Significant Diastolic Dysfunction Research Articles

Abstract 1590: Association Between Arterial Stiffness, Coronary Microcirculation And Left Ventricular Function In Patients With Newly Diagnosed Arterial Hypertension.

Arterial stiffness is an independent marker of cardiovascular morbidity and mortality. Coronary microcirculation is impaired in patients with arterial hypertension. We investigated the relationship between arterial stiffness, coronary microcirculation and left ventricular (LV) systolic and diastolic function. METHODS: 80 untreated consecutive patients (mean age: 55±11 years 38 males), with newly diagnosed arterial hypertension and 20 healthy controls matched for sex, age and atherosclerotic factors, were studied. We measured a) Carotid to femoral artery pulse wave velocity (PWV) using the Complior apparatus b) Peak Systolic (Vs) and diastolic (Vd) coronary blood flow velocity, Vd/Vs ratio, Deceleration Time (DT-Vd) and time integral (VTI-Vd) of Vd using a 7MHZ transducer by means of colour-guided Doppler echocardiography at the distal tract of the LAD c) Ratio of VTI-Vd after adenosine infusion (140 μ g/kg/min) to VTI-Vd at baseline to assess coronary flow reserve (CFR) d) E and A doppler, Em, Am mitral annulus velocities TDI and E/Em ratio to assess LV diastolic function d) Mean Longitudinal, Transverse, Circumferential and Radial Strain and Strain Rate by 2-D Strain to assess LV systolic function. RESULTS: Patients and controls had normal ejection fraction. Compared to controls, patients with hypertension had higher PWV (10.4±1.7 vs. 8.2±1.4 m/s, p<0.001), E/Em (8.3±2.8 vs. 5.7±1.4, p=0.001) and lower CFR (2.6±0.6 vs. 3.4±0.7, p<0.001), Vd/Vs (1.78±0.31 vs. 1.97±0.38, p=0.04), DT-Vd (973±226 vs 1113±332 ms, p<0.001), Em/Am (0.93±0.42 vs. 1.6±0.51, p<0.001), mean longitudinal strain (−17.8±3 vs. −19.8±3.1%, p=0.031) and mean circumferential strain ( −19.6±4.5 vs. −22±3.4 %, p=0.04). Increasing PWV was related to increasing E/Em (r=0.26, p=0.045) and decreasing CFR (r=−0.68, p<0.001). Increasing E/Em was related to decreasing Vd/Vs (r=−0.3, p<0.005) and CFR (r=−0.32, p=0.002). CONCLUSIONS: Patients with arterial hypertension present subclinical systolic LV dysfunction and significant LV diastolic dysfunction compared to healthy controls. Increased LV diastolic filling pressures caused by arterial stiffness may increase the resistance of myocardial microcirculation leading to impaired coronary flow

Echocardiographic findings in former professional cyclists after long-term deconditioning of more than 30years

In professional cyclists, typical changes include reversible dilatation of atria and left ventricle (LV), LV hypertrophy but normal diastolic function. Data on long-term outcome are limited. Of all 134 former Swiss professional cyclists (PC) participating >or=1x in the professional bicycle race Tour de Suisse from 1955 to 1975, 62 (42%) were recruited for a prospective case control study. The PC and a control group of 62 golfers (matched for age, gender, hypertension, present physical activity) were screened [clinical examination, history, echocardiography, measurement of proBNP (normal <227 pg/mL)]. The interval since the last bicycle race as PC was 38 (15-49) years. Average age at exam was equal in controls and PC (66+/-6 vs 66+/-7 years; P = 0.73). Percentage of participants undergoing >4 h of endurance training per week was identical (P = 0.72). Total kilometers (km) on the bicycle were higher in PCs with 311,000 (60,000-975,000) than in controls (2500 [0-120,000]; P < 0.0001). PC had larger atrial volume indices (P = 0.002) and tended to have higher LV muscle mass indices (P = 0.07). Multiple regression analysis identified the total number of bicycle km as an independent factor for LV muscle mass. For left atrial size, heart rate at rest, age, years since the last bicycle race and the current hours of endurance training were identified as independent predictors. Long axis function of both ventricles (systolic velocities of mitral and tricuspid annulus) was decreased in PC (P <or= 0.04). There were signs of diastolic dysfunction with lower annular E' and A' velocities. ProBNP levels were comparable in both groups (P = 0.21). Among former PC, there seems to be incomplete cardiac remodelling with differences in systolic and diastolic function between former PCs and controls in the long time follow-up. Former high level endurance training may have a persisting impact on cardiac size and function.

Systolic and Diastolic Myocardial Dysfunction in Cats with Hypertrophic Cardiomyopathy or Systemic Hypertension

Background:Hypertrophic Cardiomyopathy (HCM) and chronic systemic hypertension (SHT) can both lead to left‐ventricular hypertrophy (LVH) in cats. Assessment of LVH‐associated myocardial dysfunction could provide new insights in the understanding of the pathophysiology of these diseases.Hypothesis:Quantification of left‐ventricular free‐wall (LVFW) motion using tissue Doppler imaging (TDI) could permit differentiation of feline HCM from SHT‐related LVH (LVH‐SHT).Animals:A total of 108 cats of different breeds were enrolled in this study: 35 cats with HCM, 17 with concentric LVH and SHT, and 56 healthy cats as a control group.Methods:All cats were examined by conventional echocardiography and 2‐dimensional color TDI.Results:Radial and longitudinal diastolic LVFW velocities were similarly altered in cats with HCM and LVH‐SHT, compared to controls. Systolic velocities were also lower in the groups with hypertrophy than in the controls, for longitudinal but not radial motion. To determine whether these diastolic and systolic alterations could also be observed in cats without LVFW hypertrophy, we performed a subgroup analysis in cats with a normal M‐mode examination, that is, with only a localized subaortic interventricular septum hypertrophy. A significant radial and longitudinal diastolic dysfunction was still observed in both the HCM and LVH‐SHT groups compared to controls, and systolic dysfunction was detected in the longitudinal motion.Conclusions: LVFW motion is similarly altered in cats with HCM and LVH‐SHT. This dysfunction occurs independently of the presence of myocardial hypertrophy, demonstrating that TDI is capable of detecting systolic and diastolic segmental functional changes in nonhypertrophied wall segments in cats with HCM and SHT.

NT-proBNP levels, echocardiographic findings, and outcomes in breathless patients: results from the ProBNP Investigation of Dyspnoea in the Emergency Department (PRIDE) echocardiographic substudy

The objective of this study was to determine the integrative utility of measuring plasma NT-proBNP levels with echocardiography in the evaluation of dyspnoeic patients. Of 599 emergency department patients enrolled in a clinical study of NT-proBNP at a tertiary-care hospital, 134 (22%) had echocardiographic results available for analysis. Echocardiographic parameters correlating with NT-proBNP levels were determined using multivariable linear-regression analysis. Independent predictors of 1-year mortality were determined using Cox-proportional hazard analysis. Independent relationships were found between NT-proBNP levels and ejection fraction (P = 0.012), tissue Doppler early and late mitral annular diastolic velocities (P = 0.007 and 0.018), right ventricular (RV) hypokinesis (P = 0.006), and tricuspid regurgitation severity (P < 0.001) and velocity (P = 0.007). An NT-proBNP level <300 pg/mL had a negative predictive value of 91% for significant left ventricular systolic and diastolic dysfunction. Overall 1-year mortality was 20.1% and was independently predicted by NT-proBNP level [HR 8.65, 95% confidence interval (CI) 2.7-27.8, P = 0.0003], ejection fraction (HR 0.95, 95% CI 0.91-0.99, P = 0.009), RV dilation (HR 2.98, 95% CI 1.05-12.8, P = 0.04), and systolic blood pressure (HR 0.97, 95% CI 0.96-0.99, P = 0.01). NT-proBNP levels correlate with, and provide important prognostic information beyond, echocardiographic parameters of cardiac structure and function. Routine NT-proBNP testing may thus be useful to triage patients to more timely or deferred echocardiographic evaluation.

Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy–causing mutations in the β-myosin heavy chain, α-tropomyosin, and myosin-binding protein C genes

We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children. In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations. All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children. Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children. In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

Systolic and Diastolic Myocardial Dysfunction in Cats With Hypertrophic Cardiomyopathy or Systemic Hypertension

Hypertrophic cardiomyopathy (HCM) and chronic systemic hypertension (SHT) can both lead to left-ventricular hypertrophy (LVH) in cats. Assessment of LVH-associated myocardial dysfunction could provide new insights in the understanding of the pathophysiology of these diseases. Quantification of left-ventricular free-wall (LVFW) motion using tissue Doppler imaging (TDI) could permit differentiation of feline HCM from SHT-related LVH (LVH-SHT). A total of 108 cats of different breeds were enrolled in this study: 35 cats with HCM, 17 with concentric LVH and SHT, and 56 healthy cats as a control group. All cats were examined by conventional echocardiography and 2-dimensional color TDI. Radial and longitudinal diastolic LVFW velocities were similarly altered in cats with HCM and LVH-SHT, compared to controls. Systolic velocities were also lower in the groups with hypertrophy than in the controls, for longitudinal but not radial motion. To determine whether these diastolic and systolic alterations could also be observed in cats without LVFW hypertrophy, we performed a subgroup analysis in cats with a normal M-mode examination, that is, with only a localized subaortic interventricular septum hypertrophy. A significant radial and longitudinal diastolic dysfunction was still observed in both the HCM and LVH-SHT groups compared to controls, and systolic dysfunction was detected in the longitudinal motion. LVFW motion is similarly altered in cats with HCM and LVH-SHT. This dysfunction occurs independently of the presence of myocardial hypertrophy, demonstrating that TDI is capable of detecting systolic and diastolic segmental functional changes in nonhypertrophied wall segments in cats with HCM and SHT.

Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease

Left ventricular diastolic dysfunction has been shown in patients with autosomal-dominant polycystic kidney disease (ADPKD). However, there is no study evaluating right ventricular functions in these patients. In the present study, diastolic functions of both ventricles in normotensive and hypertensive ADPKD patients with well-preserved renal function were investigated. Fifteen hypertensive and 16 normotensive patients with ADPKD with well-preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Conventional left and right ventricular echocardiographic measurements were performed in all subjects. Left and right ventricular functions were investigated both by myocardial performance index (MPI) [calculated by dividing the sum of isovolumic contraction time and isovolumic relaxation time (IVRT) by ejection time] and by tissue Doppler imaging (TDI). Left ventricular deceleration time and IVRT were significantly prolonged in hypertensive patients with ADPKD compared with patients with essential hypertension and even in normotensive patients with ADPKD compared with healthy subjects. Left and right MPIs were significantly higher in patients with ADPKD compared with healthy subjects, showing systolic and diastolic dysfunction. Moreover, by using TDI, the peak early diastolic mitral annular velocity (Em) to peak late diastolic mitral annular velocity (Am) ratio and the peak early diastolic tricuspid annular velocity (Et) to peak late diastolic tricuspid annular velocity (At) ratio were decreased in patients with ADPKD, suggesting biventricular diastolic dysfunction. Both hypertensive and normotensive patients with ADPKD show significant biventricular diastolic dysfunction, suggesting cardiac involvement very early in the course of ADPKD.

Systolic and diastolic functions in elderly patients with and without heart failure

Background A considerable number of patients with heart failure (HF) have a normal left ventricular ejection fraction (LVEF). In these subjects, HF has usually been related to diastolic heart failure (DHF), still a frequently overlooked clinical entity. Methods This study reports the clinical, instrumental, and conventional echocardiographic evaluation of 159 consecutive, hospitalized elderly patients, 87 admitted with HF and 72 admitted for other reasons without overt HF. Results All of the 87 HF patients had signs of diastolic dysfunction (DDYS), yet 44.8% of them had a normal LVEF. Forty-four of the 72 patients admitted without overt HF (61.1%) had mild DDYS and 14 (19.5%) also had a reduced LVEF. There was a clear relationship between LVEF reduction and the severity of DDYS. Conclusions HF is often a combination of diastolic and systolic function abnormalities. DHF may be difficult to detect in HF subjects with normal LVEF because their DDYS is often mild. However, there are signs of DDYS in all HF patients that increase in severity as LVEF decreases. DDYS could be considered a marker for all forms of HF, especially in elderly patients.

Assessment of aortic stiffness and ventricular diastolic functions in patients with Behçet’s disease

Behçet's disease is a systemic vasculitis in which studies have given conflicting results about ventricular diastolic functions. However, tissue Doppler echocardiography has never been used in any of these studies. Aortic stiffness, a cardiovascular risk factor, may also precede ventricular dysfunction. The aim of this study was to assess aortic stiffness and biventricular diastolic functions in patients with Behçet's disease. A total of 26 patients with Behçet's disease (mean age; 33+/-10 years) and 20 age- and sex-matched controls (mean age; 33+/-7 years) were included. Aortic stiffness was evaluated by aortic strain and distensibility. Ventricular diastolic functions were evaluated with both conventional and tissue Doppler echocardiography. Mitral E and A wave, E/A ratio of E wave, deceleration time, and isovolumic relaxation time were calculated. There was no significant difference in diastolic Doppler parameters between patients and controls. Similarly, there was no significant difference in mitral annular E and A velocities between these two groups. Aortic strain in patients with Behçet's disease was found to be significantly less than in the controls (8.3+/-4.9% and 15.7+/-2.7% respectively, p<0.001). Aortic distensibility was also significantly low in patients with Behçet's disease when compared to controls (0.45+/-0.28 and 0.78+/-0.13 respectively, p<0.001). Beta index values were significantly high in Behçet's patients (7.23+/-5.93 and 2.69+/-0.55 respectively, p<0.001). No significant diastolic dysfunction was found in left and right ventricles in patients with Behçet's disease by using both conventional and tissue Doppler echocardiography. However, an increase in aortic stiffness was found, suggesting an inflammatory involvement of proximal aorta.

Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic β-adrenergic stimulation

Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme. The mice were viable and demonstrated no visible signs of distress at rest. Microscopic examination of the hearts showed myocardial fibrosis and hypertrophy. Hemodynamic analysis of the Tg mice revealed impaired systolic function and significant diastolic dysfunction. Furthermore, significant mortality was observed in MLK7 Tg mice following 24–48 h of isoproterenol administration. Isoproterenol activation of JNK and p38, but not extracellular signal-regulated kinase, was significantly greater in the MLK7 Tg mice compared to littermate controls. These data indicate that MLK7 is an important signal transducer in cardiac compensation. Simultaneous activation of JNK and p38 by MLK7 may contribute to cardiac decompensation during the periods of acute cardiac stress.

Persistent diastolic dysfunction despite complete systolic functional recovery after reperfused acute myocardial infarction demonstrated by tagged magnetic resonance imaging.

This study was designed to characterise both the systolic and diastolic mechanical properties of regions with different degrees of myocardial ischaemic injury after reperfused acute myocardial infarction (AMI). Fourteen dogs underwent 90-min coronary artery occlusion followed by reperfusion. Image acquisition was performed 24 h after reperfusion using three techniques: tagged, first-pass perfusion and delayed-enhancement magnetic resonance imaging (MRI). Systolic circumferential strain and both systolic and diastolic strain rates were calculated in 30 segments/animal. Transmural AMI segments displayed reduced systolic contractility when compared to subendocardial AMI segments (systolic strain = -2.5 +/- 0.5% versus -6.0 +/- 0.9%, P < 0.01 and systolic strain rate = -0.11 +/- 0.12 versus -0.82 +/- 0.16 s(-1), P < 0.01), and both exhibited significant systolic and diastolic dysfunction compared to remote. Moreover, AMI segments presenting with microvascular obstruction ("no-reflow") displayed further compromise of systolic and diastolic regional function (P < 0.05 for both). Importantly, risk region segments only exhibited diastolic impairment (diastolic strain rate = 1.62 +/- 0.14 versus 2.99 +/- 0.13 s(-1), P < 0.001), but not systolic dysfunction compared to remote 24 h after reperfusion. Reversibly injured regions can demonstrate persistent diastolic dysfunction despite complete systolic functional recovery after reperfused AMI. Moreover, the presence of no-reflow entails profound systolic and diastolic dysfunction. Finally, tagged magnetic resonance imaging (MRI) strain rate analysis provides detailed mechanical characterisation of regions with different degrees of myocardial ischaemic injury.

DIASTOLIC DYSFUNCTION IN HYPERTENSIVES AS ASSESSED BY TISSUE DOPPLER; RELATION TO MATRIX METALLOPROTEINASES

Objectives: To assess the severity of diastolic dysfunction in hypertensive patients as compared to normal controls and correlate it with plasma matrix metalloproteinases (MMPs). Methods: 52 patients with controlled hypertension (HT) (38 male, age 57+ 11 yrs) and 24 normotensive controls 15 male, mean age 53+ 12 years) had tissue doppler echocardiography to assess diastolic dysfunction (e′ and e′/e ratios). They also had plasma MMP‐9 and TIMP‐1 measured. Results: The HT patients had significantly lower e′ and higher e′/e ratios as compared to normotensive controls. They also had higher MMP‐9 and TIMP‐1 values. There was a significant inverese correlation between MMP‐9 and TIMP‐1 with e′ and a significant positive correlation between the MMPs and e′/e ratio. THe e/a ratios as assessed by pulse wave doppler were also higher in the controls than the hypertensive patients suggesting abnormal diastolic function. Conclusions: There is significant diastolic dysfunction even in controlled hypertensives which can be assessed by tissue doppler. This newer technique compares favourably with established methods such as e/a ratio. The tissue doppler indices also correlate well with abnormalities in the matrix metalloproteinases suggesting that abnormal matrix turnover is responsible for the diastolic dysfunction.

Mechanisms of exercise intolerance: insights from tissue Doppler imaging.

A decreased ratio of early to late diastolic mitral inflow velocities (E/A <1.0) reflects slowing of left ventricular (LV) relaxation. This finding is widely believed to indicate significant diastolic dysfunction. However, E/A <1.0 is common during normal aging and often is not associated with symptoms of heart failure. We asked (1) whether slowed LV relaxation is associated with exercise intolerance and (2) whether tissue Doppler imaging of the early diastolic mitral annular velocity (Ea) is helpful in understanding mechanisms of exercise intolerance. Patients (n=121) underwent echocardiography before maximal exercise testing. Fifty-nine subjects had E/A <1.0, and 36 subjects had E/Ea > or =10. Exercise capacity was similar in the population with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10. In contrast, the subjects with slow relaxation and E/Ea > or =10 had reduced exercise tolerance. Of all the echo and clinical parameters assessed, E/Ea had the best correlation with exercise capacity (r=-0.684, P<0.001) and was the strongest independent predictor of exercise capacity < or =7 METs by multivariate analysis (prevalence-corrected odds ratio=12.6, P<0.001). E/Ea continued to be strongly associated with exercise capacity in all age groups and in those with preserved or reduced systolic function. Of the subjects with slow LV relaxation, only those with E/Ea > or =10 have objective evidence of reduced exercise tolerance. These data suggest that elevated LV filling pressures rather than slow relaxation per se reduce exercise capacity.

132 Increased arterial stiffness is associated with left ventricular diastolic dysfunction in patients with Adamantiades-Behcet's disease

Adamantiades-Behcet’s disease (ABD) is multisystem disorder characterized by vasculitis leading to arterial aneurysm formation, stroke and arterial or venous occlusive disease. We investigated whether arterial stiffness is related with left ventricular (LV) dysfunction in patients with ABD. Methods: We studied 73 patients with ABD (age 3911 years) by 2D and Doppler echocardiography for assessment of thoracic and abdominal Ao (ABAO) diameters (mm/BSA), LV diastolic function [E/A ratio, deceleration (DT-ms) and isovolumic relaxation time (IVRT-ms)] and radial artery tonometry with pulse wave analysis (Sphygmocor) for estimation of arterial stiffness [central augmentation index (CAI%), reflection time index,(RTI-%))] Results: All patients had normal systolic LV function. Abnormal CAI and RTI were related to increased ABAO diameters (r=0.36 and r=-0.28, P 125 ms (n=36) or RTI 14 (table). CAI >125 would predict an IVRT >95 with 72% sensitivity and 61% specificity (ROC curve area:71% (CI:57-83)). CAI DT IVRT ABAO RTI DT IVRT ABAO >125 (n=36) 210±40 92±16 11±1.8 14(n=34) 189±36 83±15 9.9±1.7 p <0.01 <0.01 <0.01 p <0.01 <0.01 <0.01 Conclusion: Patients with ABD present increased aortic diameters, associated with significant arterial stiffness possibly due to vasa vasorum vasculitis. Increased arterial stiffness may reduce coronary blood flow or increase LV afterload and thus, cause significant LV diastolic dysfunction in these patients.

Determination of cardiac involvement in sarcoidosis by magnetic resonance imaging and Doppler echocardiography.

To elucidate whether cardiac magnetic resonance imaging (MRI) could be useful in disclosing structural changes in the myocardium in sarcoidosis patients and to relate echo-Doppler derived indices of left ventricular function to electrocardiogram (ECG) findings. The MRI was performed in 18 consecutive patients with sarcoidosis. Left ventricular ejection fraction (LVEF), i.e. systolic function, was estimated echocardiographically by Simpson's two-dimensional method (n = 16). Diastolic function was estimated by age-corrected Doppler-derived indices: isovolumetric relaxation time (IVRT), deceleration time (DT) and early filling/atrial contraction ratio (E/A ratio). Eleven patients had conduction defects or dysrhythmias (ECG+) whilst seven patients had a normal ECG (ECG-). In two patients, high signalling, contrast-enhanced, isolated regions, suggestive of deposits, were seen in the left ventricular myocardium on MRI. Both these patients had abnormal ECGs and signs of systolic and/or diastolic dysfunction on echocardiography. LVEF was subnormal in seven of 10 of the ECG+ patients and in two of six of the ECG-. Signs of diastolic dysfunction were found in 59% and 56% of the measurements in the ECG+ and ECG- patients, respectively. We conclude (i) that myocardial deposits on MRI in sarcoidosis patients have a high specificity for cardiac involvement but a rather low sensitivity; (ii) that a substantial proportion of sarcoidosis patients with abnormal ECGs have echocardiographic signs of systolic and/or diastolic dysfunction.

Alteration of mitochondrial function in a model of chronic ischemia in vivo in rat heart.

The aim of this study was to investigate mitochondrial alterations in an animal model of chronic myocardial ischemia in rats obtained by surgical constriction of the left coronary artery. Resting coronary blood flow was measured using the fluorescent microsphere technique. Contractile function, defined by rate-pressure product, and myocardial oxygen consumption were measured in a Langendorff preparation. The mitochondrial function was evaluated on permeabilized skinned fibers. Three weeks after surgery, ischemic hearts showed a significant decrease in coronary blood flow compared with sham. Hemodynamic measurements showed a significant systolic and diastolic dysfunction. Alterations in mitochondrial function in ischemic hearts were mainly characterized by a significant decrease in the maximal velocity and apparent half-saturation constant for ADP, loss of the stimulatory effect of creatine, and a stimulatory effect of exogenous cytochrome c. These functional alterations were supported by structural alterations characterized by mitochondrial clustering and swelling associated with membrane rupture. We conclude that the alterations in systolic function after chronic ischemia are supported by severe modifications of mitochondrial structure and function.

Transmural distribution of three-dimensional systolic strains in stunned myocardium.

Regional function in stunned myocardium is usually thought to be more depressed in the endocardium than the epicardium. This has been attributed to the greater loss of blood flow at the endocardium during ischemia. We measured transmural distributions of 3D systolic strains relative to local myofiber axes in open-chest anesthetized dogs before 15 minutes of left anterior descending coronary artery occlusion and during 2 hours of reperfusion. During ischemia, regional myocardial blood flow was reduced 84% at the endocardium and 32% at the epicardium (P<0.005, n=7), but changes in end-systolic fiber length from baseline were transmurally uniform. Relative to baseline, radial segments in stunned tissue were significantly thinner at the endocardium than the epicardium at end systole (24+/-5% versus 16+/-3%; P<0.05, n=8), consistent with previous reports. Unlike radial and cross-fiber segments, however, the increase of end-systolic fiber lengths in stunned myocardium had no significant transmural gradient (23+/-8% epicardium versus 21+/-4% endocardium). We also observed significant 3D diastolic dysfunction in the ischemic-reperfused region transmurally. Myocardial ischemia/reperfusion in the dog results in a significant transmural gradient of dysfunction between epicardial and endocardial layers in radial and cross-fiber segments, but not for fiber segments, despite a gradient in blood flow reduction during ischemia. Perhaps systolic fiber dysfunction rather than the degree of perfusion deficit during the preceding ischemic period may be the main determinant of myocardial dysfunction during reperfusion.

Right Ventricular Dysfunction in Adult Severe Cystic Fibrosis

This study sought to assess the extent of impairment of cardiac function in adult patients with end-stage cystic fibrosis (CF) and to examine the relationship between cardiovascular abnormalities and the degree of hypoxemia and hypercapnia. A retrospective study in a tertiary cardiac and CF center. A total of 103 adult patients with end-stage CF awaiting lung or heart and lung transplantation (mean age [+/- SD], 26+/-7 years; 54 men) underwent Doppler echocardiography and arterial blood gas analysis (mean PaO(2), 54+/-10 mm Hg; mean PaCO(2), 47+/-8 mm Hg). The findings were compared to those of 17 healthy control subjects (mean age, 24+/-7 years; 13 men) who had no history of cardiac or pulmonary disease. All patients were in sinus rhythm with a mean tachycardia of 112+/-18 beats/min (control subjects, 76+/-16; p<0.0001) and had a cardiac output of 5.3 L/min (control subjects, 4.3 L/min; p<0.04). In the patient group, the left ventricular (LV) dimensions, systolic and diastolic function, and wall thickness were all within normal limits. The mean amplitude of long-axis excursion in patients was normal at the LV site, but that of the right ventricular (RV) free wall was significantly reduced as compared with control subjects (1.6+/-0.4 vs. 2.2+/-0.4 cm, respectively; p<0.001), which was found to correlate with the degree of hypoxemia (r = 0.63; p<0.02) and hypercapnia (r = -0.68; p<0.01). RV diastolic function, which was represented by the relative isovolumic relaxation time to cardiac cycle length, was longer in patients than in control subjects (8.7+/-4.8% vs. 5.0+/-3.0%, respectively; p<0.03). The pulmonary flow acceleration time (90+/-22 vs 121+/-34 ms, respectively; p<0.01) and the systolic stroke distance (7.0+/-2.2 vs. 10.5+/-1.9 cm/s(2); p<0.001) were both lower than normal. This study confirms the presence of significant RV systolic and diastolic dysfunction in the setting of consistent tachycardia and increased cardiac output in adult CF patients with severe disease. No specific LV abnormalities were detected in these patients.

Transgenic rat hearts expressing a human cardiac troponin T deletion reveal diastolic dysfunction and ventricular arrhythmias.

Familial hypertrophic cardiomyopathy (FHC) due to mutations of cardiac troponin T (cTnT) is associated with a high frequency of sudden death even in the absence of cardiac hypertrophy. To investigate the causal relationship of cTnT mutations and this particular phenotype, we sought to establish a transgenic rat model for the disease. Transgenic rats were generated expressing human wild-type cTnT or two truncated cTnT molecules (del ex16, del ex15/16), resulting from an intron 15 splice donor site mutation previously observed in FHC patients. Transgenic rat hearts were characterized by histology, immunohistochemistry and in the 'working heart'. Human wild-type and del ex16 cTnT were stably expressed and incorporated into the sarcomere of transgenic cardiomyocytes. Del ex16 transgenic rats revealed a lower level of expression (4-5%) than human wt cTnT animals (25-40%). In the 'working heart' model del ex16 hearts exhibited significant systolic and diastolic dysfunction without cardiac hypertrophy. In contrast, human wt cTnT hearts showed improved contractile performance and moderate myocardial hypertrophy. After 6 months of daily physical exercise one del ex16 rat died suddenly and three out of five del ex16 hearts revealed ventricular tachycardia/fibrillation. No arrhythmia was observed in human wt cTnT expressors. Myofibrillar disarray was present in del ex16 hearts after training but not in human wild-type cTnT rats or non-transgenic controls. A human cTnT deletion overexpressed in transgenic rats exerts a dominant-negative effect and mimics the phenotype of FHC with diastolic dysfunction and arrhythmias. By contrast, human cTnT wild-type animals reveal a gain of function and cardiac hypertrophy without arrhythmias.

New insights in cardiac structural changes in patients with Fabry’s disease

Background Fabry’s disease is an X-linked recessive genetic deficiency of the enzyme α-galactosidase leading to the pathologic intracellular deposition of neutral glycosphingolipids. Although cardiac involvement is frequent, there is controversy regarding the character of the associated left ventricular (LV) changes and the severity of valvular involvement. Methods Clinical evaluation (disease severity scaling, laboratory tests, and echocardiography) was performed in 13 hemizygous men (mean age 39 ± 10 years) and 17 heterozygous women (mean age 35 ± 19 years). Results LV hypertrophy (LVH) was frequent in subjects older than 30 years, more often in men (61%) than in women (18%, P <.001). The degree of LVH was independently associated with age and the logarithm of α-galactosidase activity (r2 = 0.70, P <.001). The predominant LV geometric patterns were concentric LVH and remodeling, both present in 11 subjects (36%). Three patients had an asymmetric septal hypertrophy mimicking hypertrophic cardiomyopathy. In most subjects with LVH, the systolic function was normal and severe diastolic dysfunction (restrictive pattern) was not noted. Minor structural abnormalities of the mitral valve were found in 17 subjects (57%). The aortic valve was affected in 14 patients (47%). Valvular abnormalities were frequently accompanied by regurgitation of minor to mild degree. The presence of LVH or valvular changes was associated with increased disease severity. Conclusions Echocardiographically detectable cardiac involvement is frequent with Fabry’s disease, particularly in older subjects, and more pronounced in affected hemizygous men than in heterozygous women. LVH is frequently observed but usually not associated with significant systolic or restrictive diastolic dysfunction. Concentric LVH and remodeling appear to be the major manifestations of LV structural alteration. The frequently noted valvular abnormalities were not associated with a significant degree of regurgitation. Valvular and especially LV structural changes may serve as a useful marker of disease severity. (Am Heart J 2000;139:1101-8.)