Significant Diastolic Dysfunction Research Articles

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.)

Assessment of Right Ventricular and Right Atrial Systolic and Diastolic Performance Using Automated Border Detection.

Noninvasive assessment of right ventricular (RV) function is important clinically, but current techniques have limitations. Acoustic quantification (AQ) is an automated endocardial border detection technique that allows continuous determination of RV and right atrial (RA) area waveforms and may be useful for the assessment of RA and RV systolic and diastolic performance. Fifty patients (10 normal, 40 with RV pathology) were studied. Signal-averaged RA and RV AQ area waveforms were obtained and analyzed to compute parameters of diastolic and systolic function. All groups demonstrated significant diastolic dysfunction on the RA AQ waveform as manifested by a reduced percentage of passive atrial emptying and increased dependence on active atrial emptying. Abnormalities of diastolic performance were noted in all subgroups on RV AQ analysis as evidenced by a reduction in the percentage of ventricular filling occurring during early diastole and an increased contribution from active atrial contraction. This study demonstrates the feasibility of using automated analysis of signal-averaged RA and RV area waveforms for the evaluation of RV systolic and diastolic performance. This technique identified significant systolic and diastolic dysfunction in four groups of commonly seen right heart pathologies including biventricular heart failure, pulmonary hypertension, pressure and volume overloaded RVs, and biventricular hypertrophy.

No evidence for systolic or diastolic left ventricular dysfunction at rest in selected patients with long‐term Type I diabetes mellitus

We assessed left ventricular systolic and diastolic function using pulsed-waved Doppler echocardiography in a selected group of 20 patients with insulin-dependent diabetes mellitus (IDDM) (mean age, 35 +/- 8 years; mean diabetes duration, 17 + 7 years). Our patients were free of autonomic neuropathy and major micro- or macrovascular complications and had no evidence of ischemic heart disease or hypertension. The results were compared with those of 20 age- and sex-matched control subjects. We found that left ventricular geometry and mass, systolic function by M-mode and 2D-echocardiography, isovolumetric relaxation time, deceleration time and the PEP/LVET ratio were not significantly different between patients and control subjects. Hemodynamic parameters were also not significantly different except for a slightly higher heart rate in the patient group (75 +/- 11 vs. 68 + 6 bpm, P = 0.019). After correction of A-peak velocities for differences in heart rate, there was no significant difference of Doppler indices of diastolic left ventricular function between patients and control subjects. The absence of significant left ventricular systolic and diastolic dysfunction by Doppler echocardiography in our study patients may be explained by our patient selection. Left ventricular dysfunction in diabetic patients without concomitant hypertensive or ischemic heart disease may only occur in conjunction with microvascular disease in other organ systems, with autonomic neuropathy or with poor metabolic control.

Echocardiography in systemic lupus erythematosus.

Two dimensional echocardiography with doppler examination was performed in 54 patients with systemic lupus erythematosus (SLE). Nine (17%) had significant cardiac involvement (four left ventricular hypertrophy, one moderate pericardial effusion, one severe aortic regurgitation, and three ventricular systolic dysfunction). We further studied diastolic function in 45 patients who did not have a major abnormality in echo. SLE was graded as active in 16 patients (SLEDAI > 5) and inactive in 29 patients. Twenty age- and sex-matched subjects acted as controls. The data were compared using one way ANOVA test. Patients with active disease had significant diastolic dysfunction compared to inactive patients and controls as indicated by increased peak A (P < 0.01) and decreased E/A ratio (P < 0.01). There was no linear correlation between disease activity and diastolic dysfunction if SLEDAI was considered as a continuous variable (r=0.29 for E/A). Anticardiolipin antibodies (both IgG and IgM) were elevated in five patients (13 studied). One of them had severe mitral regurgitation, one had trace mitral and aortic regurgitation and one had diastolic dysfunction. We conclude that asymptomatic diastolic dysfunction is present in SLE patients.

A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.

Hypertension and renal failure.

A 74-year-old man with a history of intermittent claudication, cigarette-smoking, hypertension, and a successful recent right nephro-ureterectomy for a right ureter transitional cell carcinoma, presented with abnormal renal function and...

Treatment of hypertrophic cardiomyopathy with coenzyme Q 10

Hypertrophic cardiomyopathy (HCM) is manifested by severe thickening of the left ventricle with significant diastolic dysfunction. Previous observations on the improvement in diastolic function and left ventricular wall thickness through the therapeutic administration of coenzyme Q 10 (CoQ 10) in patients with hypertensive heart disease prompted the investigation of its utility in HCM. Seven patients with HCM, six non-obstructive and one obstructive, were treated with an average of 200 mg/day of CoQ 10 with mean treatment whole blood CoQ 10 level of 2.9 μg/ml. Echocardiograms were obtained in all seven patients at baseline and again 3 or more months post-treatment. All patients noted improvement in symptoms of fatigue and dyspnea with no side effects noted. The mean interventricular septal thickness improved significantly from 1.51±0.17 cm to 1.14±0.13 cm, a 24% reduction ( P < 0.002). The mean posterior wall thickness improved significantly from 1.37±0.13 cm to 1.01±0.15 cm, a 26% reduction ( P<0.005). Mitral valve inflow slope by pulsed wave Doppler (EF slope) showed a non-significant trend towards improvement, 1.55±0.49 m/sec 2 to 2.58±1.18 m/sec 2 ( P<0.08). The one patient with subaortic obstruction showed an improvement in resting pressure gradient after CoQ 10 treatment (70 mmHg to 30 mmHg).

Iodine-123 Metaiodobenzylguanidine Scintigraphic Assessment of Myocardial Sympathetic Innervation in Patients With Familial Amyloid Polyneuropathy

Objectives. This study attempted to assess myocardial sympathetic innervation using iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging in patients with familial amyloid polyneuropathy.Background. Signs and symptoms of cardiac autonomic dysfunction are commonly seen in patients with cardiac amyloidosis. However, the incidence and magnitude of abnormalities in myocardial sympathetic nerve function by means of I-123 MIBG imaging and their relation to clinical findings, cardiac function and the results of thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) myocardial scanning have not yet been clarified.Methods. We performed M-mode, two-dimensional and Doppler echocardiography and I-123 MIBG, Tl-201 and Tc-99m PYP imaging of the heart in 12 patients with familial amyloid polyneuropathy and biopsy-proved cardiac amyloidosis.Results. Ten of 12 patients had no clinical evidence of overt heart disease, but left ventricular (LV) wall thickening was observed in 4 of these 10. Left ventricular percent fractional shortening and Doppler transmitral flow velocity patterns were found to be normal in all 12 patients. Eight of 12 patients showed no myocardial MIBG accumulation, with limited uptake in the remaining 4 demonstrated only in the LV anterior wall. Diffuse but mild myocardial uptake of Tc-99m PYP occurred in only 4 of 12 patients, and all 12 had normal results on Tl-201 myocardial scanning. Complete defects on myocardial MIBG scans were found in five of eight patients with negative findings on Tc-99m PYP myocardial scanning. The incidence and magnitude of myocardial uptake of MIBG were independent of clinical findings, extent of endomyocardial amyloid deposition, electrocardiographic QRS voltage and ventricular wall thickness.Conclusions. Patients with familial amyloid polyneuropathy show a high incidence of myocardial adrenergic denervation with viable myocardium that can be identified very early in cardiac amyloidosis, before the development of clinically apparent heart disease, ventricular wall thickening, significant LV systolic and diastolic dysfunction and positive findings on Tc-99m PYP myocardial scanning.(J Am Coll Cardiol 1997;29:168–74)>

Left ventricular diastolic function in hypertensive patients with unstable angina and single coronary artery disease

The present study was performed to investigate left ventricular diastolic (LVD) function in hypertensive patients with unstable angina. Three groups of 17 patients each were studied. Group 1 consisted of hypertensives with unstable angina (HTU); group 2, normotensives with unstable angina (NTU); and group 3, untreated, uncomplicated hypertensives (HT). The LVD function was assessed echocardiographically by transmitral valve Doppler flow to measure the ratio between the early diastolic filling (E) and the atrial contraction phase (A). An E/A ratio of < 1 was suggestive of LVD dysfunction. Left ventricular mass (LVM), from an M-mode echocardiogram using the Penn-Cube formula, was corrected to body surface area (LVM/S) using a standard nomogram. Data are represented as median values and analyzed by Mann-Whitney test. P was significant at < .05. The HTU group had an E/A ratio of 0.8, and the NTU and HT groups had ratios of 1.17 and 1.1, respectively. There was significant diastolic dysfunction in the HTU group compared with the NTU and HT groups (P = .037 and .049, respectively). Although the LVM/S was significantly higher in the HTU group when compared with the HT group (110.6 and 96.9, respectively, P = .017), there was no significant difference between the HTU and NTU groups (123.1), P = .67. Hypertensive patients with unstable angina have significant LVD dysfunction that seems to be independent of LVM and ischemia. This may be attributable to increased stiffness of the left ventricle or structural left ventricular abnormalities.

World atlas of holocene sea-level changes

In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1H −/−), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1H −/− mice with rapamycin. Six to eight week old Acsl1H −/− mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10 weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1H −/− hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1H −/− hearts exhibited an 8-fold higher uptake of 2-deoxy[1-14C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-14C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1H −/− mice.