Humoral antibody response following mRNA vaccines against SARS-CoV-2 in solid organ transplant recipients; a status after a fifth and bivalent vaccine dose.

Background: In solid organ transplant (SOT) recipients, the humoral response following COVID-19 vaccination is reduced, as a result of their immunosuppressed treatment. In this study, we investigated antibody concentrations after booster vaccinations until the fifth dose, the latter by monovalent or bivalent BA1 or BA4/5 vaccines. In addition, we evaluated the efficacy of vaccination by recording breakthrough infections, hospitalizations, and deaths. Method: This prospective cohort study included 438 SOT recipients (>18 years) vaccinated with mRNA vaccines against COVID-19 from January 2021 until March 2023. Blood samples were drawn before and after each vaccination and tested for SARS-CoV-2 spike RBD IgG antibodies with the lowest and highest cut-off at 7.1 and 5,680 BAU/mL, respectively. Vaccine information, breakthrough infections, and hospitalizations were collected from the medical records. Results: Most participants received BNT162b2 and 61.4% received five vaccine doses. The response proportion in SOT recipients increased from 86.7% after the fourth dose to 93.0% following the fifth dose. Antibody concentration decreased with 142.7 BAU/mL between the third and fourth dose (median 132 days, Quartile 1: 123, Quartile 3: 148) and 234.3 BAU/mL between the fourth and fifth (median 250 days, Quartile 1: 241, Quartile 3: 262) dose among those without breakthrough infection (p=0.34). When comparing the Omicron BA.1 or Omicron BA.4/BA.5 adapted vaccines, no significant differences in antibody concentration were found, but 20.0% of SOT recipients receiving a monovalent fifth vaccine dose had a breakthrough infection compared to 4.0% and 7.9% among those who received BA.1 and BA.4/BA.5 adapted vaccines, respectively (p=0.04). Since January 2021, 240 (54.8%) participants had a breakthrough infection, and 22 were hospitalized, but no deaths were observed. Conclusions: The fifth COVID-19 vaccine dose raised antibody response to 93.0% of the study population. Additional booster doses, as well as bivalent vaccines, led to higher levels of antibody concentration in SOT recipients. We found a lower incidence of breakthrough infections among SOT recipients after receiving a bivalent vaccine as a fifth dose compared to those receiving a monovalent dose. Antibody concentrations did not wane when the time between doses was prolonged from four to eight months.

Specialized heart failure clinics versus primary care: Extended registry-based follow-up of the NorthStar trial.

BACKGROUND: Whether continued follow-up in specialized heart failure (HF) clinics after optimization of guideline-directed therapy improves long-term outcomes in patients with HF with reduced ejection fraction (HFrEF) is unknown. METHODS AND RESULTS: 921 medically optimized HFrEF patients enrolled in the NorthStar study were randomly assigned to follow up in a specialized HF clinic or primary care and followed for 10 years using Danish nationwide registries. The primary outcome was a composite of HF hospitalization or cardiovascular death. We further assessed the 5-year adherence to prescribed neurohormonal blockade in 5-year survivors. At enrollment, the median age was 69 years, 24,7% were females, and the median NT-proBNP was 1139 pg/ml. During a median follow-up time of 4.1 (Q1-Q3 1.5-10.0) years, the primary outcome occurred in 321 patients (69.8%) randomized to follow-up in specialized HF clinics and 325 patients (70.5%) randomized to follow-up in primary care. The rate of the primary outcome, its individual components, and all-cause death did not differ between groups (primary outcome, hazard ratio 0.96 [95% CI, 0.82-1.12]; cardiovascular death, 1.00 [0.81-1.24]; HF hospitalization, 0.97 [0.82-1.14]; all-cause death, 1.00 [0.83-1.20]). In 5-year survivors (N = 660), the 5-year adherence did not differ between groups for angiotensin-converting enzyme inhibitors (p = 0.78), beta-blockers (p = 0.74), or mineralocorticoid receptor antagonists (p = 0.47). CONCLUSIONS: HFrEF patients on optimal medical therapy did not benefit from continued follow-up in a specialized HF clinic after initial optimization. Development and implementation of new monitoring strategies are needed.

Multiorgan ultrasonographic findings in patients with pulmonary embolism at diagnosis and clinical follow-up: a proof of concept study.

PURPOSE: The purpose of this descriptive feasibility study was to assess the clinical impact and feasibility of conducting a multiorgan ultrasound examination of patients with pulmonary embolism at both time of diagnosis and at clinical follow-up. METHODS: Hemodynamically stable patients with pulmonary embolism verified by CT pulmonary angiography or ventilation perfusion scintigraphy were eligible for inclusion. Enrolled patients underwent multiorgan ultrasound investigation encompassing echocardiography supplemented with focused lung and deep venous ultrasound emphasizing right ventricular strain, subpleural consolidations and presence of deep venous thrombi. Identical investigations were conducted at 3 months follow-up. The presence of ultrasonographic findings at diagnosis and follow-up was compared and the clinical impact of any remaining pathology or strain was described. RESULTS: Twenty-one patients were enrolled in the study of whom 20 survived to attend follow-up. Mean age was 62 ± 15 years and 48% were female. At diagnosis, the most prevalent ultrasonographic findings were subpleural consolidations in 11 patients and right ventricular dilation in eight. At follow-up, signs of right ventricular strain had resolved in all patients. However, in one patient, no resolution was seen in a subpleural consolidation observed at the time of pulmonary embolism diagnosis, resulting in referral to a chest CT. Additionally, one patient exhibited residual deep venous thrombotic material, leading to prolongation of anticoagulative treatment. CONCLUSION: In patients with pulmonary embolism, multiorgan ultrasound is feasible in follow-up and adequately powered studies should determine the clinical utility of such an approach.

Effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial.

AIMS: It remains unknown whether the consistently observed increase in haematocrit with sodium-glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I-III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8-4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59-0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86-1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (pinteraction >0.05). CONCLUSION: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.

Humoral immune response following a third SARS-CoV-2 mRNA vaccine dose in solid organ transplant recipients compared with matched controls.

Background: Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated. Method: This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups. Results: Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80). Conclusion: A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups.

High output cardiac failure in 3 patients with hereditary hemorrhagic telangiectasia and hepatic vascular malformations, evaluation of treatment.

BACKGROUND: This report addresses how patients with hereditary hemorrhagic telangiectasia (HHT) and high output cardiac failure (HOCF) due to hepatic vascular malformations, should be evaluated and could be treated. HHT is a genetic disorder, leading to vascular abnormalities with potentially serious clinical implications. In the liver, arteriovenous malformations occur in more than 70% of patients, but only about 8% present clinical symptoms such as HOCF with pulmonary hypertension and less commonly portal hypertension, biliary ischemia and hepatic encephalopathy. RESULTS: Three female patients with HHT type 2 and HOCF caused by severe arteriovenous malformations in the liver are presented in this case series. The patients were seen at the HHT-Centre at Odense University Hospital. Treatment with either orthotopic liver transplantation (one patient) or bevacizumab (two patients) was initiated. All patients experienced marked symptom relief and objective improvement. New York Heart Association-class were improved, ascites, peripheral edema and hence diuretic treatment was markedly reduced or discontinued in all three patients. Bevacizumab also resulted in notable effects on epistaxis and anemia. CONCLUSION: Our findings substantiate the importance of identification of symptomatic arteriovenous malformations in the liver in patients with HHT. Bevacizumab may possibly, as suggested in this case series and supported by previous case studies, postpone the time to orthotopic liver transplantation or even make it unnecessary. Bevacizumab represents a promising new treatment option, which should be investigated further in clinical trials.

Early Diastolic Strain Rate in Relation to Systolic and Diastolic Function and Prognosis in Aortic Stenosis.

OBJECTIVES: This study examined the impact of early mitral inflow velocity-to-early diastolic strain rate (E/SRe) ratio on long-term outcome after aortic valve replacement (AVR) in aortic stenosis (AS). BACKGROUND: In AS, increased filling pressures are associated with a poor prognosis and can be estimated using the early diastolic mitral inflow velocity-to-early diastolic velocity of the mitral annulus (E/e') ratio. Recent studies suggest that the E/SRe ratio surpasses the E/e' ratio in estimating outcome. METHODS: Pre-operative evaluation was performed in 121 patients with severe AS (aortic valve area <1 cm(2)) and left ventricular ejection fraction (LVEF) of >40% who were scheduled for AVR. Patients were divided according to E/SRe median and followed for 5 years. The primary endpoint was overall mortality. RESULTS: LVEF was lower (53 ± 7% vs. 56 ± 7%, respectively; p = 0.03) and a restrictive filling pattern more common (28% vs. 8%, respectively, p = 0.005) in patients with increased E/SRe ratio. Five-year overall mortality was increased in patients with high E/SRe (40% vs. 15%, respectively; p = 0.007). In univariate Cox regression analysis, E/SRe, age, European System for Cardiac Operative Risk Evaluation (EuroSCORE), LV mass index, left atrial volume index, LVEF, global longitudinal strain, E/e' ratio, and N-terminal pro-B-type natriuretic peptide level were univariate predictors of overall mortality, although when we adjusted for the predefined variables age, history of diabetes mellitus and LVEF, only E/SRe and left atrial volume index remained associated with overall mortality. Even when we included left atrial volume index in the multivariate model, E/SRe was significantly associated with overall mortality (hazard ratio [HR]: 2.2; 95% confidence interval [CI]: 1.1 to 4.4; p < 0.05); additionally, in a model with forward selection, E/SRe was the sole predictor (HR: 2.9; 95% CI: 1.6 to 5.5; p = 0.001. The overall log likelihood chi-square analysis of the predictive power of the multivariate model containing E/SRe was statistically superior to models based on the E/e' ratio. CONCLUSIONS: Pre-operative E/SRe ratio was significantly associated with long-term post-operative survival and was superior to the E/e' ratio in patients with severe AS undergoing AVR. (Effect of Angiotensin II Receptor Blockers (ARB) on Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis; NCT00294775).

Impact of chronic obstructive pulmonary disease on survival and symptoms of severe aortic valve stenosis.

BACKGROUND: As patients with severe aortic valve stenosis (AS) develop symptoms their survival decreases rapidly, if treated conservatively. Transcatheter aortic valve implantation (TAVI) has been introduced as a less invasive treatment alternative, especially in inoperable patients, who often have severe comorbidities, including chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Since the beginning of our TAVI program in March 2008, data on all 131 TAVI patients were prospectively and consecutively collected in this registry with complete follow-up. COPD was present in 37 patients. By January 2012 survival data were collected from the Danish Civil Registration System. Median follow-up duration was 559 days. RESULTS: Overall survival and survival from cardiac death was equivalent in both patients with and without COPD (p = 0.98 and p = 0.26) in the follow-up period. Further, patients with COPD had higher New York Heart Association (NYHA) class prior to intervention compared with those without (3.1 ± 0.5 vs. 2.9 ± 0.5, p = 0.02). In multivariate regression analysis COPD was associated with 30-day postoperative NYHA class (0.43; 95% confidence interval (CI): 0.10-0.75; p = 0.01), but not to NYHA class improvement from pre- to postintervention (0.25; 95% CI: - 0.12 to -0.63; p = 0.18). CONCLUSIONS: In patients with symptomatic severe AS treated with TAVI, the presence of COPD neither affects overall survival nor survival from cardiac death. Patients with COPD had, however, both higher pre- and postoperative NYHA class compared with patients without COPD, but NYHA class improvement from pre- to postintervention was equivalent in both groups.

Plasma copeptin as marker of cardiovascular disease in asymptomatic type 2 diabetes patients.

Recently, copeptin was found associated with cardiovascular disease (CVD) and all-cause mortality in type 2 diabetes mellitus (T2DM) patients treated in primary care. This study aimed to evaluate whether plasma copeptin correlated to CVD in asymptomatic T2DM patients intensively investigated for sub-clinical CVD. A total of 302 T2DM patients referred to the Diabetes Clinic at Odense University Hospital, Denmark, entered the study. None of the patients had known or suspected CVD. As a control group, 30 healthy adults were recruited from the DanRisk study - a random sample of middle-aged Danes. A variety of clinical investigations were performed, including blood pressure measurements, carotid intima media thickness evaluation and myocardial perfusion scintigraphy. Blood sample analyses included copeptin measurements. Median plasma copeptin concentrations were similar in the T2DM group and the control group. However, men had significantly higher copeptin concentrations than women in the T2DM group (p < 0.001), and also, T2DM men had significantly higher copeptin concentrations than men without T2DM (p = 0.038). Copeptin correlated significantly with a number of variables, but the strongest correlation was with creatinine (R = 0.432, p < 0.001), and in multiple regression analysis, only this correlation remained significant. When association with clinical scores were investigated, plasma copeptin remained significantly associated with peripheral arterial disease (PAD) (p = 0.01). We found correlations between creatinine, copeptin levels and PAD in T2DM patients, and if confirmed, plasma copeptin combined with plasma creatinine could be a candidate for PAD screening in T2DM patients.

Left ventricular diastolic function is associated with symptom status in severe aortic valve stenosis.

BACKGROUND: In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients. METHODS AND RESULTS: In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P=0.002), presented less often with atrial fibrillation (13% versus 24%; P=0.05) and chronic obstructive pulmonary disease (2% versus 19%; P<0.001), and had a lower prevalence of hypertension (73% versus 40%; P<0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m2; P<0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P<0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P<0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m2; P=0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms. CONCLUSIONS: The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775.

Left atrial volume index: relation to long-term clinical outcome in type 2 diabetes.

OBJECTIVES: The study sought to determine the prognostic importance of left atrial (LA) dilation in patients with type 2 diabetes mellitus (T2DM) and no history of cardiovascular disease (CVD). BACKGROUND: T2DM is associated with the development of CVD, and morphological changes in the heart may appear before symptoms arise. METHODS: A total of 305 T2DM patients without known CVD referred to a diabetes clinic were included consecutively (age 58.6 ± 11.3 years, diabetes duration 2.0 [interquartile range: 0 to 6.0] years). Each patient underwent a comprehensive echocardiogram and a myocardial perfusion scintigraphy (MPS) at inclusion. Patients were divided according to left atrial volume index (LAVi) ≥32 ml/m(2). Patients were followed for median of 5.6 (interquartile range: 5.1 to 6.1) years for the occurrence of major cardiac events and death. RESULTS: LAVi ≥32 ml/m(2) was found in 105 patients (34%). During follow-up, 60 patients (20%) experienced the composite endpoint, of whom 28 (9%) died. Patients with LAVi ≥32 ml/m(2) had a significantly higher cardiac event rate and death rate (p < 0.001 and p = 0.002, respectively). Univariate predictors of the composite endpoint were age, hypertension, left ventricular diastolic function, E/e'septum-ratio and LAVi ≥32 ml/m(2); however, myocardial ischemia on MPS was not a predictor. When adjusting for age and hypertension, only LAVi ≥32 ml/m(2) was a predictor of the composite endpoint (hazard ratio: 1.82 [95% confidence interval: 1.08 to 3.07], p = 0.024). CONCLUSIONS: Increased LAVi was an independent and incremental predictor of cardiovascular morbidity and mortality in T2DM patients with no history of CVD. (Presence of Macrovascular Disease in Type 2 Diabetes Mellitus; NCT00298844).

Relation of osteoprotegerin in severe aortic valve stenosis to postoperative outcome and left ventricular function.

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and is known to be among the mediators of the calcification process that has been shown to increase in patients with aortic stenosis (AS). The aim of this study was to characterize the association of OPG with left ventricular (LV) function and remodeling and to evaluate the significance of preoperative OPG on long-term outcome in terms of survival and symptomatic improvement in 124 patients with severe AS scheduled for aortic valve replacement (AVR). Patients were divided according to tertiles of preoperative OPG. Preoperative OPG was associated with age, EuroSCORE, and preoperative functional capacity. Despite similar ejection fraction and diastolic function among groups, longitudinal LV systolic function consistently decreased and markers of filling pressure increased across groups. During median follow-up of 4 years, 41 patients died of a presumed cardiovascular cause or remained in New York Heart Association functional class III or IV. The risk of a poor postoperative outcome after AVR increased with increasing OPG tertiles (15% vs 33% vs 51%, p = 0.002). In a multivariate model containing age, ejection fraction, N-terminal pro-brain natriuretic peptide and left atrial volume index, OPG was still significantly associated with postoperative outcome. In addition, OPG levels associated with cardiovascular mortality during follow-up. In conclusion, OPG is associated with LV and left atrial remodeling in patients with symptomatic severe AS undergoing AVR. Moreover, plasma OPG is associated with long-term postoperative outcome and may identify patients with poor symptomatic improvement after surgery.

Non-invasive assessments reveal that more than half of randomly selected middle-aged individuals have evidence of subclinical atherosclerosis: a DanRisk substudy.

Screening of the general population for subclinical atherosclerosis is controversial. We assessed the prevalence of subclinical atherosclerosis in healthy middle-aged individuals by 4 non-invasive modalities. In 277 randomly selected males (n = 121) and females (n = 156), aged 50 or 60 years, without known cardiovascular disease or diabetes, intima-media thickness/presence of carotid plaques by ultrasound; coronary artery calcification (CAC) by non-contrast enhanced cardiac CT; occurrence of peripheral artery disease (PAD) by ankle brachial index (ABI), and vascular leakage by urine albumin creatinine ratio (ACR), were evaluated. Traditional risk factors were obtained and HeartScore was calculated. A total of 56 % had morphological signs of atherosclerosis in one of the vascular territories; 41 % had CAC and 31 % a carotid plaque. Among individuals with atherosclerosis, 28 % had lesions in both vascular territories. Subclinical atherosclerosis was significantly more frequent in older males. Signs of PAD and microalbuminuria were very uncommon and detected in only 1 % of the entire population. No association was found between morphological signs of subclinical atherosclerosis and ABI or ACR. More than half of randomly selected apparently healthy middle aged individuals had subclinical atherosclerosis located in the coronary or carotid arteries.

Prevention of atrial fibrillation in patients with aortic valve stenosis with candesartan treatment after aortic valve replacement.

BACKGROUND: Accumulating data has suggested that treatment with Angiotensin-II receptor antagonists can prevent the new onset of atrial fibrillation (AF). The aim of this study was to evaluate whether treatment with candesartan on top of conventional treatment could prevent new onset AF in patients with aortic valve stenosis (AS) after aortic valve replacement. METHODS AND RESULTS: The study was a single centre, consecutive; investigator initiated study using a prospective randomised blinded endpoint design. 91 patients with severe AS without known AF scheduled for aortic valve replacement (AVR) were randomised to candesartan 32 mg once daily on top of conventional treatment or conventional therapy immediately after AVR. Patients were examined with ECG 3, 6, 9 and 12 months after surgery, and Holter-ECG analysis after 3 and 12 months. Primary endpoint was episode of AF with a duration exceeding 30s, on the ECG or Holter-ECG and/or patients hospitalised due to AF. 14 patients developed new onset AF during follow up. AF-free survival was significantly higher (94% vs 74%, p=0.02) in patients treated with candesartan. CONCLUSION: In patients with symptomatic severe AS undergoing AVR, treatment with candesartan may prevent the new onset of atrial fibrillation.

Global strain in severe aortic valve stenosis: relation to clinical outcome after aortic valve replacement.

BACKGROUND: Global longitudinal systolic strain (GLS) is often reduced in aortic stenosis despite normal ejection fraction. The importance of reduced preoperative GLS on long-term outcome after aortic valve replacement is unknown. METHODS AND RESULTS: A total of 125 patients with severe aortic stenosis and ejection fraction >40% scheduled for aortic valve replacement were evaluated preoperatively and divided into 4 groups according to GLS quartiles. Patients were followed up for 4 years. The primary end points were major adverse cardiac events (MACEs) defined as cardiovascular mortality and cardiac hospitalization because of worsening of heart failure; the secondary end point was cardiovascular mortality. MACE and cardiac mortality were significantly increased in patients with lower GLS. Estimated 5-year MACE was increased: first quartile 19% (n=6) / second quartile 20% (n=6) / third quartile 35% (n=11) / fourth quartile 49% (n=15); P=0.04. Patients with increased age, left ventricular hypertrophy, and left atrial dilatation were at increased risk. In Cox regression analysis, after correcting for standard risk factors and ejection fraction, GLS was found to be significantly associated with cardiac morbidity and mortality. In a stepwise Cox model with forward selection, GLS was the sole independent predictor: hazard ratio=1.13 (95% confidence interval, 1.02-1.25), P=0.04. Comparing the overall log likelihood χ(2) of the predictive power of the multivariable model containing GLS was statistically superior to models based on EuroScore, history with ischemic heart disease, and ejection fraction. CONCLUSIONS: In patients with symptomatic severe aortic stenosis undergoing aortic valve replacement, reduced GLS provides important prognostic information beyond standard risk factors.

Plasma fibulin-1 is linked to restrictive filling of the left ventricle and to mortality in patients with aortic valve stenosis.

BACKGROUND: Plasma fibulin-1 levels have been associated with N-terminal pro-B-type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. METHODS AND RESULTS: One hundred twenty-five patients with severe aortic stenosis who were scheduled for aortic valve replacement (AVR) were evaluated with preoperative echocardiography and their plasma fibulin-1 levels were determined with ELISA. The cohort was followed for a median of 4 years after AVR. Increased restrictive left ventricular (LV) filling pattern was observed with increased plasma fibulin-1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin-1 tertile groups, P=0.004). Likewise, reduced longitudinal systolic LV function (6.6 ± 1.1 versus 6.1 ± 1.3 versus 5.7 ± 1.5 cm/s, P=0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin-1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13 ± 4 versus 15 ± 5 versus 16 ± 6 in the fibulin-1 tertile groups, P=0.04). CONCLUSIONS: In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin-1 is associated with restrictive filling of the LV, decreased longitudinal systolic function of the LV, and increased LV filling pressures. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrial.gov with Identifier: NCT00294775.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes. METHODS: Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured. RESULTS: The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia. CONCLUSIONS: Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

Noninvasive assessment of filling pressure and left atrial pressure overload in severe aortic valve stenosis: relation to ventricular remodeling and clinical outcome after aortic valve replacement.

OBJECTIVE: One of the hemodynamic consequences of aortic valve stenosis is pressure overload leading to left atrial dilatation. Left atrial size is a known risk factor providing prognostic information in several cardiac conditions. It is not known if this is also the case in patients with aortic valve stenosis after aortic valve replacement. METHODS: A total of 119 patients with severe aortic valve stenosis scheduled for aortic valve replacement were evaluated preoperatively and divided into 2 groups according to left atrial volume index (≥40 mL/m(2)). Echocardiography was repeated 12 months after surgery. Patients were followed up for 24 months. The primary end point was the composite end point overall mortality and hospitalization due to congestive heart failure. RESULTS: Preoperative left atrial dilation was associated with left ventricular hypertrophy and increased filling pressure. Preoperative left atrial volume index was associated with persistent abnormalities in left ventricular filling pressure and left ventricular mass index at 1 year after surgery. Event-free survival in patients with left atrial volume index of 40 mL/m(2) or more at 1 year was 71% compared with 88% in patients with left atrial volume index less than 40 mL/m(2) (P = .002). Patients with preoperative increased E/e' ratio and left ventricular hypertrophy were at increased risk. In Cox regression analysis after correcting for standard risk factors, left atrial volume index was found to be the only significant predictor of the composite end point. In a forward conditional multivariable model, left atrial volume index 40 mL/m(2) or greater (hazard ratio, 4.2 [1.6-10.7]; P = .003) remained an independent predictor, whereas E/e' was borderline significant (P = .06). CONCLUSIONS: In patients with symptomatic severe aortic valve stenosis undergoing aortic valve replacement, left atrial volume provides important prognostic information beyond standard risk factors.

Effect of candesartan treatment on left ventricular remodeling after aortic valve replacement for aortic stenosis.

In hypertension, angiotensin receptor blockers can augment regression of left ventricular (LV) hypertrophy. It is not known whether this also is the case after aortic valve replacement (AVR) for severe aortic stenosis (AS). To test the hypothesis that treatment with candesartan in addition to conventional treatment is able to augment LV and left atrial (LA) reverse remodeling in patients with AS undergoing AVR, we studied 114 patients scheduled for AVR. Patients were randomized to treatment with candesartan 32 mg 1 time/day or conventional therapy immediately after AVR. Patients were followed with echocardiographic evaluations 3, 6, and 12 months after surgery. Primary end point was change in LV mass index. At baseline and during follow-up no differences in systolic, diastolic, and pulse pressures were seen between groups. Baseline LV mass index was 134 +/- 41 g/m(2) with no difference between groups. Mean decrease in LV mass index in the control group was 12 +/- 28 g/m(2) compared to 30 +/- 40 g/m(2) in the candesartan group (p = 0.015) during follow-up. After 12 months LV mass index was significantly lower in the candesartan group (103 +/- 29 vs 119 +/- 31 g/m(2), p = 0.01). In addition, the candesartan group had greater improvement in longitudinal LV systolic function assessed by tissue Doppler S' wave (0.6 +/- 0.1-cm/s increase in control group vs 1.4 +/- 0.1 cm/s in candesartan group, p = 0.01, p for trend = 0.02) and a decrease in LA volume (p for trend = 0.01). Treatment had no effect on diastolic E/e' ratio or B-type natriuretic peptide. In conclusion, angiotensin receptor blockade with candesartan after AVR in patients with AS is associated with augmented reverse LV and LA remodeling compared to conventional management.