Left Ventricular Reverse Remodeling in Recent Onset Idiopathic Dilated Cardiomyopathy Using Contemporary Echo Techniques.

BACKGROUND: Early identification of patients with a likelihood of cardiac improvement has important implications for management strategies. OBJECTIVES: To evaluate whether tissue Doppler imaging (TDI) and two-dimensional (2D) strain measures may predict left ventricular (LV) improvement in patients with recent onset dilated cardiomyopathy (ROCM). METHODS: Clinical and comprehensive echo were performed at baseline and at 6 months. Patients who achieved an increase of ≥ 10 LV ejection fraction (LVEF) units and LV reverse remodeling (LVRR) (group 1) and those who improved beyond the device threshold achieving LVEF of ≥ 0.40 (group 2) were compared to patients who did not improve to this level. RESULTS: Among 37 patients with ROCM (mean age 56.3 ± 12.9 years and LVEF 29.1 ± 7.0%), 48% achieved LVEF ≥ 0.40 and 37.8% demonstrated LVRR. Patients with LVEF improvement ≥ 40% presented at diagnosis with higher LVEF (P = 0.006), smaller LV end-diastolic diameter (LVEDd) (P = 0.04), higher E' septal (P = 0.02), lower E/E' ratio (P = 0.02), increased circumferential strain (P = 0.04), and apical rotation (P = 0.009). Apical rotation and LVEDd were found to be independent predictors of LVRR. End-systolic LV volume was a significant predictor of LVEF improvement (≥ 40%). CONCLUSIONS: Nearly half of the patients with ROCM demonstrated cardiac function improvement beyond the device threshold by 6 months. Apical rotation was introduced in our study as 2D strain prognostic parameter and found to be an independent predictor of LVRR. LV size and volume were predictors of LV improvement.

Autoantibodies to oxidized low-density lipoprotein in patients with aortic regurgitation: association with aortic diameter size.

BACKGROUND: Aortic regurgitation (AR) is a condition associated with volume overload, causing left-ventricular (LV) remodeling, eccentric LV hypertrophy and eventually heart failure. LV remodeling associated with AR is regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress. Since anti-oxidized low-density lipoprotein (LDL) antibodies (Abs) are a measurable marker of oxidative stress, we hypothesized that an increased level of circulating oxidized LDL (oxLDL) Abs may be related to remodeling of the left ventricle in patients with significant AR. METHODS: We assessed IgG anti-oxLDL Abs in 31 patients with significant AR and compared them to 30 patients with similar risk factors and no valvular disease. Abs to oxLDL were determined by ELISA. RESULTS: The 2 groups had similar clinical characteristics. There was no difference between patients with AR and patients with no AR in the level of anti-oxLDL Abs. However, in all patients and controls, anti-oxLDL Abs correlated positively with the diameter of the ascending aorta (AA; r = 0.32, p = 0.016) and the level of oxLDL Abs was significantly higher in patients with an AA diameter ≥39 mm. On multivariate analysis, only white blood cell count and AA diameter were related to anti-oxLDL Abs in all patients. CONCLUSIONS: We did not find a difference in the level of anti-oxLDL Abs between patients with AR and controls; however, there was a strong correlation between anti-oxLDL Abs and AA diameter.

Circulating progenitor and apoptotic progenitor cells in patients with aortic regurgitation.

BACKGROUND: Endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury. Reduced numbers of EPCs are related to endothelial dysfunction and adverse clinical events, suggesting that endothelial injury in the absence of sufficient repair by circulating EPCs promotes the progression of vascular disease or valvular disorder. The aim of the present study was to assess the number and role of EPCs in patients with aortic valve regurgitation (AR). METHODS AND RESULTS: We assessed the number of EPCs and apoptotic EPCs in 31 patients with significant AR and compared them with 30 patients who had similar risk factors and no valvular disease. The numbers of EPCs and apoptotic EPCs were assessed by flow cytometry. The 2 groups had similar clinical characteristics. Patients with AR had fewer circulating EPCs and late apoptotic EPCs as compared with the control group (0.054 ± 0.03% vs. 0.079 ± 0.06%, P=0.039 and 0% (0-3.4%) vs. 5% (0-14%), P=0.03, respectively). In patients with AR, circulating EPCs correlated negatively with septal thickness (r=-0.47, P=0.01), whereas late apoptotic EPCs had a negative correlation with left ventricular end-systolic diameter (r=-0.57, P=0.01). CONCLUSIONS: Patients with AR have fewer EPCs and late apoptotic EPCs. These data suggest an impaired valvular endothelial cell regenerative process in patients with AR.

Low circulating monocyte count is associated with severe aortic valve stenosis.

BACKGROUND: The pathophysiology of aortic stenosis (AS) involves inflammatory features including infiltration of the aortic valve (AV) by activated macrophages and T cells, deposition of lipids, and heterotopic calcification. OBJECTIVES: To evaluate the correlation between white blood cell (WBC) differential count and the occurrence and progression of AS. METHODS: We identified in our institutional registry 150 patients with AS who underwent two repeated echo studies at least 6 months apart. We evaluated the association between the average of repeated WBC differential counts sampled during the previous 3 years and subsequent echocardiographic AS indices. RESULTS: There was no significant difference in total WBC, lymphocyte or eosinophil count among mild, moderate or severe AS groups. There was a progressive decrease in monocyte count with increasing AS severity (P = 0.046), more prominent when comparing the mild and severe groups. There was a negative correlation between AV peak velocity or peak or mean gradient and monocyte count in the entire group (r = -0.31, -0.24, and -0.25 respectively, all P < 0.01). Similar partial correlations controlling for age, gender, hypertension, smoking, dyslipidemia and ejection fraction remained significant. The median changes over time in peak velocity and peak gradients in AS patients were 0.44 (0-1.3) m/sec/ year and 12 (0-39) mmHg/year, respectively. There was no correlation between any of the WBC differential counts and the change in peak velocity or peak gradient per year. CONCLUSIONS: Severe AS is associated with decreased total monocyte count. These findings may provide further clues to the mechanism underlying the pathogenesis of aortic stenosis.

Elevated Serum Levels of IgG4 in Patients with Heart Failure with Reduced Ejection Fraction: A Prospective Controlled Study.

(1) Background: Immunoglobulin gamma subclass 4 (IgG4) is a serum protein belonging to the immunoglobulin superfamily. It has a central role in certain immune-mediated conditions defined as IgG4-related disease. There is a paucity of data regarding the potential association of IgG4 and cardiovascular diseases. Our aim is to study the serum levels of IgG4 in patients with ischemic and non-ischemic dilated cardiomyopathy (DCM). (2) Methods: patients with ischemic and non-ischemic DCM were included in this study. Non-ischemic DCM was defined as a left ventricular ejection fraction (LVEF) < 40% without coronary artery disease (CAD). Ischemic DCM was defined as a LVEF < 40% and proven CAD. The serum concentrations of IgG4 were measured by turbidimetry. (3) Results: Overall 98 patients with cardiomyopathy had significantly higher levels of IgG4 compared with the control group (77.4 ± 64.0 vs. 50.3 ± 28.8 mg/dL, p < 0.01). Although there was no difference in the total IgG levels in patients with ischemic DCM, the serum concentrations of IgG4 were significantly higher than the corresponding values in the control group (89.8 ± 67.3 vs. 50.3 ± 28.8 mg/dL; interquartile ranges: 40.4−126.5 vs. 31.8−66.8 mg/dL, p < 0.01). This was altered by gender and smoking. (4) Conclusions: The patients with ischemic DCM had increased serum concentrations of IgG4. Future studies are warranted to explore the potential role of an IgG4-mediated process in patients with heart failure with reduced LVEF.

Residual alterations of cardiac and endothelial function in patients who recovered from Takotsubo cardiomyopathy.

INTRODUCTION: Takotsubo cardiomyopathy (TCM) is characterized by transient left ventricle dysfunction. HYPOTHESIS: A residual cardiac and endothelial dysfunction is present in patients who recovered from TCM. METHODS: In this single-center prospective study, patients with prior TCM were included and followed for 6.4 ± 1.6 years. All underwent comprehensive cardiac function assessment, including tissue Doppler imaging (TDI) and 2-dimensional strain (2DS) echocardiography at their first visit. The number of circulating endothelial progenitor cells and levels of proangiogenic vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) were measured. All measurements were compared with healthy controls. RESULTS: Forty-two women (age 58. ±8.6 years, LVEF 58.1 ± 6.1%) comprised the TCM group. Patients post-TCM had significantly lower early velocities E' (6 (5.0-8.0) vs. 9 (7.0-11.0) cm/s, p = .001) by TDI and higher E/E' ratio (p = .002), lower LV global average longitudinal strain (LGS) (-18.9 ± 3.5% vs. -21.7 ± 2.3%, p = .002) and RV LGS (-20.1 ± 3.9% vs. -23.4 ± 2.8%, p = .003) were evident. There was a trend toward a higher VEGF-R (p = .09) along with decreased VEGF/VEGF-R ratio representing inadequate VEGF production. In-hospital mortality was not reported and only two non-cardiac deaths occurred at long-term follow-up. CONCLUSIONS: Altered TDI and 2DS indices suggest residual biventricular myocardial injury in post-TCM patients with the apparent LV function recovery. Inappropriate production of VEGF and VEGF-R were observed, suggesting a possible underlying endothelial dysfunction in these patients.

Wild-type TTR amyloidosis among patients with unexplained heart failure and systolic LV dysfunction.

AIM: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) with preserved left ventricular ejection fraction (LVEF), typically presenting as restrictive cardiomyopathy. The potential co-existence of ATTR-CA with systolic heart failure has not been studied. The aim of this study is to describe the prevalence of ATTR-CA and its clinical characteristics in HF patients with reduced LVEF. METHODS: Patients with an unexplained cause of LV systolic dysfunction were screened for ATTR-CA by a 99mTc-PYP planar scintigraphy. Patients in whom presence of ≥ 2 uptake was confirmed by SPECT imaging were included. Their clinical, laboratory and echocardiographic data were collected. RESULTS: Out of 75 patients (mean age 65±12 years, LVEF 35.8±7.9%) included in this study, 7 (9.3%) patients (mean age 75±6 years, LVEF 32.0±8.3%) had ATTR-CA. Patients with ATTR-CA were more symptomatic at diagnosis (NYHA FC 3-4 (86% vs 35% (p = 0.03)) and had a more severe clinical course evident by recurrent hospitalizations for HF, and a need for intravenous diuretic treatment (p = 0.04 and p<0.01, respectively) at follow-up, compared with patients with no ATTR-CA. Patients with ATTR-CA had similar LVEF but a clear trend for larger LV mass index (157.1±60.6 g/m2 vs. 121.0±39.5 g/m2, p = 0.07) and a larger proportions of ATTR-CA patients had IVS thickness >13 mm (57.1% vs 13.1%, p = 0.02) as compared to HF patients with no ATTR-CA. CONCLUSION: In our study, a meaningful percentage of patients with unexplained LV dysfunction had a co-existing ATTR-CA indicating that the clinical heterogeneity of ATTR-CA is much broader than previously thought.

The Association Between Longitudinal Strain at Rest and Stress and Outcome in Asymptomatic Patients With Moderate and Severe Aortic Stenosis.

BACKGROUND: Calcific aortic stenosis (AS) is a progressive disease, and once moderate AS is present, the likelihood of symptom onset within 5 years is significant. The aim of this study was to determine the incremental value of global longitudinal strain (GLS) and basal longitudinal strain (BLS) at rest and during exercise on outcomes among asymptomatic patients' with moderate and severe AS. METHODS: Seventy-five patients with isolated, asymptomatic AS and preserved left ventricular function were retrospectively enrolled and underwent symptom-limited exercise echocardiography. Clinical and echocardiographic data, including GLS and BLS at rest and during exercise, were assessed. Occurrence of AS-related cardiovascular events was recorded. RESULTS: The mean age was 71 ± 10 years, and 63% were men. The mean aortic valve gradient was 30 ± 11 mm Hg, and the mean aortic valve area was 0.98 ± 0.21 cm2. Resting GLS and BLS were -16.5 ± 4% and -16.9 ± 3.6%, respectively. Exercise stress test results were positive in 27 patients (36%). Mean exercise GLS was -17.8 ± 3.5%, and mean exercise BLS was -17.9 ± 4%. During mean follow-up of 34.5 ± 3.5 months, cardiovascular events were observed in 45 patients. In multivariate analysis, aortic valve mean gradient (HR, 1.073; 95% CI, 1.032-1.115; P < .001) and peak exercise BLS (HR, 1.177; 95% CI, 1.07-1.295; P = .001) were associated with cardiac events during follow-up. CONCLUSIONS: Reduced exercise BLS is associated with future cardiovascular events in patients' with asymptomatic AS, independently of clinical factors and conventional echocardiographic parameters. Detection of postexercise myocardial dysfunction in patients with asymptomatic AS with preserved left ventricular function can aid in risk assessment of these patients.

The impact of left ventricular ejection fraction on heart failure patients with pulmonary hypertension.

BACKGROUND: The most common cause of pulmonary hypertension (PH) in developed countries is left heart disease (LHD, group 2 PH). The development of PH in heart failure (HF) patients is indicative of worse outcomes. OBJECTIVE: The aim of this study was to evaluate the long term outcomes of HF patients with PH in a national long-term registry. METHODS: Study included 9 cardiology centers across Israel between 01/2013-01/2015, with a 12-month clinical follow-up and 24-month mortality follow-up. Patients were age ≥18 years old with HF and pre-inclusion PH due to left heart disease determined by echocardiography [estimated systolic pulmonary arterial pressure (SPAP) ≥ 50 mmHg]. Patients were categorized into 3 groups: HF with reduced (HFrEF < 40%), mid-range (HFmrEF 40-49%), and preserved (HFpEF ≥ 50%) ejection fraction. RESULTS: The registry included 372 patients, with high prevalence of cardiovascular risk factors. Median HF duration was 4 years and 65% were in severe HF New York Heart Association (NYHA) classification ≥3. Mean systolic pulmonary artery pressure (SPAP) was 62 ± 11 mmHg. During 2-years of follow-up, 54 patients (15%) died. Univariable predictors of mortality included NYHA grade 3-4, chronic renal failure, and SPAP ≥ 65 mmHg. Severe PH was associated with mortality in HFpEF, but not HFmrEF or HFrEF, and remained significant after multivariable adjustment with an adjusted hazard ratio of 2.99, (95%CI 1.29-6.91, p = 0.010). CONCLUSIONS: The combination of HFpEF with severe PH was independently associated with increased mortality. Currently, HFpEF patients are included with group 2 PH patients. Defining HFpEF with severe PH as a sub-class may be more appropriate, as these patients are at increased risk and deserve special consideration.

Angiogenic Imbalance and Residual Myocardial Injury in Recovered Peripartum Cardiomyopathy Patients.

BACKGROUND: Recent studies suggest that angiogenic imbalance during pregnancy may lead to acute peripartum cardiomyopathy (PPCM). We propose that angiogenic imbalance and residual cardiac dysfunction may exist even after recovery from PPCM. METHODS AND RESULTS: Twenty-nine women at least 12 months after presentation with PPCM, who exhibited recovery of left ventricular (LV) ejection fraction (≥50%), were included in the study (mean age 35±6 years, LV ejection fraction 61.0±3.9%). The number of circulating endothelial progenitor cells (EPCs) and plasma levels of proangiogenic vascular endothelial growth factor and of soluble vascular endothelial growth factor receptor Flt1 (sFlt1) were measured. All patients underwent comprehensive cardiac function assessment, including tissue Doppler imaging and 2-dimensional (2D) strain echocardiography. All measurements were compared with healthy controls. Patients with a history of PPCM have significantly higher sFlt1 concentrations (median [25th-75th percentile]; 149.57, [63.14-177.89] versus 20.29, [15.00-53.89] pg/mL, P<0.001) and significantly decreased vascular endothelial growth factor/sFlt1 ratio (P=0.012) compared with controls, with a trend toward lower concentration of circulating CD34+/KDR+ levels. In addition, patients with PPCM had lower early velocities E' septal (9.9±2.1 versus 11.0±1.5 cm/s, P=0.02), with a significantly lower systolic velocity S' septal (7.6±1.2 versus 8.5±1.2 cm/s, P=0.003) by tissue Doppler imaging. Significantly lower LV global longitudinal (-19.1±3.3 versus -22.7±2.2%, P<0.001) and apical circumferential 2D strain (-16.6±4.9 versus -21.2±7.9, P=0.02) were present in patients with PPCM compared with controls. CONCLUSIONS: Higher concentration of sFlt1 with concomitant decreased circulating endothelial progenitor cell levels along with inappropriate attenuated vascular endothelial growth factor levels may imply an angiogenic imbalance that exists even after recovery and may thus predispose to PPCM. In addition, tissue Doppler imaging and 2D strain were able to identify residual myocardial injury in post-PPCM women with apparent recovery of LV systolic function. Both angiogenic imbalance and residual myocardial injury may play an important role in the recurrence of LV dysfunction during subsequent pregnancies.

Thoracic aortic atherosclerosis in patients with aortic regurgitation.

OBJECTIVE: Hemodynamic forces are potential determinants of aortic atherosclerosis. Aortic regurgitation (AR) alters the flow pattern in the aorta. However, the association between AR and aortic atherosclerosis is not well known. METHODS: We assessed the presence, extent and distribution of atherosclerotic lesions in the aorta of 42 patients with chronic AR and compared them to 40 patients with similar risk factor profile for atherosclerosis and no valvular disease. RESULTS: There was no difference in the extent of atheroma in the ascending aorta and aortic arch between patients with and without AR. Descending aortic atheroma was evident in 25 patients with AR (60%) and 12 patients without AR (30%, p=0.01). AR was found to be the only predicting factor for the presence of aortic atherosclerosis in the descending aorta (odds ratio 4.1; 95% CI 1.2-14.3, p=0.03). CONCLUSIONS: There is an increased prevalence of descending aortic atherosclerosis in patients with significant AR.

Microinflammation in patients with Crohn's disease in clinical remission.

BACKGROUND AND AIMS: It is not clear whether Crohn's disease patients in clinical remission (Crohn's disease activity index<150) display normal concentrations of inflammation sensitive biomarkers. Our goal in this work was to explore the intensity of the microinflammatory response in a group of Crohn's disease patients in clinical remission. METHODS: High sensitivity C-reactive protein, quantitative fibrinogen, erythrocyte sedimentation rate as well as platelet and leukocyte counts were examined in a group of 76 patients with Crohn's disease in remission and in 228 matched controls. RESULTS: Crohn's disease patients in clinical remission displayed a statistically significant (p<0.001) elevated concentration of hs-CRP (4.83±3.8 mg/l) compared to controls (1.05±2.9 mg/l). All other bio-markers were also significantly higher in Crohn's disease patients in remission compared to controls. Similar results were obtained in a subgroup of Crohn's disease patients with very low disease activity - CDAI<75. CONCLUSIONS: Clinical remission is not equivalent to biochemical remission raising a question concerning the true definition of remission in Crohn's disease.

Correlated expression of high-sensitivity C-reactive protein in relation to disease activity in inflammatory bowel disease: lack of differences between Crohn's disease and ulcerative colitis.

BACKGROUND/AIMS: As opposed to regular C-reactive protein (CRP) assays, the introduction of high-sensitivity ones has enabled us to detect low grade inflammation in patients with inflammatory bowel disease (IBD). We addressed the subject of the degree of correlation between the concentration of high-sensitivity CRP (hs-CRP) and the inflammatory IBD activity score. METHODS: Included were 90 patients with Crohn's disease (CD), 70 with ulcerative colitis (UC) and 160 controls. Disease activity was determined using CD activity index (CDAI) for CD and Mayo score for UC. The Dade Boering BNII Nephelometer was used to determine the hs-CRP concentrations. RESULTS: The coefficient of correlation between hs-CRP and the disease activity score was similar for both UC (0.26) and CD (0.36). CONCLUSIONS: These findings are relevant for therapeutic intervention in which a greater absolute reduction in the hs-CRP concentration in CD patients (who generally present higher CRP concentrations than those found in UC) might be interpreted as a better response compared to the same absolute reduction in UC patients. This information is needed for clinicians using the hs-CRP assay to estimate IBD disease activity in daily practice.

Inflammation-related erythrocyte aggregation in patients with inflammatory bowel disease.

Chronic inflammation is associated with increased erythrocyte adhesiveness/aggregation. This might have deleterious effects on the microcirculatory flow and tissue oxygenation. We aimed to determine the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of individuals with inflammatory bowel disease (IBD). Fifty-two patients (24 women and 28 men) with ulcerative colitis (UC) at a mean age of 44.0+/-16.8 years and 96 patients (44 women and 52 men) with Crohn's disease (CD) at a mean age of 38.0+/-15.5 years, with various degrees of disease activity, were matched to normal controls. A simple slide test and image analysis were used to determine the degree of erythrocyte adhesiveness/aggregation. CD activity index (CDAI) was determined in patients with CD, while clinical colitis activity index was applied for patients with UC. A significant (P < 0.0005) increment in the degree of erythrocyte adhesiveness/aggregation was noted in both groups of IBD patients compared with matched control groups. This increment was evident even in individuals with a low index of disease activity and during remission. The highly significant correlation with the concentrations of fibrinogen suggests that the degree of erythrocyte adhesiveness/aggregation is an inflammation-related phenomenon. An enhanced state of erythrocyte adhesiveness/aggregation was noted in the peripheral blood of patients with IBD. This might have a deleterious effect on intestinal microcirculatory flow and tissue oxygenation.