Marta Hlawaty

Effect of aortic valve stenosis on haemostasis is independent from vascular atherosclerotic burden

OBJECTIVE The aim of study was to assess whether activation of blood coagulation and platelets is enhanced in aortic stenosis (AS) and if so, to determine factors that might modulate these processes. PATIENTS/METHODS Seventy-five patients with AS (48 males, 27 females, aged 65+/-10 years) were enrolled in the study. A control group comprised 75 age- and sex-matched subjects. We determined markers of thrombin generation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2]), platelet activation (soluble CD40 ligand [sCD40L], beta-thromboglobulin [beta-TG], P-selectin) in peripheral blood plasma. The extent of atherosclerosis in the carotid and coronary arteries was assessed as a potential confounding factor. RESULTS Mean concentrations of thrombin and platelet markers were higher approximately two-fold in the AS group than in controls (p<0.005 for all comparisons). Maximal gradient was positively associated with TAT (r=0.61, p<0.001), F1+2 (r=0.60, p<0.001), sCD40L (r=0.52, p<0.01) and beta-TG (r=0.70, p<0.001). Aortic valve area (AVA) negatively associated only with one platelet marker, beta-TG (r=-0.30, p<0.05). The presence of concomitant atherosclerotic plaque in the carotid (in 65% of patients) or coronary arteries (in 43% of patients) did not influence thrombin generation and platelet activation in patients with AS. CONCLUSIONS AS predisposes to prothrombotic state. Maximal gradient as an index of turbulent flow associated with activation of coagulation and platelets. In contrast, the small aortic valve area was not closely related to these parameters.

Increased thrombin generation and platelet activation are associated with deficiency in high molecular weight multimers of von Willebrand factor in patients with moderate-to-severe aortic stenosis

Background High molecular weight von Willebrand factor (vWF) multimers (HMWM) are often deficient in patients with severe aortic stenosis (AS) owing to shear stress-enhanced proteolysis of vWF. It has also been reported that AS is associated with increased activation of blood coagulation. Objective To investigate whether patients with AS with a deficiency in vWF HMWM have enhanced thrombin generation and platelet activation in vivo. Design Based on the analysis of vWF HMWM performed using immunolocalisation, 11 subjects with vWF HMWM deficiency (low %HMWM group) were identified and compared with 42 patients with AS with a normal distribution of vWF HMWM (normal %HMWM group). Plasma thrombin markers thrombin-antithrombin complexes (TAT) and prothrombin factor 1+2 (F1.2) plus platelet activation markers soluble CD40 ligand (sCD40L), β-thromboglobulin and P-selectin were also measured. Patients 48 consecutive patients with severe AS and five with moderate AS, free of angiographically-proven coronary artery disease and clinically overt bleeding, were studied. Results Patients in the low %HMWM group had 34.8% higher maximal transvalvular gradient (p=0.0003) and 44.8% higher mean gradient (p=0.0002) than those in the normal %HMWM group. Thrombin formation was enhanced in the low %HMWM group (F1.2, 284.5±63.7 vs 216.9±62.5 pmol/l, p=0.004; thrombin-antithrombin, 4.89±1.3 vs 4.06±0.9 μg/l, p=0.02) and both markers showed inverse correlations with the percentage of vWF HMWM (r=−0.59, p=0.002; r=−0.42, p=0.03, respectively). In the low %HMWM group sCD40L (279.4±60.7 vs 221.4±41.7 pmol/l, p=0.003) and β-thromboglobulin (73.1±9.2 vs 64.5±8.5 IU/ml, p=0.04), but not P-selectin, were also higher than in the remaining patients with AS. Conclusion Patients with advanced AS deficient in vWF HMWM are characterised by enhanced thrombin formation and platelet activation. This observation indicates the ambivalent impact of high shear stress in AS on haemostasis and might help explain two aspects of AS—Heyde syndrome and increased risk of thromboembolism.

Fibrin presence within aortic valves in patients with aortic stenosis: Association with in vivo thrombin generation and fibrin clot properties

A role of coagulation in the pathogenesis of aortic stenosis (AS) is unknown. The aim of this study was to investigate the fibrin (Fn) presence and its determinants in calcified stenotic aortic valve leaflets. Twenty-one patients with dominant AS and 17 well-matched patients with dominant aortic insufficiency (AI) undergoing aortic valve replacement were studied. Immunofluorescence analysis was performed on decalcified leaflets using antibodies against human Fn and tissue factor (TF). Fn-positive (41.4%) and TF-positive (25.3%) areas were increased in AS valves compared with AI valves (7.9% and 5.9%, respectively, both p<0.001). Patients with AS had elevated plasma D-dimer (236.4 ± 28 ng/ml, p=0.002) and prothrombin fragment 1+2 (F1.2) (261.7 ± 27.1 pM, p=0.005) compared to AI subjects (142.8 ± 10 ng/ml and 131.2 ± 1.3 pM, respectively). In AS patients Fn-positive areas correlated with TF-positive areas (r=0.68, p=0.0005), D-dimer (r=0.45, p=0.018), F1.2 (r=0.64, p=0.002), the time required for plasma fibrin clot formation (r=0.44, p=0.015) and maximum absorbance of fibrin clots (r=-0.38, p<0.0001), but not with clot permeability or lysis time. Thickness of Fn layer within AS valves was associated with maximum transvalvular gradient (r =0.41, p=0.048). Patients with maximal gradient above 75 mmHg (n=11) showed significant associations between Fn-positive area and both maximal (r =0.63) and mean (r =0.67) transvalvular gradients. Large fibrin amounts, mostly co-localised with TF, are present within the valve leaflets of patients with advanced AS. In vivo thrombin generation and fibrin clot formation are associated with the extent of Fn presence within leaflets, which might contribute to the AS progression.

Treatment strategies in severe symptomatic carotid and coronary artery disease

Summary Coexistent carotid artery stenosis (CS) and multivessel coronary artery disease (CAD) is not infrequent. One in 5 patients with multivessel CAD has a severe CS, and CAD incidence reaches 80% in those referred for carotid revascularization. We reviewed treatment strategies for concomitant severe CS and CAD. We performed a literature search (MEDLINE) with terms including carotid artery stenting (CAS), coronary artery bypass grafting (CABG), carotid endarterectomy (CEA), stroke, and myocardial infarction (MI). The main therapeutic option for CS-CAD has been (simultaneous or staged) CEA-CABG. This, however, is associated with a high risk of MI (in those with CEA prior to CABG) or stroke (CABG prior to CEA), and the cumulative major adverse event rate (MAE – death, stroke or MI) reaches 10–12%. With increasing adoption of CAS, a sequential strategy of CAS followed by CABG has emerged. Registries (usually single-centre) indicate an MAE rate of ≈7% for CAS followed by CABG (frequently after >30 days, due to double antiplatelet therapy). Recently, 1-stage CAS-CABG has been introduced. This involves different antiplatelet regimens and, in some centers, preferred off-pump CABG, with a cumulative MAE of 1.4–4.5%. No randomized trial comparing different treatment strategies in CS-CAD has been conducted, and thus far reported series are prone to selection/reporting bias. In addition to the established surgical treatment (CEA-CABG, sequential/simultaneous), hybrid revascularization (CAS-CABG) is emerging as a viable therapeutic option. Larger, preferably multi-centre, studies are required before this can become widely applied.

Myocardial ischemia assessed by Tc99m MIBI SPECT and left ventricle regional systolic and diastolic function evaluated by tissue Doppler echocardiography

Background: Tc99m MIBI single-photon emission computed tomography (SPECT) study facilitates the evaluation of the regional myocardial perfusion and tissue Doppler echocardiography imaging facilitates the quantitative assessment of the regional systolic and diastolic function of the myocardium. The aim of the study was an assessment of the correlation between regional rest myocardial perfusion defects and regional rest systolic and diastolic myocardial velocities in patients with ischemic heart disease (IHD). Material and methods: In 40 IHD patients (33 men, 7 women) aged 43–74 years (mean 56 years) rest SPECT imaging with Tc99m MIBI and rest tissue Doppler examinations were performed. The control group consisted of 35 healthy sex and age matched pesons. The left ventricle was divided into 13 segments. The number of non-perfused segments in three myocardial perfusion regions (left anterior descending artery, circumflex artery, right coronary artery) was assessed in IHD patients. During tissue Doppler examination the maximal systolic and maximal early diastolic velocity of the myocardium in each segment were established in both examined groups. Results: The systolic and diastolic myocardial velocities were significantly lower in IHD group as compared to control group. In the IHD group statistically significant decrease of systolic and diastolic velocities in relation to the number of non-perfused segments was found. In comparing the linear regression slopes for systolic and for diastolic myocardial velocities in terms of intensification of perfusion defects, a more pronounced decrease in diastolic velocity was encountered. Conclusions: Both systolic and diastolic myocardial velocities are decreased in the myocardial regions with perfusion defects, but the reduction of the diastolic velocity is higher than the reduction of the systolic velocities. Thus our results indicate a good correlation between the intensity of perfusion abnormalities and myocardial velocities. The levels of diastolic dysfunction is more pronounced than the level of systolic dysfunction in the ischemic myocardium.

Regression of left ventricular hypertrophy with moexipril, an angiotensin-converting enzyme inhibitor, in hypertensive patients.

Left ventricular hypertrophy (LVH) is a common complication of essential hypertension and an independent risk factor for the development of cardiovascular disease. Therefore, antihypertensive treatment should decrease blood pressure (BP) and reverse LVH. However, antihypertensive drugs have been shown to have different effects on LVH despite similar effects on BP reduction. Although lowering BP produces a beneficial effect on LVH per se, metaanalyses of clinical trials have indicated that angiotensin-converting enzyme (ACE) inhibitors decrease left ventricular mass (LVM) to a greater extent than do some other antihypertensives. The aim of this study was to evaluate the effect of a 24-week treatment with the ACE inhibitor moexipril (15 mg once daily) on the regression of LVH in hypertensive patients. This was a multicenter, international, single-blind, single-group, nonrandomized study. After a wash-out placebo period of 2 weeks, 15 mg moexipril once daily was administered for 24 weeks followed by a 2-week follow-up placebo period. Subjects with mild to moderate essential hypertension were screened; those with LVH [defined as an LVM indexed for body surface area (LVMIs) >111 g/m2 in men and LVMIs >106 g/m2 in women] were eligible to participate in this study. Echocardiograms were recorded on videotape and sent to a centralized laboratory for reading by 2 independent experts blinded for treatment, center, and visit; the mean values of these readings were calculated and used for analysis. Valid echocardiographic data were obtained from 72 patients (50 males, 22 females) with a mean age of 49 ± 11 years. Analysis showed significant decrease of LVMIs (121 ± 20 versus 103 ± 17 g/m2; P < 0.001) and BP (152 ± 12/96 ± 9 versus 140 ± 13/86 ± 9 mm Hg; P < 0.001) with moexipril. For patients who met LVMI inclusion criteria after centralized, blinded readings, the decrease from baseline in LVMIs was 23.4 g/m2. The decrease in LVMIs was independent from the regression to the mean phenomenon as observed from the follow-up placebo period. Moexipril 15 mg once daily administered for 24 weeks resulted in a significant reversal of LVH in patients with essential hypertension. The result compares favorably with results previously obtained in trials of similar duration with other ACE inhibitors.

12-month patterns of serum markers of collagen synthesis, transforming growth factor and connective tissue growth factor are similar in new-onset and chronic dilated cardiomyopathy in patients both with and without cardiac fibrosis

HighlightsKinetics of collagen type I and III synthesis in DCM move in opposite directions.Production of collagen type I increases but collagen type III decreases.TGF and CTGF levels over 12‐month follow‐up had a tendency to decrease.Regardless of DCM duration or fibrosis, kinetics of fibrosis markers were similar.Improved understanding of fibrosis may translate into tailored therapy. Abstract Background: The dynamics of the extracellular matrix (ECM) fibrosis process in dilated cardiomyopathy (DCM) may be assessed non‐invasively by means of serum markers of fibrosis. Aim: To explore the kinetics of serum markers of fibrosis during a 12‐month follow‐up in DCM. Methods: We included 70 consecutive DCM patients (pts) (48 ± 12.1 years, EF 24.4 ± 7.4%) with new‐onset (n = 35, duration <6 months) and chronic DCM (n = 35, >6 months). Markers of collagen type I and III synthesis – procollagens type I and III carboxy‐ and amino‐terminal peptides (PICP, PINP, PIIICP, PIIINP), and ECM metabolism controlling factors – tumor growth factor beta‐1 (TGF1‐&bgr;), and connective tissue growth factor (CTGF) – were measured in serum at baseline, and at 3‐ and 12‐month follow‐up. All pts underwent endomyocardial biopsy to determine the presence and extent of ECM fibrosis. Results: Markers of collagen type I synthesis (PICP and PINP) were almost homogenously increased over the 3‐ and 12‐month period, whereas PIIINP values decreased and PIIICP levels were unchanged in new‐onset and chronic DCM, and in pts with and without ECM fibrosis. Both TGF‐&bgr; and CTGF levels decreased over the observation period. Kinetics of serum markers of collagen synthesis and fibrosis controlling factors did not differ between DCM pts categorized according to disease duration and fibrosis status. Conclusions: The kinetics of collagen type I and III synthesis in DCM move in opposite directions, with production of collagen type I consistently increasing, and the synthesis of collagen type III decreasing. Levels of TGF and CTGF, which are proven fibrosis‐stimulating factors, had a tendency to decrease. Regardless of disease duration or fibrosis status, the kinetics of serum markers of collagen synthesis, TGF and CTGF were similar in DCM. A better understanding of the kinetics of serum markers of fibrosis in DCM may help to develop more tailored therapeutic approaches to fibrosis.

Clinical and echocardiographical study of the aortic homograft implantations in patients with Marfan syndrome

The aim of the study was to assess the long-term results of surgical treatment with homogenic aortic grafts (HAGs) implantation in patients with Marfan syndrome. There were 31 patients with Marfan syndrome and aortic aneurysm who were operated on between 1980 and 1996. Aortic dissection was diagnosed in 14 patients, DeBakey Type I in six patients and Type II in eight patients. Four patients had to be operated urgently in cardiogenic shock with cardiac tamponade. Sealing up and reinforcement with strip of felt or Gore-Tex has been applied in 22 patients. The surgical modifications mentioned above have been applied since 1987 in all patients with the diameter of the aortic ring exceeding 30 mm or with active infective endocarditis or during reoperation. In 16 patients the space between the aortic homograft and patients own aortic wall was joined to the right atrial auricle. Patients were followed up for 12-179 months (average: 94.6 +/- 499). Three patients died in the early postoperative period and four patients died in the late postoperative period. Rethoracotomy because of bleeding complications was necessary in five patients. HAG damage was responsible for six other reoperations-new HAGs have been implanted in three patients and artificial prostheses were implanted in the other three patients. In the late follow-up period significant improvement in cardiac performance was observed in 24 patients (NYHA I or II). Survival probability of 15 years for the whole group was 80%. The lowest survival probability has been shown in the group of patients with DeBakey Type I aortic dissection (35% survived 15 years after operation). Echocardiographic follow-up has shown that the pressure gradient in HAG was low (7.4 +/- 6.2 mmHg). Only in two patients did the HAG gradient exceeded 20 mmHg. There were no significant differences concerning aortic ring diameters, dimensions of HAG and echocardiographic parameters between the group with surgical modifications, i.e. sealing up and reinforcement with strip of felt or Gore-Tex applied and the group in which these modifications were not applied. Homogenic aortic graft implantation as a method of surgical treatment of aortic aneurysm in patients with Marfan syndrome avoids postoperative anticoagulation, results in substantial improvement of cardiac performance and prolongs life. Surgical treatment should be considered in asymptomatic patients with large aneurysms (exceeding 55-65 mm) in patients with Marfan syndrome because there is a high risk of death in this group of patients in the case of dissection.

A 34‐year‐old man with non‐obstructive apical hypertrophic cardiomyopathy (RCD code: III‐2A.1)

Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium that is defined by the presence of regional (more frequent) or global myocardial hypertrophy, which usually re‐ sults in functional cardiac impairment. The prevalence of HCM is about 0.2% to 0.5% in the general population and affects equally men and women [2,3,4,5]. In the majority of patients of Caucasian descent, hypertrophy is local and usually confined to the basal septum. On the other hand, the morphology of cardiac hyper‐ trophy can be variable. Although hypertrophy of apical segments is rare in Europe, it is more common in patients of east Asian descent [1]. The primary causes of this disease are hereditary or newly‐created mutations of genes encoding contractile proteins of cardiac sarcomeres. These comprise over 90% of HCM cases [6]. At present there are over 600 identified mutations responsible for the disease, predominantly single‐point missense mutations in the genes coding for beta‐myosin heavy chain, myosin bind‐ ing protein C, cardiac troponin T and tropomyosin [7]. HCM is a disease characterized by unexplained, asymmetric left ven‐ tricular (LV) hypertrophy, defined as a maximal wall thickness of ≥15 mm, without any dilatation in the absence of another disease capable of inducing wall thickening [8]. HCM is divided into obstructive and non‐obstructive types, based on the blockage of blood flow out of the LV, which results in a substantial increase of the LV outflow tract (LVOT) gradi‐ ent by more than 30 mm Hg [9]. LVOT obstruction is present in two‐thirds of HCM patients – one‐third with a resting gradient and one‐third with an exercise‐induced gradient [10]. In both types of HCM the thickened muscle reduces the volume of the LV, leading to diastolic heart failure. The clinical course of HCM is variable, progressing to non‐specific cardiac symptoms such as: dyspnoea, exertional chest pain, palpitations, arrhythmias, fatigue, and syn‐ cope [11]. However, occasionally the disease can be asymptomatic – manifesting for the first time as sudden cardiac death (SCD). The annual rate of SCD is lower than 1%, but within the general population of HCM patients, there are subgroups with a much higher incidence [12].

Hypertrophic cardiomyopathy or hereditary hemochromatosis? (RCD code: III‑2B.3.o)

Hemochromatosis is a disease resulting from excessive deposition of iron in parenchymal tissues. The most common form of this disease is associated with the homozygous p.Cys282Tyr mutation of the HFE gene. It leads to multisystemic disease including iron overload cardiomyopathy. Heterozygotes usually do not express a hemochromatosis phenotype, however there are known cases of iron overload in this group of patients. We present a case of 48-year old man, with family history of hereditary hemochromatosis, p.Cys282Tyr mutation carrier, who was admitted to cardiology department due to persistent atrial fibrillation episode. Laboratory tests revealed transferrin serum iron saturation value of 47,8% with other parameters of iron metabolism within the reference range. Transthoracic echocardiographic study showed image consistent with hypertrophic cardiomyopathy. Sinus rhythm was successfully restored by synchronized electrical cardioversion. Based on cardiovascular magnetic resonance imaging cardiac iron overload cardiomyopathy was ruled out. He was discharged home in good general condition without symptoms. JRCD 2016; 3 (1): 24–27