Jordi S. Dahl

Left Ventricular Diastolic Function in Type 2 Diabetes Mellitus Prevalence and Association With Myocardial and Vascular Disease

Background—Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results—A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction (P=0.002) or LA volume index ≤32 mL/m2 (P<0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score (P<0.001) and valvulo-arterial impedance (P=0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score (P<0.001) was a predictor of LA dilation. Conclusions—Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration—The trial has been registered at www.clinicaltrial.gov with Identifier: NCT00298844.Background— Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results— A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction ( P =0.002) or LA volume index ≤32 mL/m2 ( P <0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score ( P <0.001) and valvulo-arterial impedance ( P =0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score ( P <0.001) was a predictor of LA dilation. Conclusions— Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration— The trial has been registered at www.clinicaltrial.gov with Identifier: [NCT00298844][1]. Received December 13, 2008; accepted October 20, 2009. # CLINICAL PERSPECTIVE {#article-title-2} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00298844&atom=%2Fcirccvim%2F3%2F1%2F24.atom

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 χ2 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. Clinical Trial Registration— URL: [http://www.clinicaltrials.gov][1]. Unique identifier: [NCT00294775][2]. [1]: http://www.clinicaltrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00294775&atom=%2Fcirccvim%2F5%2F5%2F613.atomBackground—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 &khgr;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. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775.

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.

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

BackgroundCardiovascular 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.MethodsType 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.ResultsThe 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.ConclusionsIncreased 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.Trial registration numberat http://www.clinicaltrial.gov: NCT00298844

Development of paradoxical low-flow, low-gradient severe aortic stenosis

Objective Among patients with severe aortic stenosis (sAS) and preserved LVEF, those with low-flow, low-gradient sAS (LFLG-sAS) have an adverse prognosis. It has been proposed that LFLG-sAS represents an end-stage point of sAS, but longitudinal information has not been described. The aim was to determine whether LFLG-sAS represents an end-stage consequence of normal-flow, high-gradient sAS (NFHG-sAS) or a different entity. Methods From our transthoracic echocardiogram (TTE) database, we identified patients with sAS (aortic valve area <1 cm2) and preserved LVEF (≥50%), and from these, patients with LFLG-sAS (stroke volume index <35 mL/m2 and mean transvalvular gradient <40 mm Hg) who had ≥1 additional TTE within five years prior to the index TTE. Patients were age/sex/date matched 2:1 with patients with NFHG-sAS and normal-flow, low-gradient (NFLG)-sAS who also had ≥1 TTE. Included were 1203 TTEs (383 index studies and 820 preceding studies). Results In 78 patients with LFLG-sAS, an HG stage preceded the index TTE in only 4 (5%). During the five years preceding the index TTE, patients with LFLG-sAS developed increasing relative wall thickness (0.42 to 0.49; p<0.001) without change in LV mass index. Patients with NFHG-sAS had a marked increase in LV mass index (87 to 115 g/m2; p<0.001). Patients with LFLG-sAS demonstrated the greatest reduction in LV end-diastolic diameters (−3 vs −1 for NFLG-sAS vs +2 mm for NFHG-sAS; p=0.001), deceleration time (−55 vs −3 vs +3 ms, respectively; p<0.01) and LVEF (−4 vs 0 vs 0%, respectively; p=0.01). Conclusions LFLG-sAS is a distinct presentation of sAS preceded by a unique remodelling pathway and is uncommonly preceded by an HG stage.

Effect of Left Ventricular Ejection Fraction on Postoperative Outcome in Patients With Severe Aortic Stenosis Undergoing Aortic Valve Replacement

Background—In asymptomatic patients with severe aortic stenosis, guidelines recommend left ventricular ejection fraction (LVEF) of <50% as the threshold for referral for aortic valve replacement. We investigated the importance of LVEF on long-term outcome after aortic valve replacement in symptomatic and asymptomatic patients with severe aortic stenosis. Methods and Results—We retrospectively identified 2017 patients with severe aortic stenosis (aortic valve area<1 cm2, mean gradient≥40 mm Hg, or indexed aortic valve area<0.6 cm2/m2) who underwent surgical aortic valve replacement from January 1995 to June 2009. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 [15%] patients, 50%–59% in 331 [17%], 60%–69% in 908 [45%], and ≥70% in 478 [24%]). During follow-up of 5.3±4.4 years, 1056 (52%) patients died. A decrease in mortality was observed with increasing LVEF, P<0.0001; 5-year mortality estimates (95% confidence interval) were 0.41 (0.35–0.47), LVEF<50%; 0.35 (0.29–0.41), LVEF 50% to 59%; 0.26 (0.23–0.29), LVEF 60% to 69%; and 0.22 (0.18–0.26), LVEF≥70%. Compared with patients with LVEF≥60%, patients with LVEF 50% to 59% had increased mortality (hazard ratio [HR], 1.58; P<0.001), with similar risk increase in both symptomatic (HR, 1.56; P<0.001) and asymptomatic patients (HR, 1.58; P=0.006). Correcting for risk factors, LV mass index, aortic valve area, and stroke volume index, LVEF was independently predictive of mortality (HR, 0.88 per 10%; P<0.001). When this analysis was repeated in the subset of 1333 patients without history of coronary artery disease, LVEF remained associated with mortality (HR, 0.90 per 10%; P=0.009). Conclusions—LVEF is a powerful predictor of outcome in patients with severe aortic stenosis undergoing aortic valve replacement, independent of the presence of valve-related symptoms.

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

Incidence of cancer in patients with chronic heart failure: a long-term follow-up study

With improvement in survival of chronic heart failure (HF), the clinical importance of co‐morbidity is increasing. The aim of this study was to assess the incidence and risk of cancer and all‐cause mortality in a large Danish HF cohort.

Aortic Valve Stenosis and Atrial Fibrillation Influence Plasma Fibulin-1 Levels in Patients Treated with Coronary Bypass Surgery

Objectives: Aortic valve stenosis (AS) causes cardiac fibrosis and left ventricular hypertrophy, and over time heart failure can occur. To date, a reliable marker to predict progression of AS or the development of heart failure is still lacking. In this study, we addressed the hypothesis that fibulin-1 levels reflect myocardial fibrosis. Methods: Patients undergoing heart surgery at the Odense University were investigated. By 2012 data on outcome were obtained. Results: In 293 patients, plasma fibulin-1 levels were measured. Patients with AS or atrial fibrillation (AF) had significantly higher fibulin-1 levels compared to those with coronary artery disease only (p = 0.005). Patients with preoperatively diagnosed chronic AF had significantly higher levels of fibulin-1 compared to those without (p = 0.004). Plasma fibulin-1 levels showed no relationship to echocardiographic size and had no impact on outcome, death or other adverse events. Conclusion: This study shows that plasma fibulin-1 levels are increased in patients with AS and AF compared to patients with coronary disease only. Our study results suggest fibulin-1, a vascular extracellular matrix (ECM) protein, as a marker of ECM turnover perhaps due to the increased myocardial stretch that is related to pressure overload.

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.