX. METHODS: Prospective, multicenter, "real-world" registry including consecutive patients undergoing LAAO with the Watchman FLX at 26 Spanish sites (FLX-SPA registry). Implanting centers were classified according to the center's prior experience with the Watchman 2.5. A further division of centers according to whether or not they had performed ≤ 10 or > 10Watchman FLX implants was prespecified at the beginning of the study. Procedural outcomes of institutions stratified according to their experience with the Watchman 2.5 and FLX devices were compared. RESULTS: 359 patients [mean age 75.5 (SD8.1), CHA2DS2-VASc 4.4 (SD1.4), HAS-BLED 3.8(SD0.9)] were included. Global success rate was 98.6%, successful LAAO with the first selected device size was achieved in 95.5% patients and the device was implanted at first attempt in 78.6% cases. There were only 9(2.5%) major peri-procedural complications. No differences in efficacy or safety results according to the centers previous experience with Watchman 2.5 and procedural volume with Watchman FLX existed. CONCLUSIONS: The Watchman FLX attains high procedural success rates with complete LAA sealing in unselected, real-world patients, along with a low incidence of peri-procedural complications, regardless of operators experience with its previous device iteration or the number of Watchman FLX devices implanted.

Cost-Effectiveness of Therapeutic Drug Monitoring-Guided Adalimumab Therapy in Rheumatic Diseases: A Prospective, Pragmatic Trial.

INTRODUCTION: To assess the clinical and cost-effectiveness of therapeutic drug monitoring (TDM) based on serum adalimumab levels compared to standard of care in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. METHODS: This was a non-inferiority, multicentric, non-randomized, pragmatic trial including adult patients diagnosed with moderate-to-severe, clinically stable rheumatic diseases treated with adalimumab. Consecutive patients were assigned 1:2 to the control (CG) or the intervention group (IG), based on the site of inclusion, and followed up for 18 months. Adalimumab serum levels were measured at each study visit and released to the IG only to modify dosing strategy. Data on disease activity, healthcare resource utilization and health-related quality of life (HRQoL) measured through the EQ-5D-5L were collected. Number of persistent and overall flares, time to first flare, days experiencing high disease activity, total direct costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. RESULTS: Of the 169 recruited patients, 150 were included in the analysis (52 and 98 patients in the CG and IG, respectively). The primary endpoint was not met as persistent flares were not significantly lower in the IG, although mean (SD) number of flares was numerically lower in the IG (0.67 [0.70] versus 0.90 [0.82], P = 0.073), respectively. Based on EQ-5D-5L utilities, HRQoL was significantly higher in the IG at 3 (P = 0.001) and 6 months (P = 0.035), which overall translated into 0.075 QALYs gained per patient for the IG at month 18. Overall, direct costs were significantly lower for the IG patients (€15,311.59 [4,870.04] versus €17,378.46 [6,556.51], P = 0.030), resulting in the intervention being dominant, leading to increased QALY at a lower overall cost CONCLUSION: Adalimumab dose tapering based on TDM for rheumatic patients led to an increased quality of life and QALY gain and entailed lower costs, being a more cost-effective alternative than clinically guided management.

Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction.

Aims: To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis. Methods and results: We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88-0.99); 0.87 (0.79-0.94); 0.61 (0.49-0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin. Conclusion: T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis.

T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure.

OBJECTIVES: The study sought to examine prognostic relevance of T1 mapping parameters (based on a T1 mapping method) in nonischemic dilated cardiomyopathy (NIDCM) and compare them with conventional markers of adverse outcome. BACKGROUND: NIDCM is a recognized cause of poor clinical outcome. NIDCM is characterized by intrinsic myocardial remodeling due to complex pathophysiological processes affecting myocardium diffusely. Lack of accurate and noninvasive characterization of diffuse myocardial disease limits recognition of early cardiomyopathy and effective clinical management in NIDCM. Cardiac magnetic resonance (CMR) supports detection of diffuse myocardial disease by T1 mapping. METHODS: This is a prospective observational multicenter longitudinal study in 637 consecutive patients with dilated NIDCM (mean age 50 years [interquartile range: 37 to 76 years]; 395 males [62%]) undergoing CMR with T1 mapping and late gadolinium enhancement (LGE) at 1.5-T and 3.0-T. The primary endpoint was all-cause mortality. A composite of heart failure (HF) mortality and hospitalization was a secondary endpoint. RESULTS: During a median follow-up period of 22 months (interquartile range: 19 to 25 months), we observed a total of 28 deaths (22 cardiac) and 68 composite HF events. T1 mapping indices (native T1 and extracellular volume fraction), as well as the presence and extent of LGE, were predictive of all-cause mortality and HF endpoint (p < 0.001 for all). In multivariable analyses, native T1 was the sole independent predictor of all-cause and HF composite endpoints (hazard ratio: 1.1; 95% confidence interval: 1.06 to 1.15; hazard ratio: 1.1; 95% confidence interval: 1.05 to 1.1; p < 0.001 for both), followed by the models including the extent of LGE and right ventricular ejection fraction, respectively. CONCLUSIONS: Noninvasive measures of diffuse myocardial disease by T1 mapping are significantly predictive of all-cause mortality and HF events in NIDCM. We provide a basis for a novel algorithm of risk stratification in NIDCM using a complementary assessment of diffuse and regional disease by T1 mapping and LGE, respectively.

Echogenic mobile images in intraprocedural three-dimensional transesophageal echocardiographic monitoring during percutaneous aortic valve implantation: Incidence, characteristics and clinical implications.

INTRODUCTION AND OBJECTIVES: To investigate the incidence and clinical relevance of the presence of mobile echogenic images (MEI) during transesophageal echocardiography (TEE) for monitoring of transcatheter aortic valve implantation (TAVI). METHODS: Consecutive patients referred to our center for transfemoral or transapical TAVI were included. The procedure was monitored by three-dimensional (3D) TEE and images were analyzed by two independent experts. In-hospital follow-up was carried out and correlated with imaging findings. RESULTS: A total of 104 patients were included. MEI were visualized in 11 patients during the procedure (11%) and in over 50% of cases were identified as thrombi, however no differences in periprocedural stroke were found in follow-up. CONCLUSIONS: Visualization of MEI during 3D TEE monitoring of TAVI is relatively common (11%) and in over 50% of cases they are identified as thrombi. The clinical implications of this finding are uncertain, as despite their frequency, the incidence of clinical stroke in this patient population was no higher. 3D TEE is a useful tool for diagnosis of MEI and can alert the operator to their presence.

Characterization of Patients With Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry of Patients With Systemic Lupus Erythematosus (RELESSER).

The aim of the study was to profile those patients included in the RELESSER registry with histologically proven renal involvement in order to better understand the current state of lupus nephritis (LN) in Spain. RELESSER-TRANS is a multicenter cross-sectional registry with an analytical component. Information was collected from the medical records of patients with systemic lupus erythematosus who were followed at participating rheumatology units. A total of 359 variables including demographic data, clinical manifestations, disease activity, severity, comorbidities, LN outcome, treatments, and mortality were recorded. Only patients with a histological confirmation of LN were included. We performed a descriptive analysis, chi-square or Student's t tests according to the type of variable and its relationship with LN. Odds ratio and confidence intervals were calculated by using simple logistic regression. LN was histologically confirmed in 1092/3575 patients (30.5%). Most patients were female (85.7%), Caucasian (90.2%), and the mean age at LN diagnosis was 28.4 ±â€Š12.7 years. The risk for LN development was higher in men (M/F:47.85/30.91%, P < 0.001), in younger individuals (P < 0.001), and in Hispanics (P = 0.03). Complete response to treatment was achieved in 68.3% of patients; 10.35% developed ESRD, which required a kidney transplant in 45% of such cases. The older the patient, the greater was the likelihood of complete response (P < 0.001). Recurrences were associated with persistent lupus activity at the time of the last visit (P < 0.001) and with ESRD (P < 0.001). Thrombotic microangiopathy was a risk factor for ESRD (P = 0.04), as for the necessity of dialysis (P = 0.01) or renal transplantation (P = 0.03). LN itself was a poor prognostic risk factor of mortality (OR 2.4 [1.81-3.22], P < 0.001). Patients receiving antimalarials had a significantly lower risk of developing LN (P < 0.001) and ESRD (P < 0.001), and responded better to specific treatments for LN (P = 0.014). More than two-thirds of the patients with LN from a wide European cohort achieved a complete response to treatment. The presence of positive anti-Sm antibodies was associated with a higher frequency of LN and a decreased rate of complete response to treatment. The use of antimalarials reduced both the risk of developing renal disease and its severity, and contributed to attaining a complete renal response.

Native T1 in discrimination of acute and convalescent stages in patients with clinical diagnosis of myocarditis: a proposed diagnostic algorithm using CMR.

OBJECTIVES: This study investigated whether T1 mapping by cardiac magnetic resonance (CMR) reflects the clinical evolution of disease in myocarditis and supports its diagnosis independently of the disease stages. BACKGROUND: Acute viral myocarditis is characterized by a range of intracellular changes due to viral replication and extracellular spill of debris within days of viral infection. Convalescence may be characterized by a chronic low-grade inflammation leading to ventricular remodelling, but also a complete resolution of myocardial changes. METHODS: Patients with clinical diagnosis of viral myocarditis (N = 165) underwent routine clinical CMR protocol (1.5- and 3.0-T) for assessment of cardiac function and structure, and tissue characterization with T2-weighted imaging and late gadolinium enhancement. T1 mapping was obtained in a mid-ventricular short-axis slice before and >20 min after administration of 0.2 mmol/kg of gadobutrol. RESULTS: Compared with control subjects (n = 40), T1 indexes were increased in patients with myocarditis. Patients with acute symptoms (n = 61) had higher values of T1 indexes compared with patients in clinical convalescence (n = 67). Native T1 is an independent discriminator between health and disease, as well as a discriminator between acute and convalescent stage of the disease. Native T1- was superior to T2-weighted imaging and late gadolinium enhancement with high diagnostic accuracy and positive and negative predictive values. Using pre-defined cutoff values for normal ranges, we demonstrated that acute myocarditis can be independently identified by native T1 of >5 SD above the mean of normal range, whereas convalescence is best defined by either abnormal native T1 (>2 SD) or presence of late gadolinium enhancement. We prospectively tested a new diagnostic algorithm in an independent dataset of patients with clinical diagnosis of myocarditis and achieved similar diagnostic performance. CONCLUSIONS: The new diagnostic algorithm using native T1 can reliably discriminate between health and disease and determine the clinical disease stage in patients with a clinical diagnosis of myocarditis.

T1 Mapping in Discrimination of Hypertrophic Phenotypes: Hypertensive Heart Disease and Hypertrophic Cardiomyopathy: Findings From the International T1 Multicenter Cardiovascular Magnetic Resonance Study.

BACKGROUND: The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere-gene mutations in subexpressed family members (G+P- subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P- subjects. METHODS AND RESULTS: Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P- subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P- subjects (P<0.0001) and 65% of G+P- subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P- subjects from controls. CONCLUSIONS: Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P- subjects.