Unexplained Left Ventricular Hypertrophy Research Articles

Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy phenotype is shared by heterogeneous entities. The purpose of the study was to evaluate the diagnostic role of left ventricular endomyocardial biopsy. One hundred fifty-one consecutive patients with unexplained left ventricular hypertrophy and normal/elevated QRS voltages or left bundle-branch block underwent left ventricular endomyocardial biopsy because of associated left ventricular dysfunction (37%), presence of sporadic form of left ventricular hypertrophy (32%), or patient desire for a definite diagnosis (31%). Biopsy samples were processed for histology and electron microscopy. Blood samples were collected for histologically oriented gene analysis of major sarcomeric (MYH7, MYBPC3, TNNT2, TPM1) and lysosomal (LAMP2, PRKAG2, α-galactosidase A) proteins. Histology showed changes consistent/compatible with hypertrophic cardiomyopathy in 124 patients: myocardial storage disease in 18 due to Fabry disease in 12 and glycogen-storage disease in 6 and myocardial infiltrative disease in 9 because of amyloidosis in 7 and sarcoidosis in 2. Gene analysis was positive in 67% of patients with hypertrophic cardiomyopathy (MYH7 mutation in 36, MYBP in 29, TNNT2 in 14, and TPM1 in 5) and in 83% of patients with lysosomal storage disease (α-galactosidase A mutation in 12, PRKAG2 in 2, and LAMP2 in 1). In patients with hypertrophic cardiomyopathy phenotype, left ventricular endomyocardial biopsy is safe and may recognize infiltrative/storage diseases in up to 18% of evolving and sporadic cases.

Left ventricular hypertrophy in Fabry disease: a practical approach to diagnosis

Left ventricular hypertrophy (LVH) is prevalent and associated with a poor long-term prognosis. The Framingham Heart Study, for example, showed that LVH was present in 15–20% of adults, and that, for each 50 g/m2 increment of left ventricular mass, the relative risk of cardiovascular death increased by 1.73 in men and 2.12 in women.1 Although hypertension, obesity and valvulopathies account for most causes of LVH, it is important to investigate patients with otherwise unexplained LVH since many causes are treatable. Although several electrocardiographic (ECG) criteria for the identification of LVH are available, additional investigations [notably transthoracic echocardiography (echo)] are invariably required due to the lack of sensitivity and specificity of ECG. The European Association of Echocardiography definition of LVH includes the demonstration of interventricular septal and/or posterior wall thickness in end-diastole ≥13 mm.2 Echocardiography can additionally interrogate valve function and characterize LVH as concentric (uniform mechanism, e.g. LV pressure overload, myocardial infiltration), or eccentric [e.g. asymmetrical septal hypertrophy in hypertrophic cardiomyopathy (HCM)]. After the identification of LVH, a practical approach to its further assessment includes a clinical review with targeted investigations aimed firstly to exclude common causes; e.g. hypertension, obesity and valve disease. Thereafter, evaluation involves a systematic approach to exclude less common causes, e.g. hypertrophic and other cardiomyopathies, myocardial infiltration, metabolic disorders, and syndromic conditions associated with LVH. Table 1 provides a systematic scheme incorporating clinical pearls and diagnostic pointers to help target adjunctive investigations and help identify the aetiology of LVH. Disorders causing or associated with LVH are arranged in a pathological hierarchical manner with common conditions appearing first, followed by rarities. View this table: Table 1 Clinical characteristics of conditions causing left ventricular hypertrophy and diagnostic pointers Many heart muscle disorders presenting with LVH are due to inherited mutations in genes encoding contractile proteins of the cardiac sarcomere, metabolic pathways, …

Transcriptional Regulation of Cardiac Genes Balance Pro- and Anti-Hypertrophic Mechanisms in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy. HCM is often hereditary, but our knowledge of the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocar - dium of HCM patients may contribute to understanding the mechanisms that drive and stabilize the hypertrophy. Cardiac myectomies/biopsies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls were studied with whole genome Illumina microarray gene expression (detecting 18 189 mRNA). When comparing HOCM myocardium to controls, there was significant transcriptional down-regulation of the MYH6, EGR1, APOB and FOS genes, and significant transcriptional up-regulation of the ACE2, JAK2, NPPA (ANP), APOA1 and HDAC5 genes. The transcriptional regulation revealed both pro- and anti-hypertrophic mechanisms. The pro-hypertrophic response was explained by the transcriptional down-regulation of MYH6, indicating that the switch to the fetal gene program is maintained, and the transcriptional up-regulation of JAK2 in the JAK-STAT pathway. The anti-hypertrophic response was seen as a transcriptional down-regulation of the immediate early genes (IEGs), FOS and EGR1, and a transcriptional up-regulation of ACE2 and HDAC5. This can be interpreted as a transcriptional endogenous protection system in the heart of the HOCM patients, neither growing nor suppressing the already hypertrophic myocardium.

Role of Multimodality Imaging in the Diagnosis and Treatment of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), or the presence of unexplained left ventricular (LV) hypertrophy, has a diverse phenotypic expression, making diagnosis often challenging. By using a variety of cardiac noninvasive imaging modalities, our diagnostic capabilities have been amplified. Imaging plays a key role in the diagnosis of disease, characterization of phenotype, classification of disease severity, risk stratification, family screening, and selection of appropriate therapy. This is achieved through assessment of cardiac structure and function as well as the presence of myocardial ischemia, fibrosis and metabolism, the presence of dynamic obstruction, mitral valve abnormalities, and the severity of mitral regurgitation. This review focuses on the variety of imaging modalities, with special attention to cardiac computed tomography (CT) and magnetic resonance (MR) in detection, characterization, and risk stratification of this phenotypically diverse disease.

Genetic Considerations in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy that develops in the absence of pressure overload or storage/infiltrative processes. Approximately 20 years ago, mutations in genes encoding sarcomere proteins were identified as the cause of HCM. Although there are limitations to current clinical application, genetic testing can identify the specific gene mutation responsible for causing HCM in patients and their family. This provides a definitive means to identify at-risk relatives, as well as new opportunities to study pathogenesis, and developing novel strategies for disease prevention and modification.

Prevalence of Anderson–Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson–Fabry Disease Survey

ObjectivesThe prevalence of Anderson–Fabry disease (AFD) in patients presenting with unexplained left ventricular hypertrophy (LVH) is controversial. The aim of this study was to determine the prevalence of AFD in...

Hypertrophic Cardiomyopathy Is Associated with Abnormal Echocardiographic Aortic Elastic Properties and Arteriograph-Derived Pulse-Wave Velocity

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease and defined by the presence of unexplained left ventricular hypertrophy (LVH). Vascular alterations are frequently associated with HCM including microvascular and/or peripherial endothelial dysfunction. This study was designed to evaluate echocardiographic ascending aortic elastic properties and arteriograph-derived pulse-wave velocity (PWV) and augmentation index (Aix) in HCM. This study comprised 38 patients with typical features of HCM. Their results were compared to 20 hypertensive patients with LVH and 23 controls. Systolic and diastolic ascending aortic diameters were recorded in M-mode at a level of 3 cm above the aortic valve from a parasternal long-axis view. The following echocardiographic aortic elastic properties were measured from aortic data and forearm blood pressure values: aortic strain, distensibility, and stiffness index. Arteriograph-derived PWV and AIx were also measured. Aortic stiffness index (18.4 ± 17.6 vs. 6.88 ± 3.63, P < 0.05), PWV (9.44 ± 4.08 vs. 7.97 ± 1.20 m/sec, P < 0.05) and Aix (-24.9 ± 32.6 vs. -41.4 ± 24.3, P < 0.05) were increased, while aortic strain (0.061 ± 0.053 vs. 0.100 ± 0.059, P < 0.05) and aortic distensibility (1.94 ± 1.68 cm(2) /dynes 10(-6) vs. 3.08 ± 1.77 cm(2) /dynes 10(-6) , P < 0.05) were decreased in HCM patients compared to controls. Aortic elastic properties of hypertensive patients with LVH showed similar alterations to HCM patients. Abnormal echocardiographic aortic elastic properties and arteriograph-derived PWV and Aix could be demonstrated in HCM patients compared to matched controls.

Amyloidotic Cardiomyopathy: Multidisciplinary Approach to Diagnosis and Treatment

Amyloidotic cardiomyopathy (ACMP) occurs in the setting of rare genetic diseases, blood dyscrasias, chronic infection and inflammation, and advanced age. Cardiologists are on the front lines of diagnosis of ACMP when evaluating patients with unexplained dyspnea, congestive heart failure, or arrhythmias. Noninvasive detection of diastolic cardiac dysfunction and unexplained left ventricular hypertrophy should be followed by biopsy to demonstrate the presence of amyloid deposits and appropriate genetic, biochemical, and immunologic testing to accurately define the type of amyloid. Growing numbers of treatment options exist for these diseases, and timely diagnosis and institution of therapy is essential for preservation of cardiac function.

New paradigms in hypertrophic cardiomyopathy: Insights from genetics

Understanding the genetic basis of hypertrophic cardiomyopathy (HCM) provides a remarkable opportunity to predict and prevent disease. HCM is caused by mutations in sarcomere genes and is the most common monogenic cardiovascular disorder. Although unexplained left ventricular hypertrophy (LVH) is considered diagnostic, LVH is not always present. LV wall thickness is often normal until adolescence or later, even in individuals known to carry pathogenic sarcomere mutations. In contrast, genetic testing can identify both individuals who carry pathogenic sarcomere mutations and have a clinical diagnosis of HCM, as well as mutation carriers who have not yet manifested LVH but are very likely to develop disease. Studying this important new patient subset, designated early or preclinical HCM, allows characterization of the initial consequences of sarcomere mutations, prior to the onset of overt hypertrophic remodeling. Such study has defined novel early phenotypes, including impaired left ventricular relaxation, myocardial energetic deficiencies, and altered collagen metabolism, in mutation carriers with apparently normal cardiac morphology. These results indicate that sarcomere mutations have substantial impact on myocardial function and biochemistry before the onset of frank hypertrophy. Furthermore, animal models of preclinical HCM have identified promising new treatment strategies that may diminish the emergence of overt disease. We can now begin to reshape the paradigm for treating genetic disorders. With improved mechanistic insight and the capability for early diagnosis, genetic advances can lead to new approaches for disease modification and prevention.

THE CONTRIBUTION OF THE EKG / ECHOCARDIOGRAPHIC MASS RATIO TO THE DIAGNOSIS OF CARDIAC AL AMYLOIDOSIS IN UNEXPLAINED LV HYPERTROPHY: 4C.05

Background: In cardiac amyloidosis (AL) the increase in wall thickness caused by extracellular amyloid deposition leads to marked increases in left ventricular (LV) mass. At variance with other forms of cardiac hypertrophy, this is often associated with abnormally low electrocardiographic (EKG) voltages, due to amyloid negative effects on intracardiac electrical conduction. Although such a discrepancy (low EKG “electrical” LV mass / high echo-derived LV mass) might be a powerful diagnostic clue, this is often missed since almost 40% of cardiac AL patients do not strictly fulfil the definition of “EKG low voltages” (<5 mV in all peripheral leads). Methods: To evaluate the possible relevance of this finding, we compared an index of the EKG/ echo mass estimate in patients with cardiac AL (n = 218), non-cardiac AL (n = 69), hypertension with different degrees of LV hypertrophy (n = 125), and in normotensive patients with normal LV mass (n = 99). Echo-derived LV mass was estimated via the Devereux's formula (g/m2), whereas QRS score (the sum of QRS voltages in the peripheral leads, mV) was used as an index of “electrical” LV mass. EKG/Echo ratio was expressed as [mV/(g/m2)]. Patients with other potential causes of low EKG voltages (large pericardial effusions, obesity, chronic obstructive lung disease, and severe peripheral oedema) were excluded. Results: The EKG/echo mass ratio was superimposable in non-cardiac AL, normotensive, and hypertensive subjects [0.51±0.12, 0.54±0.13, and 0.49±0.15 mV/(g/m2), respectively]. In contrast, the EKG/echo mass ratio was markedly depressed in patients with cardiac AL [0.19±0.10 mV/(g/m2), p<0.001]. The area under the ROC curve for the detection of cardiac AL involvement was high: 0.96 (95% CI, 0.93 to 0.98). The best cutoff for the diagnosis of heart involvement was 0.33 mV/(g/m2), giving a 93.8% sensitivity and a 91.1% specificity. Conclusions: In patients with unexplained LV hypertrophy, an abnormally low EKG/echo mass ratio might be a powerful clue suggesting the diagnosis of cardiac amyloidosis, overcoming the limited diagnostic accuracy of the presence of “EKG low voltages”.

Late-Onset Cardiac Variant of Fabry Disease Responsive to Short-Term Treatment with Agalsidase Alpha

Cardiac involvement is very frequent with Fabry disease, an X-linked lysosomal storage disorder caused by defi ciency of α-galactosidase A. Enzyme replacement therapy has been proven effective in reducing gycosphingolipid accumulation in endothelial cells of the kidney, heart and skin, as well as improving cardiac morphology and function. However, Fabry disease cardiomyopathy (FC) is often indistinguishable from hypertrophic cardiomyopathy (HCM) or other causes of left ventricular hypertrophy (LVH), based on clinical and instrumental fi ndings. We describe a 60-yearold patient with unexplained HCM and progressive renal disease who was admitted to our centre for echocardiography evaluation. He had a history of dysrhythmias (for which he had undergone implantation of an ICD device) and presented with ECG abnormalities, echocardiographic evidence of LVH and reduced tissue Doppler imaging velocities and lateenhancement areas at gadolinium enhanced cardiac magnetic resonance evaluation. Demonstration of a total defi ciency of αgalactosidase A in the leukocytes confi rmed the diagnosis of Fabry disease. The patient experienced improvement of pain, oedema, exercise capacity and cardiac and renal haematological parameters after 6 weeks’ treatment with agalsidase α. Fabry disease should always be considered in the differential diagnosis of unexplained LVH.

Hypertrophic Cardiomyopathy: Preclinical and Early Phenotype

Hypertrophic cardiomyopathy (HCM) is caused by dominant mutations in sarcomere genes. Although the diagnosis of HCM is traditionally based on identifying unexplained left ventricular hypertrophy (LVH) by cardiac imaging, LVH is not an invariable feature of disease. The expression of LVH is highly age-dependent, and LV wall thickness is typically normal during childhood. Overt cardiac hypertrophy often does not develop until adolescence or later. With genetic testing, family members who have inherited a pathogenic sarcomere mutation (G+) can be identified prior to a clinical diagnosis (LVH-). This allows characterization of a new and important subset, denoted preclinical HCM (G+/LVH-). Although there are no distinguishing morphologic features of early disease, there is evidence of myocardial dysfunction prior to the development of LVH. Otherwise healthy sarcomere mutation carriers frequently have subtle impairment of diastolic function, detectable by tissue Doppler interrogation. These findings can assist in differentiating such at-risk family members from those who did not inherit the mutation, despite the presence of normal LV wall thickness. In contrast, systolic function appears relatively preserved in preclinical HCM but impaired in overt disease, suggesting that both the sarcomere mutation and the characteristic changes in myocardial architecture (LVH, fibrosis, and disarray) are required to perturb force generation. Better characterization of preclinical HCM will identify the initial manifestations of sarcomere mutations, characterize intermediate disease phenotypes, and foster efforts to develop novel therapeutic strategies based on genetic identification of at-risk individuals and early initiation of therapy to prevent disease progression when treatment may be most effective.

The Effects of Candesartan on Left Ventricular Hypertrophy and Function in Nonobstructive Hypertrophic Cardiomyopathy: A Pilot, Randomized Study

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.

A Case of Fabry Cardiomyopathy

In the absence of hypertension, hypertrophic cardiomyopathy is the most common cause of left ventricular hypertrophy (LVH). However, it has been reported that up to 3% of males with unexplained LVH have Fabry disease, an X-linked disorder of glycophospholipid metabolism that is due to a deficiency in the lysosomal enzyme α-galactosidase A (α-Gal A). A 44-year-old man was admitted to our hospital with palpitations. He had a history of chronic renal failure diagnosed at age 33 followed by kidney transplantation performed at our institution 2 years later, as well as long-standing hypohidrosis. His medications included prednisolone (5 mg daily), mycophenolate mofetil (1,000 mg, bid), and cyclosporine (150 mg, bid). On hospital day two, an echocardiogram demonstrated increased left ventricular wall thickness (septal wall thickness of 28 mm, posterior wall thickness of 20 mm). Diastolic dysfunction was noted on transmitral flow patterns and tissue Doppler imaging. The patient was found to have low plasma α-Gal A activity. A previously reported H46R missense mutation was detected in his α-Gal A gene and the patient was subsequently diagnosed with Fabry disease.

A Case of Suspected Danon Disease Presenting as a Hypertrophic Cardiomyopathy

Introduction Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy (LVH). HCM is usually inherited as an autosomal dominant trait. Mutations in 10 genes related to the sarcomeric proteins account for approximately 60% of all cases of HCM. According to a recent gene analysis, abnormalities in many genes were found. Danon disease is one of them. Danon disease is caused by mutation of LAMP-2 gene and has a unique clinical manifestation of cardiomyopathy, myopathy and mental retardation. There is no case of Danon disease reported in Korea. The authors experienced a 30 year-old male patient who had unique clinical features of Danon disease such as cardiomyopathy, myopathy and mental retardation. Therefore, we report this case with review of literature.

Thick hearts, high stakes, great uncertainties: screening athletes for hypertrophic cardiomyopathy

In 1958, British pathologist Donald Teare described a family in which eight victims of sudden death had marked asymmetric hypertrophy of the left ventricle,1 a condition now known as hypertrophic...

Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. An increase in extracellular matrix produces interstitial fibrosis, by raised amounts of collagen type I/III. Regions of myocardial late gadolinium enhancement by cardiac magnetic resonance (CMR) represented increased myocardial collagen. Regarding the role of matrix metalloproteinases (MMPs) in myocardial remodeling and subsequent fibrosis, the aim of our study was to explore the relation between MMP system and myocardial late gadolinium enhancement by CMR (as expression of image-documented fibrosis) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (as a marker of cardiac overload) in HCM. We included 67 HCM patients (44 men aged 49 +/- 14 years) and were compared to 58 controls with similar age and sex. Risk factors for sudden death were recorded. A blinded CMR was performed with gadolinium. Matrix metalloproteinase 1, MMP-2, and MMP-9 plasma levels were assayed by enzyme-linked immunosorbent assay. Serum samples were used for measurement of NT-proBNP. In patients, >50% of MMP-1 values were below the lowest limit of detection of the technique. Raised levels of MMP-2, MMP-9, and NT-proBNP were observed in HCM patients (all P < .01). Matrix metalloproteinase 2 was associated with dyspnea (P = .049) and correlated with MMP-9 (r = 0.28, P = .025) and NT-proBNP (r = 0.39, P = .001). Matrix metalloproteinase 9 was associated with the presence of gadolinium enhancement in CMR (P = .001) and correlated with NT-proBNP (r = 0.52, P < .001). NT-proBNP was also associated with gadolinium enhancement (P = .006). Both MMP-2 and MMP-9 correlated negatively with exercise capacity (metabolic equivalent units), (r = -0.36 and r = -0.42 respectively, both P < .01). On multivariate analysis (adjusted by sudden death risk factors and echocardiographic markers), only MMP-9 was associated with fibrosis (P = .011). Matrix metalloproteinase 9 is independently associated with gadolinium enhancement on CMR in patients with hypertrophic cardiomyopathy, suggesting that the MMP system has an important role in cardiac remodeling and fibrosis in this condition.

Fabry's disease presenting as ventricular tachycardia and Left Ventricular 'Hypertrophy'

Fabry's disease (FD) is a genetic disorder leading to deficiency of alpha-galactosidase A. Enzymatic replacement therapy has recently become available. Patients with classical FD develop multi-system involvement; however, there is an increasingly recognized cardiac variant that presents as unexplained left ventricular hypertrophy. We describe a patient with Fabry's disease who presented with ventricular tachycardia.

Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression

Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy, is the most common inherited cardiac disorder. This condition is the major cause of sudden death in the young (<30 years of age) and in athletes. The clinical phenotype is heterogeneous, and mutations in a number of sarcomeric contractile-protein genes are responsible for causing the disease in approximately 60% of individuals with HCM. Other inherited syndromes, as well as metabolic and mitochondrial disorders, can present as clinical phenocopies and can be distinguished by their associated cardiac and noncardiac features and on the basis of their unique molecular genetics. The mode of inheritance, natural history and treatment of phenocopies can differ from those of HCM caused by mutations in sarcomere genes. Detailed clinical evaluation and mutation analysis are, therefore, important in providing an accurate diagnosis in order to enable genetic counseling, prognostic evaluation and appropriate clinical management. This Review summarizes current knowledge on the genetics, disease mechanisms, and correlations between phenotype and genotype in patients with HCM, and discusses the implications of genetic testing in routine clinical practice.

Increasing evidence for the safety and efficacy of alcohol septal ablation during medium- and long-term follow-up

Prof. Dr. Andre Keren ()) Center for Heart Failure and Heart Muscle Diseases Heart Institute Hadassah University Hospital Hadassah-Hebrew University Medical School Jerusalem 91120, Israel E-Mail: andrek@cc.huji.ac.il Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy [1], is the most common inherited cardiac disorder affecting one in 500 people [2, 3]. Approximately 25% of patients have left ventricular outflow obstruction at rest and 70% can develop outflow gradients during exercise [4]. The dynamic outflow obstruction is caused by the abnormal systolic contact between the hypertrophied basal interventricular septum and the anterior mitral leaflet