Low-gradient aortic valve stenosis myocardial fibrosis and its influence on function and outcome.

OBJECTIVES: This prospective cohort study in patients with aortic stenosis (AS) aimed to identify surrogates of myocardial fibrosis that are easy to derive in clinical practice, allow the differentiation of low-gradient severe AS from moderate AS, and have an impact on clinical outcome. BACKGROUND: In patients with symptomatic aortic AS, a characteristic subgroup (i.e., up to one-third) exhibits severe AS with a concomitant low mean valve gradient either with preserved or reduced ejection fraction (EF). It is hypothesized that these patients tend to have an advanced stage of myocardial fibrosis and poor clinical outcome. METHODS: Eighty-six patients with moderate or severe AS were examined by echocardiography including conventional aortic valve assessment, mitral ring displacement, and strain-rate imaging. Replacement fibrosis was quantified by late-enhancement magnetic resonance imaging. Biopsy samples were taken from patients with severe AS (n = 69) at aortic valve replacement. All patients were followed for 9 months. RESULTS: Patients were divided into 4 groups according to aortic valve area (<1.0 cm(2)), mean valve gradient ≥40 mm Hg, and EF (<50%): group 1, moderate AS (n = 17); group 2, severe AS/high gradient (n = 49); group 3, severe AS/low gradient/preserved EF (n = 11); and group 4, severe AS/low gradient/decreased EF (n = 9). At baseline, a significant decrease in mitral ring displacement and systolic strain rate was detected in patients with low-gradient AS. In low-gradient groups, a higher degree of interstitial fibrosis in biopsy samples and more late-enhancement magnetic resonance imaging segments were observed. A close inverse correlation was found between interstitial fibrosis and mitral ring displacement (r = -0.79, p < 0.0001). Clinical outcome was best for patients in group 1, whereas mortality risk increased substantially in groups 2 through 4. CONCLUSIONS: In severe AS, a low gradient is associated with a higher degree of fibrosis, decreased longitudinal function, and poorer clinical outcome despite preserved EF. Mitral ring displacement differentiates between moderate AS and low-gradient/severe AS with preserved EF.

A validated disease severity scoring system for Fabry disease.

Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument's total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument's domains was estimated and the DS3's quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R(2)=0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts.

Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis.

BACKGROUND: In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. METHODS AND RESULTS: Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P<0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8+/-0.4 to 1.4+/-0.5 (P<0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died. CONCLUSIONS: Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.

Functional differences of left ventricular hypertrophy induced by either arterial hypertension or aortic valve stenosis.

The aim of this study was to reveal functional differences of left ventricular (LV) hypertrophy induced by either aortic stenosis (AS) or arterial hypertension (AH) assessed by strain-rate imaging. Twenty patients with AS and 19 patients with AH were enrolled. In the 2 groups, coronary artery disease was ruled out invasively. All subjects underwent echocardiographic studies, including strain-rate imaging studies of LV long- and short-axis function. Eight patients underwent follow-up examinations after aortic valve replacement, and 20 healthy volunteers served as a control group. LV end-diastolic posterior wall thickness was not different between the 2 patient groups (12.7 +/- 2.5 mm in AS vs 12.8 +/- 1.6 mm in AH) but was significantly increased compared with the control group (8.5 +/- 1.1 mm). The LV ejection fraction was within normal limits in all groups but significantly lower in the patient groups (54 +/- 9% in AS, 55 +/- 6% in AH) compared with the control group (66 +/- 3%). Radial and longitudinal systolic strain rates were depressed in patients with AS compared with those with AH and controls (radial 1.6 +/- 0.6 vs 2.6 +/- 0.6 and 3.8 +/- 0.6 s(-1), respectively, p <0.005). After valve replacement, longitudinal strain rate remained unchanged, but radial strain rate gradually increased (1.6 +/- 0.6 vs 2.1 +/- 0.8 s(-1), p = NS). In parallel, the ejection fraction gradually improved and LV hypertrophy gradually diminished. In conclusion, despite the same degree of LV wall thickness, AS and AH have different impacts on the rate of LV deformation.

Sequential changes of myocardial function during acute myocardial infarction, in the early and chronic phase after coronary intervention described by ultrasonic strain rate imaging.

OBJECTIVE: The aim of this prospective clinical study was to follow up patients with acute myocardial infarction from the ischemic event, over the primary coronary intervention (PCI), up to the chronic phase after survived myocardial infarction by noninvasive strain rate (SR) imaging and to determine its role in the assessment of transmurality of infarction. METHODS: In all, 41 patients with acute S-T elevation infarction were examined immediately before, 3 days after, and 5 months after PCI. Regional myocardial function was assessed by the use of ultrasonic SR imaging and peak systolic SR and systolic strain were extracted. In addition, late-enhancement (LE) imaging with magnetic resonance imaging was done after 5 months to assess the transmurality of residual scar distribution. RESULTS: Magnetic resonance imaging showed that 8 patients had no LE (complete recovery = no-scar group), 16 patients had subendocardial LE (nontransmural infarction = NT group), and 17 patients had a transmural LE (transmural infarction = T group) in the region of interest. Before PCI both SR and strain were markedly reduced in the ischemic segments compared with the nonischemic remote region in all 3 groups (SR: ischemia = -0.6 +/- 0.3 s(-1); remote = -1.3 +/- 0.4 s(-1), P < .001). Three days after PCI, systolic SR only increased significantly in the regions that were not transmurally infarcted. After 5 months the measurement of systolic strain could accurately distinguish the different groups. (no-scar group = -24 +/- 5%, NT group = -13 +/- 4%, T group = -1 +/- 3%). CONCLUSIONS: This clinical study shows that with SR imaging: (1) the ischemic segment can be precisely detected; (2) the absence of transmurality early after coronary intervention can be predicted; and (3) in the chronic phase the transmurality of scar distribution can be assessed.

Dobutamine induces ineffective work in regional ischaemic myocardium: an experimental strain rate imaging study.

In the present study, we sought to investigate the effects of differing inotropic conditions on regional myocardial function in ischaemic segments. In an experimental pig model ( n =11), the regional deformation parameters peak systolic strain rate [SR(SYS) (peak velocity of thickening)], systolic strain [epsilon(SYS) (systolic wall thickening)] and post-systolic strain [epsilon(PST) (ongoing wall thickening after end of systole)] were measured during normal perfusion and regional ischaemia of the posterior wall. These parameters were compared with global contractility [E(ES) (end-systolic elastance)] measured by a conductance catheter. Ischaemia was induced by an active coronary hypoperfusion in the circumflex coronary artery. Measurements were done at baseline, during dobutamine and during esmolol infusion. In normal perfused hearts, SR(SYS) (4.8+/-0.2 s(-1) at baseline) increased during dobutamine infusion, decreased during esmolol infusion and correlated significantly with global E(ES). In addition, epsilon(SYS) averaged 93+/-3% at baseline and there was almost no epsilon(PST) (4+/-1%) in normal myocardium. In ischaemic myocardium, SR(SYS) and epsilon(SYS) were significantly reduced compared with normal myocardium at baseline (SR(SYS)=2.8+/-0.3 s(-1), and epsilon(SYS)=43+/-6%; P <0.001 compared with normal perfused hearts), whereas global E(ES) was unchanged. In contrast, epsilon(PST) was significantly increased in regional ischaemic segments compared with the non-ischaemic myocardium (15+/-2%; P <0.001). During the dobutamine infusion, SR(SYS) remained unchanged. In contrast, epsilon(SYS) decreased (25+/-5%; P <0.001) and epsilon(PST) increased (25+/-4%; P <0.05) significantly during dobutamine infusion in ischaemic myocardium. In ischaemic segments, an inotropic stimulation with dobutamine resulted in a shift of strain from systole (epsilon(SYS)) to post-systole (epsilon(PST)). Thus dobutamine induced ineffective myocardial work in ischaemic segments.

Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study.

BACKGROUND: Enzyme replacement therapy (ERT) has been shown to enhance microvascular endothelial globotriaosylceramide clearance in the hearts of patients with Fabry disease. Whether these results can be translated into an improvement of myocardial function has yet to be demonstrated. METHODS AND RESULTS: Sixteen patients with Fabry disease who were treated in an open-label study with 1.0 mg/kg body weight of recombinant alpha-Gal A (agalsidase beta, Fabrazyme) were followed up for 12 months. Myocardial function was quantified by ultrasonic strain rate imaging to assess radial and longitudinal myocardial deformation. End-diastolic thickness of the left ventricular posterior wall and myocardial mass (assessed by magnetic resonance imaging, n=10) was measured at baseline and after 12 months of ERT. Data were compared with 16 age-matched healthy controls. At baseline, both peak systolic strain rate and systolic strain were significantly reduced in the radial and longitudinal direction in patients compared with controls. Peak systolic strain rate increased significantly in the posterior wall (radial function) after one year of treatment (baseline, 2.8+/-0.2 s(-1); 12 months, 3.7+/-0.3 s(-1); P<0.05). In addition, end-systolic strain of the posterior wall increased significantly (baseline, 34+/-3%; 12 months, 45+/-4%; P<0.05). This enhancement in radial function was accompanied by an improvement in longitudinal function. End-diastolic thickness of the posterior wall decreased significantly after 12 months of treatment (baseline, 13.8+/-0.6 mm; 12 months, 11.8+/-0.6 mm; P<0.05). In parallel, myocardial mass decreased significantly from 201+/-18 to 180+/-21 g (P<0.05). CONCLUSIONS: These results suggest that ERT can decrease left ventricular hypertrophy and improve regional myocardial function.

Detection of a pseudonormal mitral inflow pattern: an echocardiographic and tissue Doppler study.

OBJECTIVE: The aim of this study was to assess the ability of several echocardiographic and tissue Doppler imaging (TDI) derived parameters to improve the noninvasive diagnosis of a pseudonormal mitral inflow pattern. METHODS: Ninety-eight consecutive patients with age-related normal transmitral Doppler profile underwent echocardiography including TDI and measurement of left ventricular end-diastolic pressure (LVEDP) using fluid-filled catheters. Peak transmitral velocities were determined at rest (E, A) and during the strain phase of a Valsalva maneuver. The difference in duration between the pulmonary venous retrograde velocity and the transmitral A-velocity (PVR-A) was calculated from pulsed Doppler recordings. Propagation velocity of the early mitral inflow (VP) was determined by color M-mode. Early diastolic peak mitral annulus velocities (E') and the early diastolic transmyocardial velocity gradient of the posterior basal wall (MVG) were obtained by TDI. RESULTS: Fifty-two patients presented with normal diastolic function (group I: LVEDP9.5 +/- 3 mm Hg, E/A1.1 +/- 0.19), while pseudonormalization, defined as LVEDP 15 mm Hg and E/A > 0.9, was found in 46 patients (group II: LVEDP23 +/- 7 mm Hg, E/A1.43 +/- 0.83). The coefficient of linear correlation (r) and the area under ROC - curve (AUC) to predict LVEDP values 15 mm Hg were maximal for the index PVR-A (AUC = 0.92, r = 0.77), followed byE/E' (AUC = 0.80, r = 0.46), MVG (AUC = 0.65, r = 0.33) and E/VP (AUC = 0.69, r = 0.30), P < 0.01, whereas the decrease in E/A ratio during Valsalva maneuver failed to reach significance. Similar results were observed when echocardiographic parameters were used to estimate the left ventricular diastolic pressure before atrial contraction. CONCLUSIONS: PVR-A enabled the most accurate estimation of LVEDP. TDI-derived indices E/E' and MVG are also reliable alternatives superior to the classical Valsalva maneuver to detect a pseudonormal transmitral Doppler profile.

Trauma induced by nontraumatic coronary devices and its impact on vascular reactivity and morphology.

This study evaluated the impact of low-pressure balloon devices on coronary morphology and function. An active coronary perfusion catheter (2.5-mm balloon diameter, inflation with 1 bar for 30 min) was placed in the left anterior descending coronary artery of 12 German landrace pigs under general anesthesia. After 3 mo, coronary segments with balloon contact were compared with control segments taken from the right coronary artery as to histology, vascular reactivity, and expression of endothelial nitric oxide synthase. Thirty-three balloon treated segments were analyzed. Twenty of these segments (61%) showed neointima formation. In these segments endothelium-independent relaxation induced by sodium nitroprusside was preserved. However, endothelium-dependent bradykinin-induced relaxation was significantly attenuated compared with both the control segments and the balloon-treated segments without neointima formation. In >60% of the ballooned arterial segments examined, low-pressure balloon devices induced neointima formation accompanied by reduced endothelium-dependent relaxation. Thus interventions with so-called nontraumatic coronary devices can induce relevant vascular injury, with potential adverse clinical consequences.