Diltiazem Reverses Tissue Doppler Velocity Abnormalities in Pre-Clinical Hypertrophic Cardiomyopathy

doi:10.1016/j.hlc.2004.02.002

Heart, Lung and Circulation

Volume 13, Issue 1, March 2004, Pages 39-40

https://doi.org/10.1016/j.hlc.2004.02.002 Get rights and content

Abstract

Background. Abnormalities in systolic and diastolic function shown by tissue Doppler imaging have been shown to be present in patients with hypertrophic cardiomyopathy who do not yet show clinical or echocardiographic evidence of the disease. These become more marked as left ventricular hypertrophy develops. We attempted to show that these abnormalities could be reversed by treatment with diltiazem.

Methods and Results. Six adults, who were carriers of a mutation involving the cardiac myosin binding, protein-C gene and who did not show clinical electrocardiographic or echocardiographic evidence of the disease were given a dose of 240 mg of diltiazem daily. Tissue Doppler peak systolic and early diastolic velocities at the lateral mitral annulus were examined before treatment and at a mean of 8 weeks after starting treatment. Improvement in both parameters occurred with early diastolic velocities returning to normal and most systolic velocities also becoming normal.

Conclusion. Diltiazem may have a role in helping to prevent abnormalities of function and perhaps the development of left ventricular hypertrophy in patients with pre-clinical hypertrophic cardiomyopathy.

Section snippets

Methods

The study population consisted of six adults who have been shown to possess the abnormal gene mutation for the myosin binding protein-C in a previously published study, but who are normal on clinical examination and whose electrocardiogram and two-dimensional echocardiogram are also normal.⁷ They have been shown to have an abnormality of tissue Doppler imaging—the peak velocity of the systolic wave and the early diastolic wave measured at the lateral mitral annulus.¹

All were symptom free and

Echocardiographic Protocol

Studies were performed with a Vingmed Systems 5 ultrasound system. Pulsed spectral tissue Doppler imaging was done at the lateral mitral annulus in the apical four chamber view. The lateral mitral annulus early diastolic velocity has been shown to be associated only with age and not heart rate or blood pressure, whereas the septal early diastolic velocity is associated with age, weight and diastolic blood pressure. Also the peak velocity in systole at the lateral mitral annulus is associated

Results

Peak systolic velocity showed an increase with treatment from a mean of 9.5±0.59 cm/s to 11.3±0.89 cm/s (P=0.012), all values rising into the normal range or towards normal, with five of the six falling into the normal range (Table 1, Table 2). Mean peak late diastolic velocity changed from 10.6 before treatment to 7.6 cm/s after treatment with both increases and decreases being recorded and no consistent change.

The greatest change occurred in peak early diastolic velocity which rose significantly

Discussion

We have previously shown that peak early diastolic velocity measured at the lateral mitral annulus is consistently abnormal in pre-clinical hypertrophic cardiomyopathy with 100% sensitivity.¹ A reduced peak mitral annular systolic velocity is usually also present.¹ It was also found that the greatest improvement in peak early diastolic velocity occurred in the two youngest patients who may have had fewer structural changes present (patients 1 and 3, Table 2).

Other workers have shown that in

References (7)

M Alam et al.
Characteristics of mitral and tricuspid annular velocities as determined by pulse wave tissue Doppler imaging in healthy subjects
J. Am. Soc. Echocardiogr.
(1999)
McTaggart DR. Tissue Doppler imaging in hypertrophic cardiomyopathy without left ventricular hypertrophy. Heart, Lung...
S.F Nagueh et al.
Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy
Circulation
(2001)

There are more references available in the full text version of this article.

Cited by (13)

Hypertrophic Cardiomyopathy
2020, Diastology: Clinical Approach to Heart Failure with Preserved Ejection Fraction
In hypertrophic cardiomyopathy (HCM), macroscopic and microscopic alterations in myocardial structure (myocardial hypertrophy, fiber disarray, increased loose connective tissue, and fibrosis) and abnormalities of the coronary microvasculature interfere with both myocyte force generation and myocardial relaxation. The mutations related to HCM result in the production of abnormal myocardial sarcomeric proteins that have altered contraction and relaxation characteristics. These include changes in the affinity between the various contractile proteins, changes in the sensitivity to Ca⁺², the efficiency of energy utilization (from ATP), and its expenditure. During stress, ischemia-induced diastolic dysfunction occurs at higher heart rates, reducing the diastolic filling period, resulting in increased intracavitary pressures aggravating subendocardial ischemia further. This is compounded by reduced left ventricular (LV) diastolic distensibility during exercise. Dyspnea is a common symptom, predominantly related to the presence of diastolic dysfunction and LV outflow tract (LVOT) obstruction. Worsening dyspnea may be precipitated by either the acute onset of atrial fibrillation or more insidiously by the development of LV systolic dysfunction. Echocardiography is the imaging modality of choice for the assessment of diastolic function in HCM, although accurate classification of diastolic function grade presents a challenge due to the compounding effects of LVOT obstruction and mitral regurgitation. Myocardial mechanics (assessment of strain rate, apical reverse rotation, and left atrial phasic volumes) may aid in diastolic functional assessment and be correlated with symptoms. Medical and invasive (septal reduction) therapy of LVOT obstruction may also improve diastolic function in patients with obstructive HCM.
A Long Term Follow-up Study of Carriers of Hypertrophic Cardiomyopathy Mutations
2017, Heart Lung and Circulation
Citation Excerpt :
Some of the patients experienced brief palpitations but no significant arrhythmias were observed at Holter monitoring and no complaints of progressive dyspnoea or chest pain. Four participants were found to have been trialled on the calcium channel blocker diltiazem for several years in an attempt to prevent progression to clinical HCM [27] but only two participants were currently taking cardiac medications (Table 1). Three participants (1.01, 1.02 AND 1.03) were found to have developed LVH on at least one imaging modality, with all three being adults when first diagnosed to be gene positive/LVH negative.
Adults who test positive for a mutation associated with the development of hypertrophic cardiomyopathy (HCM) but who have not manifested left ventricular hypertrophy (LVH) at the time of that diagnosis are now commonly identified in the era of genetic testing. There are little published data, however, on the long-term outlook for these phenotypically normal gene carriers.
Fifteen genotype positive/LVH negative patients with HCM were identified, seven of which were children when first diagnosed as gene carriers. Fourteen were followed up with clinical examinations, electrocardiography and echocardiography to determine if their clinical status had changed over time. Measurements included electrocardiographic changes, changes in wall thickness, diastolic function and global longitudinal stain.
Ten participants were followed up for a total of 18 years, two for a total of 17 years, one for 11 years and one for 8 years. In addition, magnetic resonance imaging (MRI) studies were performed on 11 participants. Eleven participants carried a mutation for the MYBPC3 gene and three carried a mutation for the MYH7 gene. One patient, an adult at the time of initial investigation, developed phenotypic features of HCM on echocardiography and MRI, one an increase in wall thickness diagnostic for HCM only on MRI and another to be borderline for HCM on MRI.
Hypertrophic cardiomyopathy can develop in adult life in carriers who may be negative for LVH at the time of gene diagnosis and warrants periodic supervision of carriers throughout their lives.
Gene expression profiling of calcium-channel antagonists in the heart of hypertensive and normotensive rats reveals class specific effects
2016, Vascular Pharmacology
Citation Excerpt :
However, the therapeutic benefit of diltiazem is less distinctive when compared to drugs like ACE-inhibitors and beta-blockers that proved to be superior over diltiazem in terms of efficacy [7]. Nowadays, diltiazem is used to treat vasospastic angina, Raynaud's syndrome and is occasionally used in supraventricular tachycardia but there is also evidence for diltiazem to possibly play a role in the early treatment of hypertrophic cardiomyopathy [8,9]. Surprisingly and despite its use for decades, little is known about the molecular effects on the regulation of cardiac genes coding for other ion channels, ion transporters and calcium handling proteins.
Calcium channel blockers (CCB) differ in their effects on the cardiovascular system with diltiazem being less negatively ionotrop as compared to verapamil. Diltiazem is mainly used to treat supraventricular tachycardia, vasospastic angina and the Raynaud's syndrome. Little is known about the molecular effects of benzothiazepins on cardiac gene expression. We therefore investigated the effects of diltiazem on cardiac gene expression in normotensive and hypertensive rats with left ventricular hypertrophy and compared the results with our previous findings on verapamil and nifedipine. Spontaneously hypertensive (SHR) and normotensive Sprague Dawley (SD) rats were treated with 15 mg/kg diltiazem b.i.d. for 3 days. Total RNA was isolated from surgically removed hearts and the gene expression of ion channels, ion transporters and their associated partners, calcium handling proteins as well as stress and cellular differentiation markers was investigated by RT-PCR. Subsequently, hierarchical gene cluster analysis was performed to decode treatment effects of different classes of CCBs. CCB treatment of normotensive and hypertensive rats revealed class specific effects with diltiazem specifically repressing cardiac genes pertinent for ion homeostasis and excitation-contraction coupling in normotensive but not hypertensive rats. Conversely, verapamil and nifedipine caused predominantly repression of genes to affect ion homeostasis and contractile dysfunction in spontaneously hypertensive rats; nonetheless, genes coding for calcium-handling proteins were up-regulated. Unlike diltiazem treatment of normotensive rats with verapamil and/or nifedipine did not influence cardiac gene expression. The effects of diltiazem on cardiac gene expression provide a molecular rationale for its use in the treatment of vasospastic angina.
Hypertrophic Cardiomyopathy
2008, Diastology: Clinical Approach to Diastolic Heart Failure
Noninvasive Cardiac Imaging in Patients With Hypertrophic Cardiomyopathy
2006, Journal of the American College of Cardiology
Citation Excerpt :
These observations have led to the investigation of TD imaging in the pre-clinical diagnosis of HCM in individuals carrying sarcomeric protein mutations encoding HCM. Four reports have provided encouraging results (42–45), with an additional study (39) showing subsequent LVH in such subjects (Fig. 7). In addition, this methodology proved accurate in the identification of patients with Fabry disease without LVH (46).
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and the most common cause of cardiac death in young athletes in the U.S. Noninvasive imaging plays an important role in detecting the disease, understanding its pathophysiology, and selecting as well as guiding appropriate therapy. In this review, we discuss the existing methodology with emphasis on current and emerging clinical applications in patients with HCM.
Preventative therapeutic approaches for hypertrophic cardiomyopathy
2021, Journal of Physiology

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Copyright © 2004 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Ltd. on behalf of The Australasian Society of Cardiac and Thoracic Surgeons and The Cardiac Society of Australia and New Zealand All rights reserved.

Original ArticleDiltiazem Reverses Tissue Doppler Velocity Abnormalities in Pre-Clinical Hypertrophic Cardiomyopathy

Abstract

Section snippets

Methods

Echocardiographic Protocol

Results

Discussion

J. Am. Soc. Echocardiogr.

Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy

Circulation

Original Article
Diltiazem Reverses Tissue Doppler Velocity Abnormalities in Pre-Clinical Hypertrophic Cardiomyopathy