Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy

OBJECTIVES: We sought to characterize stress-induced left ventricular systolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Myocardial ischemia and diastolic dysfunction occur in patients with HCM. We hypothesized that, in the setting of transient myocardial ischemia, left ventricular systolic dysfunction occurs during exercise and dobutamine stress. METHODS: We studied 39 patients with HCM but without obstructive symptoms at rest or coronary artery disease. A continuous ventricular function monitor equipped with cadmium telluride detectors (VEST) was used to evaluate left ventricular function during supine bicycle ergometer exercise. Dobutamine stress echocardiography (DSE) was also performed. The left ventricular ejection fraction (LVEF) and regional wall motion were determined from echocardiographic images. RESULTS: Changes in the LVEF correlated between exercise and dobutamine stress (r = 0.643, p < 0.0001). The LVEF decreased more than 5% at peak exercise in 17 of patients (group II), while the other patients had normal responses (group I). New regional wall motion abnormalities during dobutamine infusion were detected in 18 of 110 (16.4%) segments in group I and 42 of 85 (49.4%) segments in group II. Decreased or unchanged regional wall motion occurred more frequently in hypertrophied segments than in nonhypertrophied segments (p < 0.0001). There were significant inverse correlations between the LVEF responses during both stresses and the number of abnormal segments noted during dobutamine stress in all patients (VEST: p < 0.005; DSE: p < 0.0005). Signs of left ventricular obstruction were observed in 11 of 39 patients during DSE. However, there was no significant correlation between the LVEF response and the dobutamine-induced left ventricular pressure gradient. CONCLUSIONS: Exercise-induced systolic dysfunction occurred in 50% of patients with HCM. In these patients, regional wall motion abnormalities were present in hypertrophied segments.     

Relationship between measures of left ventricular systolic and diastolic dysfunction and clinical and biomarker status in patients with hypertrophic cardiomyopathy

The evaluation of left ventricular (dys)function is at the core of clinical cardiology practice in patients with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy proceeds along paradigms that are profoundly different and follows disease-specific patterns of progression towards heart failure. By automatically applying a standard approach, much information is lost or misplaced, and severe degrees of dysfunction may be erroneously interpreted as mild by such an assumption. This is mostly evident during the assessment of systolic function, in which a superficial evaluation of standard variables, often relatively preserved (even in advanced stages), may lead to underestimation of clinical severity, with potential consequences, such as late referral for transplantation. Currently, specific biomarkers–particularly N-terminal prohormone of B-type natriuretic peptide and high-sensitivity cardiac troponin I–play a key role in the diagnosis, treatment and risk stratification of hypertrophic cardiomyopathy. Elevated biomarkers seem to depict patients with more severe disease, adding diagnostic and prognostic information to conventional assessments, such as left ventricular ejection fraction, New York Heart Association class and left ventricular outflow tract obstruction. For all these reasons, we provide a review of current knowledge on systo-diastolic function in patients with hypertrophic cardiomyopathy, in an attempt to define clinically significant degrees of dysfunction, biomarker status and specific “red alert” thresholds in clinical practice.     

Exercise-induced ST-segment depression and systolic dysfunction in patients with nonobstructive hypertrophic cardiomyopathy

BACKGROUND: ST-segment depression is common in patients with hypertrophic cardiomyopathy (HCM). However, it is not clear whether exercise-induced ST-segment depression in patients with HCM and patent coronary arteries is associated with changes in left ventricular function. METHODS: Left ventricular function was continuously evaluated in 53 patients with nonobstructive HCM during supine ergometer exercise with a radionuclide ventricular function monitor equipped with a cadmium telluride detector. On the basis of the ST-segment changes during exercise, the patients were divided into 2 groups: group N had no ST-segment depression, and group D had >/=0.1 mV ST-segment depression. RESULTS: Exercise duration, blood pressure, heart rate, and rate-pressure product during exercise did not differ between the 2 groups. End-diastolic volume at rest and at peak exercise did not differ between groups D and N. In contrast, the end-systolic volume in group N decreased during exercise, whereas in group D it increased. As a result, the left ventricular ejection fraction in group D decreased from 70% +/- 7% to 59% +/- 15% (P <.0001), whereas ejection fraction in group N increased from 65% +/- 8% to 71% +/- 11% (P =.0002). There was a strong correlation between exercise-induced ST-segment depression and changes in ejection fraction from rest to peak exercise (P <.0001). CONCLUSIONS: These results suggest that the exercise-induced ST-segment depression seen in patients with nonobstructive HCM is associated with systolic dysfunction during exercise.     

Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) develop left ventricular (LV) wall thinning associated with LV dilatation and systolic dysfunction. Recently, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were reported to be involved in ventricular remodeling, however, little is known about MMPs and TIMPs in patients with HCM. METHODS AND RESULTS: Enzyme-linked immunoassays were used to measure the plasma concentrations of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 11 patients with HCM accompanied by systolic dysfunction (fractional shortening (FS) <25%, group A), 17 patients with HCM who had preserved systolic function (FS> or =25%, group B), and 50 age-matched clinically healthy control subjects (mean age: 57 years). The concentration of MMP-2 in group A was significantly higher than in group B and the control subjects (1,124 +/- 84, 792 +/- 49, 809 +/- 26 ng/ml, respectively), whereas there was no significant difference between group B and the control subjects. MMP-2 concentrations significantly increased as the New York Heart Association functional class increased in patients with HCM. TIMP-2 was also significantly higher in group A patients than in group B and the control subjects (45.3 +/- 4.7, 34.6 +/- 2.2, 33.7 +/- 1.8 ng/ml, respectively), but there was no difference between group B and control subjects. TIMP-1 was significantly higher in HCM patients than in control subjects. MMP-3 and MMP-9 concentrations did not differ among the 3 groups. Both MMP-2 and TIMP-2 correlated significantly with FS and LV dimension, negatively and positively, respectively. CONCLUSIONS: These results suggest that changes in the release and activity of MMP-2 and TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with HCM.     

Pregnancy-induced severe left ventricular systolic dysfunction in a patient with hypertrophic cardiomyopathy

This paper reports the first case of hypertrophic cardiomyopathy (HCM) that developed postpartum congestive heart failure (CHF) and severe left ventricular (LV) systolic dysfunction. Review of the literature and clinical implications are discussed.     

Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy

The phenomenon of cumulative exercise-induced left ventricular function impairment was studied in 40 patients with non-obstructive hypertrophic cardiomyopathy with resting normal left ventricular function and no increase in ejection fraction on exercise. All patients underwent two symptom-limited exercise tests one-hour apart. Cumulative myocardial dysfunction was seen in 13 patients (group I) but not in the remaining 27 patients (group II). During follow-up, group I showed more commonly than group II a deterioration in symptoms (67% vs 22%, P=0.025) and left ventricular function (50% vs 9%, P=0.019). In conclusion, cumulative exercise-induced myocardial dysfunction can occur in hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome.     

Association between intraventricular myocardial systolic dyssynchrony and ventricular arrhythmias in patients with hypertrophic cardiomyopathy

BACKGROUND: The distribution and magnitude of left ventricular (LV) hypertrophy are not uniform in patients with hypertrophic cardiomyopathy (HCM), which results in regional heterogeneity of LV systolic and diastolic function. The aim of the study was to evaluate LV regional systolic asynchrony in patients with HCM by pulsed Doppler myocardial imaging (DMI). METHODS: We studied 35 HCM patients and 45 age- and sex-matched controls. By the use of DMI, the following five different basal myocardial segments were measured: systolic peak velocity (Sm); early- and late-diastolic peak velocities; pre-contraction time (Q-Sm) (from the beginning of Q-wave of ECG to the onset of Sm); intraventricular systolic delay (IntraV-Del) (difference of Q-Sm in different LV myocardial segments); interventricular delay (InterV-Del) (difference of Q-Sm between the most delayed LV segment and right ventricular lateral wall). RESULTS: DMI analysis showed in HCM lower myocardial systolic and early-diastolic peak velocities of all the analyzed segments. As for time intervals, controls showed homogeneous systolic activation of the ventricular walls. Conversely, HCM group, despite the absence of intraventricular conduction defects by surface ECG, showed significant both Inter- and IntraV-Del (P < 0.0001). Linear regression models pointed out independent positive associations of IntraV-Del with LV outflow gradient and septal wall thickness in HCM (P < 0.001). An IntraV-Del >30 msec well differentiated controls and HCM. In addition, an IntraV-Del > 45 msec (ROC curve) identified a subgroup of HCM patients with nonsustained ventricular tachycardia during Holter monitoring (90.9% sensitivity and 95.8% specificity). CONCLUSIONS: The impairment of intrarventricular systolic synchronicity is strongly related to increased septal thickness and LV outflow-tract gradient in HCM. DMI analysis may be able to select subgroups of HCM patients at an increased risk of ventricular tachyarrhythmias.     

多巴酚丁胺在肥厚型心肌病激发试验的应用

目的 评价多巴酚丁胺激发试验在肥厚型心肌病激发试验中的安全性及有效性,比较潜在型肥厚型梗阻与静息型肥厚型梗阻性心肌病的临床特点. 方法 对22例确诊肥厚型心肌病患者(左心室流出道压力阶差正常或轻度增加)进行多巴酚丁胺激发试验,以5 μg·min-1·kg-1为起始剂量静脉泵人多巴酚丁胺,每隔5 min增加5 μg·min-1·kg-1,最大剂量20 μg·min-1·kg-1.每一次剂量泵入2 min后进行超声心动图检查,并对其临床特点与57例静息型肥厚型梗阻性心肌病患者进行比较. 结果 入选22例患者激发状态时左心室流出道流速峰值为(5.39±1.60)m/s,左心室流出道压力阶差(LVOTPG)峰值为(125.7±62.4)mm Hg(1 mm Hg=0.133 kPa);达到峰值时多巴酚丁胺给药平均速率为(13.9±6.85)μg·min-1·kg-1.16例(72.7%)患者达到阳性标准;6例(27.3%)患者虽达到阴性标准,但LVOTPG也有显著升高.潜在型梗阻患者的年龄、性别、各房室腔内径、左心室射血分数、室间隔厚度、LVOTPG等与静息型梗阻患者比较,差异均无统计学意义,但二尖瓣前向运动(SAM)现象发生率较低(62.5%比100%),Maron Ⅱ型较多[50.0%(8/16)比29.8(17/57)]. 结论 在肥厚型心肌病激发试验中,小剂量多巴酚丁胺负荷超声是一种较为安全和敏感性高的方法.潜在型较静息型肥厚型梗阻性心肌病患者的SAM现象发生率低,Maron Ⅱ型占优势.     

Septal wall thinning and systolic dysfunction in patients with hypertrophic cardiomyopathy caused by a cardiac troponin I gene mutation

Background Lysine 183 deletion in the cardiac troponin I gene is 1 of the mutations that causes hypertrophic cardiomyopathy (HCM). However, the clinical course and determinants of poor prognosis in patients with this mutation have not been well established. Methods and Results We analyzed 10 probands with HCM caused by this mutation and their family members. Forty-six of these 79 subjects were found to be carriers, and 33 were non-carriers. All non-carriers had a percent fractional shortening (%FS) of >25% at all ages. By contrast, 7 of 24 carriers >40 years of age had a %FS of <25%, and no carriers <40 years of age had a %FS of <25%. The change in interventricular septal thickness and the change in %FS were significantly correlated (R = 0.758; P = .0017). Conclusion These results suggest that about 30% of patients with HCM caused by a lysine 183 deletion mutation in the cardiac troponin I gene have systolic dysfunction develop after 40 years of age, and that patients with this mutation whose interventricular septal thickness shows a serial decrease should be followed-up closely for development of systolic dysfunction. (Am Heart J 2002;143:690-5.)     

Safety of stress testing in patients with hypertrophic cardiomyopathy

Two hundred sixty-three consecutive patients with hypertrophic cardiomyopathy underwent stress testing. Major complications occurred in 0.04% of patients and minor events occurred in 23%.     

扩张型心肌病患者校正QT间期与左室收缩功能的相关性

目的 探讨扩张型心肌病(DCM)患者校正QT(QTc)间期与心功能的关系。方法 选择2004年1月2014年6月入住中国中医科学院广安门医院的103例DCM患者,根据心电图QTc时限分为QTc间期>440 ms组59例,QTc间期≤440 ms组44例,比较其心脏结构和功能的差异。结果 QTc>440 ms组患者左室收缩末期内径(LVESD)、左室舒张末期内径(LVEDD)显著大于QTc≤440 ms组(均P<0.05);QTc>440 ms组患者左室射血分数(LVEF)、左心室短轴缩短率(FS)显著小于QTc≤440 ms组(均P<0.01)。LVESD、LVEDD与QTc间期呈正相关(r=0.261,P<0.01、r=0.252,P<0.05);LVEF、FS与QTc间期呈负相关(r=-0.275,P<0.01、r=-0.304,P<0.01)。结论 DCM患者QTc间期与左室内径以及收缩功能存在相关性。     

Relationship between tumor necrosis factor-alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy

OBJECTIVES

This study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM).

BACKGROUND

Oxidative stress appears to increase in the failing myocardium and may contribute to ventricular dysfunction in patients with DCM. Tumor necrosis factor-alpha (TNF-alpha), which is expressed in the failing heart, may stimulate oxidative stress.

METHODS

We measured plasma oxidized low density lipoprotein (oxLDL) by sandwich enzyme-linked immunosorbent assay using specific antibodies against oxLDL in the aortic root (AO) and the coronary sinus (CS) in control subjects (n = 8) and in 22 patients with DCM and mild congestive heart failure. We also measured the plasma levels of TNF-alpha and angiotensin II.

RESULTS

There was no difference in oxLDL between the AO and CS in control subjects. In contrast, plasma oxLDL was significantly higher in the CS than the AO in patients with DCM, suggesting that the transcardiac gradient of oxLDL reflects oxidative stress in the failing heart in these patients. Plasma TNF-alpha levels were significantly higher in the CS than the AO with a significant positive correlation of the transcardiac gradient of TNF-alpha and the transcardiac gradient of oxLDL. Moreover, a significant negative correlation existed between the transcardiac gradient of oxLDL and left ventricular ejection fraction. The transcardiac gradient of plasma oxLDL was significantly lower in 6 patients who received carvedilol than in 16 patients who did not receive carvedilol.

CONCLUSIONS

These findings indicate that the transcardiac gradient of oxLDL may be a marker of oxidative stress in the heart and that left ventricular dysfunction may be partly due to the oxidative stress in patients with DCM. In addition, TNF-alpha may stimulate oxidative stress in the failing heart in patients with DCM.     

肥厚型心肌病心律失常与心肌离子通道突变的关系

目的:探讨肥厚型心肌病(HCM)患者是否存在与心律失常有关的通道改变。方法:以PCR加SSCP方法对24例HCM患者心肌离子通道IKr、IKs和INa的编码基因KvLQT1、HERG、SCN5A进行筛查。正常对照100例。结果:在其中伴严重室性心律失常(短阵室性心动过速及因室性心动过速频发而安装ICD)的12例HCM患者中发现2例存在KvLQT1基因突变,分别为Pro448Arg突变和Val607Ala/Ile608Leu/Met619Leu三突变串联,后一种突变为首次报道。在其余无明显心律失常的12例HCM患者和正常对照中未发现突变。结论:心肌离子通道突变可能是部分HCM患者发生严重心律失常的机制之一。     

Myocardial fibrosis is associated with biventricular dysfunction in patients with hypertrophic cardiomyopathy

Aims: To assess left (LV) and right ventricular (RV) function by two‐dimensional (2D) speckle tracking echocardiography and its relation to myocardial fibrosis in hypertrophic cardiomyopathy (HCM). Methods: We enrolled 50 HCM patients (30 male; 47.3 ± 9.9 years) in our study. Each patient received echocardiography with modern high‐end scanners. For speckle tracking analysis of LV and RV function the dedicated software was used. The presence of myocardial fibrosis was detected by cardiac magnetic resonance imaging (MRI). Results: For intraobserver variability of RV global longitudinal strain, we found a correlation of r = 0.89 (p < 0.001) with a minor bias of 4.9 ± 2.9%. On cardiac MRI 30 patients (60%) demonstrated late gadolinium‐enhancement (LGE) of the LV. Of these patients only 7% showed LGE of the RV. HCM patients with myocardial fibrosis had less global longitudinal LV strain in comparison to patients without myocardial fibrosis (?12.8 ± 2.2 vs ?21.1 ± 2.6, P < 0.001), thicker interventricular septums (23.7 ± 4.0 vs 19.2 ± 5.1, P < 0.001), larger left atria (34.9 ± 7.1 vs 23.9 ± 5.1, P < 0.001), and impaired diastolic function (E/A‐ratio: 1.02 ± 0.22 vs 1.15 ± 0.18, P < 0.01). Comparable results were found for RV function. LV and RV strain correlated with r = 0.85 (p < 0.001). Conclusions: HCM is not only a disease of the LV. LGE in HCM is associated with both LV and RV dysfunction. Although RV LGE occurs only in a minority of patients with HCM and LV fibrosis, speckle tracking echocardiography is feasible for evaluating LV and RV dysfunction in these patients. (Echocardiography 2012;29:438‐444)