HCM Patients Research Articles

Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death

BACKGROUNDHypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a diverse clinical spectrum, in which many of the abnormal structural and pathophysiologic features are consequences of inappropriate left ventricular hypertrophy.METHODSWe analyzed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly. The morphologic appearance and volume fractions of interstitial (matrix) and perivascular (adventitial) collagen were analyzed with polarization microscopy and computerized videodensitometry in picrosirius red-stained sections. Findings were compared with 16 structurally normal hearts, 5 with systemic hypertension and 6 infants who died of HCM.RESULTSAdults and young children with HCM had an eightfold greater amount of matrix collagen compared with normal controls (14.1 ± 8.8% vs. 1.8 ± 1% of the tissue section; p < 0.0001), and a threefold increase compared with patients with systemic hypertension (4.5 ± 1.3%; p < 0.001) and infants with HCM (4.0 ± 2.4%; p < 0.001). Compared with normal controls and hypertensives, adults and young children (and infants) with HCM showed increased numbers and thickness of each collagen fiber component of the matrix (perimysial coils, pericellular weaves and struts), which were often arranged in disorganized patterns. In HCM patients, the amount of collagen was not a consequence of other clinical, demographic and morphologic disease variables.CONCLUSIONSLeft ventricular collagen matrix in young, previously asymptomatic patients with HCM who died suddenly is morphologically abnormal and substantially increased in size. The enlarged matrix collagen compartment is present in HCM at an early age, further expands during growth, is partially responsible for increased ventricular septal thickness and likely represents a primary morphologic abnormality in this disease. These findings support the view that the complex HCM disease process is not confined to sarcomere protein abnormalities, but also involves connective tissue elements.

The cardiac beta-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population.

The aim of the study was to screen 36 unrelated patients with hypertrophic cardiomyopathy (HCM; 16 familial and 20 sporadic cases) from a genetically homogeneous area in eastern Finland for variants in the cardiac beta-myosin heavy chain (beta-MHC) and alpha-tropomyosin (alpha-TM) genes. Mutations in the beta-MHC and alpha-TM genes have been reported to be responsible for 30% to 40% and less than 5% of familial HCM cases, respectively. However, most genetic studies have included patients from tertiary care centers and are subject to referral bias. Exons 3-26 and 40 of the beta-MHC gene and the nine exons of the alpha-TM gene were screened with the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method. Linkage analyses between familial HCM locus and two intragenic polymorphic markers (MYO I and MYO II) of the beta-MHC gene were performed in 16 familial HCM kindreds. A previously reported Arg719Trp (arginine converted to tryptophan in codon 719) mutation of the beta-MHC gene was found in one proband and two relatives. In addition, a novel Asn696Ser (asparagine converted to serine in codon 696) substitution was found in one HCM patient. No linkage between familial HCM and the beta-MHC gene was observed in 16 familial kindreds. A previously reported Aspl75Asn (aspartic acid converted to asparagine in codon 175) mutation of the alpha-TM gene was found in four probands and 16 relatives. Mutations in the beta-MHC and alpha-TM genes accounted for 6% and 25% familial HCM cases and 3% and 11% of all cases, respectively. Our results indicate that the beta-MHC gene is not the predominant gene for HCM in the Finnish population, whereas HCM caused by the Aspl75Asn mutation of the a-TM gene is more common than previously reported.

Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy.

In this study, we both investigated coronary flow velocity in hypertrophic obstructive cardiomyopathy (HOCM) and tested the hypothesis of differing coronary flow reserve (CFR) of coronary arteries perfusing left ventricular regions with nonuniform myocardial hypertrophy by measuring the relative CFR. Coronary flow velocity was assessed in left anterior descending coronary (LAD) and left circumflex (LCX) arteries in 18 patients with HOCM and marked hypertrophy only in the ventricular septum, in 13 patients without obstruction (HCM), and in 9 age- and sex-matched normal subjects at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 microg/kg per minute). Relative CFR was estimated as the ratio between absolute CFR of the LAD and absolute CFR of the LCX (LAD/LCX(CF)). At the peak of rapid atrial pacing and during dobutamine stress, LAD/LCX(CF) was reversed in HOCM patients (from 1.25+/-0.11 to 0.82+/-0.07 and 0.79+/-0.06, respectively), whereas it remained unchanged in control subjects (from 1.0+/-0.1 to 1.0+/-0.05 and 1.0+/-0.05, respectively; P<.001). In HCM patients, LAD/LCX(CF) at rest was 1.10+/-0.11, whereas during rapid atrial pacing and dobutamine stress, it was 0.92+/-0.08 and 0.90+/-0.09, respectively. Relative CFR was 0.62+/-0.05 in HOCM patients and 1.05+/-0.05 (P<.001) in normal subjects. There was an inverse correlation between relative CFR and peak systolic outflow tract gradient (r2=.74, P<.001). Regional distribution of hypertrophy in some patients with HOCM resulted in regional impairment of coronary flow. Relative CFR can be used to estimate regional disturbances of coronary flow and may help in patient selection for new interventional therapeutic techniques.

Point mutations in human beta cardiac myosin heavy chain have differential effects on sarcomeric structure and assembly: an ATP binding site change disrupts both thick and thin filaments, whereas hypertrophic cardiomyopathy mutations display normal assembly.

Hypertrophic cardiomyopathy is a human heart disease characterized by increased ventricular mass, focal areas of fibrosis, myocyte, and myofibrillar disorganization. This genetically dominant disease can be caused by mutations in any one of several contractile proteins, including beta cardiac myosin heavy chain (beta MHC). To determine whether point mutations in human beta MHC have direct effects on interfering with filament assembly and sarcomeric structure, full-length wild-type and mutant human beta MHC cDNAs were cloned and expressed in primary cultures of neonatal rat ventricular cardiomyocytes (NRC) under conditions that promote myofibrillogenesis. A lysine to arginine change at amino acid 184 in the consensus ATP binding sequence of human beta MHC resulted in abnormal subcellular localization and disrupted both thick and thin filament structure in transfected NRC. Diffuse beta MHC K184R protein appeared to colocalize with actin throughout the myocyte, suggesting a tight interaction of these two proteins. Human beta MHC with S472V mutation assembled normally into thick filaments and did not affect sarcomeric structure. Two mutant myosins previously described as causing human hypertrophic cardiomyopathy, R249Q and R403Q, were competent to assemble into thick filaments producing myofibrils with well defined I bands, A bands, and H zones. Coexpression and detection of wild-type beta MHC and either R249Q or R403Q proteins in the same myocyte showed these proteins are equally able to assemble into the sarcomere and provided no discernible differences in subcellular localization. Thus, human beta MHC R249Q and R403Q mutant proteins were readily incorporated into NRC sarcomeres and did not disrupt myofilament formation. This study indicates that the phenotype of myofibrillar disarray seen in HCM patients which harbor either of these two mutations may not be directly due to the failure of the mutant myosin heavy chain protein to assemble and form normal sarcomeres, but may rather be a secondary effect possibly resulting from the chronic stress of decreased beta MHC function.

Myocardial ultrasonic tissue characterization in pediatric and adult patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) has different clinical and prognostic aspects in young than in adult patients. This study was undertaken to determine whether these reported differences are reflected by changes in ultrasonic backscatter parameters and whether oral treatment with verapamil modifies backscatter variables in children with HCM. Sixty-eight subjects underwent backscatter analysis to assess the ultrasonic myocardial reflectivity and the amplitude of the cardiac cycle-dependent variation of the backscatter power curve. Subjects were divided into four groups: 10 HCM and 23 normal subjects < 10 years old and 17 HCM and 18 normal adults. Myocardial reflectivity and amplitude of the cyclic variation were assessed in the septum and in the posterior wall of all subjects. The children with HCM were restudied after long-term oral administration of verapamil. Both children and adult patients, compared with the normal control groups, showed a significant reduction in the amplitude of the cyclic variation both in the septum and in the posterior wall. In contrast, myocardial reflectivity, although significantly increased in adult HCM patients, was unchanged in the young HCM group. Verapamil administration did not significantly alter the results in the children with HCM. These data demonstrate that in young HCM patients, the ultrasonic myocardial reflectivity is normal, in contrast to the significant increase observed in adult patients affected by the same disease. This observation is in accord with the different clinical manifestations reported in young HCM patients and indicates an age-dependent difference in the echogenic structure of the hypertrophied myocardium in HCM.

Sudden cardiac death in hypertrophic cardiomyopathy. Variability in phenotypic expression of beta-myosin heavy chain mutations.

Recent identification of mutations in the beta-myosin heavy chain gene (MYH7), a major responsible gene for HCM, has provided the opportunity to characterize genotype-phenotype correlation in HCM families. In this study we analysed the phenotypic expression of two beta-myosin heavy chain (beta MHC) mutations in three unrelated HCM families. Living individuals from three unrelated HCM families (Families 1, 2, and 3) were screened by history, physical examination, electrocardiography, and two-dimensional echocardiography. Blood was collected from all individuals for DNA extraction. Polymerase chain reaction (PCR), restriction endonuclease digestion and chemical cleavage were utilized for detection of mutations. All mutations were confirmed by sequence analysis. Identification of mutations: A missense mutation in exon 13 of the beta MHC gene (Arg403 Gln) was detected in HCM patients from Families 1 and 2. PCR amplification of the exon 13 DNA, followed by Ddel digestion of the PCR product and gel electrophoresis, showed two fragments of 84 and 70 bp in normal individuals and four fragments of 84, 70, 52 and 32 bp in HCM patients. Sequence analysis showed substitution of an adenine for guanine at coding position 1208. In Family 3, a missense mutation in exon 16 of the beta MHC gene (Val606 Met) was detected in HCM patients. Chemical cleavage of the PCR products showed an uncleaved product of 337 bp in the normal individuals, while in the affected individuals, in addition to the uncleaved product, a 90 bp cleaved product was also detected, indicating the presence of a mismatch in one allele. Sequence analysis showed substitution of an adenine for guanine in coding position 1817. Seven members of Family 1 had HCM, of whom five are alive. One patient died from sudden cardiac death (SCD) and another from recurrent cerebral emboli. In Family 2, 15 individuals had HCM of whom nine have died, seven from SCD. The mean age at the time of SCD was 33 years. The third family is comprised of 11 affected individuals and one obligate carrier, of whom one patient died at age 17 from progressive heart failure. Two additional individuals in this family have also succumbed to SCD to age 60. A variety of clinical and echocardiographic manifestations of HCM were present in each family. Logrank test of Kaplan-Meier survival curves indicates that Arg403 Gln mutation was associated with a poor prognosis in HCM families as compared to Val606 Met (P = 0.034). beta MHC mutations despite showing variable clinical and echocardiographic manifestations of HCM are predictors of survival in HCM families.

Altered left ventricular diastolic function post-atrial pacing in coronary artery disease and left ventricular hypertrophy: further insights by pulmonary venous flow analysis.

Left ventricular filling dynamics during acute pacing-induced myocardial ischaemia were assessed using transoesophageal atrial pacing and simultaneous Doppler measurements of pulmonary venous and mitral flow. All patients (10 with CAD and 12 with left ventricular hypertrophy due to hypertrophic cardiomyopathy; HCM) were in sinus rhythm and patients with mitral insufficiency were excluded. Data were compared with those of a control group (n = 10). Measurements were obtained at baseline (heart rate 84 +/- 14 beats.min-1) and immediately after atrial pacing via the same transoesophageal echocardiography (TEE) probe after stepwise increase of the pacing rate to 133 +/- 12 beats.min-1. Heart rate immediately after pacing was 83 +/- 13 beats.min-1. Time velocity integrals (TVI) were calculated at baseline and after pacing for the following flows: early (E) and late (A) mitral flows, as well as antegrade systolic (S), diastolic (D) and retrograde diastolic (R) pulmonary venous flows. In the control group none of the flow parameters changed significantly after pacing compared with baseline data. In contrast, in CAD patients, the TVI of the E wave, the TVI E/A ratio as well as the pulmonary venous flow changed significantly after pacing (7.3 to 5.5 cm, P < 0.05, 1.7 to 1.1, P < 0.01 and 1.0 to 2.1 cm, P < 0.001, respectively). HCM patients also showed significant changes: TVI E/A ratio post-pacing decreased from 1.9 to 1.4 (P < 0.05), and the pulmonary venous reverse flow integral increased from 1.3 to 2.8 cm (P < 0.0001). Analysis of variance showed the TVI E/A ratio to be significantly dependent on pacing (P = 0.012). The pulmonary venous retrograde flow was found to be influenced by the presence of disease (P = 0.033 before and P = 0.0001 after pacing) and in all cases by pacing (before vs after pacing; P = 0.0001). Pacing resulted in significantly different changes in the TVI E/A ratio and the TVI of the retrograde pulmonary venous flow for CAD and HCM patients compared with those of control subjects. In patients with CAD and HCM, rapid atrial pacing results in a decreased early to late ventricular filling ratio because of impaired relaxation, despite presumably increased filling pressure. Retrograde pulmonary venous flow increased because of increased filling pressure and operating left ventricular stiffness.

Autoantibodies against Cardiac G-Protein-Coupled Receptors Define Different Populations with Cardiomyopathies but Not with Hypertension

It was previously shown that the second extracellular loop of cardiovascular G-protein-coupled receptors is an antigenic target for pharmacologically active autoantibodies in patients with idiopathic dilated cardiomyopathy. To extend these observations to cover patients with the same disease from different geographical origins or to patients with other cardiac diseases, peptides corresponding to the sequences of the second extracellular loops of the human M2 muscarinic receptors and β adrenoceptors were used as antigens in an enzyme immunoassay. Sera from patients from Sweden and Japan with idiopathic dilated cardiomyopathy (DCM, n = 32), hypertrophic cardiomyopathy (HCM, n = 23), malignant essential hypertension (MEH, n = 11), malignant secondary hypertension (MSH, n = 10), and sera from healthy blood donors (HBD, n = 49) were tested. Sera from patients with DCM recognized the muscarinic receptor peptide in 38% of cases and the β1 adrenoceptor peptide in 31% of cases. In 50% of the positive patients, autoantibodies against both peptides coexisted as shown by competition experiments using both peptides as inhibitors. In HCM patients, there was a lower frequency of autoantibodies but with a higher but not significant predominance against the M2 peptide. No autoantibodies were detected in sera from patients with MEH or MSH. Autoantibodies against the M2 muscarinic receptors, affinity-purified from positive patients, displayed pharmacological activity as demonstrated by changes in the affinity and number of radioligand binding sites. In contrast, antibodies purified from positive HBD had no effect. These results confirm that autoantibodies displaying pharmacological activity against G-protein-coupled cardiovascular receptors are mainly restricted to patients with idiopathic dilated cardiomyopathy and that different autoantibody populations are responsible for the recognition of the different receptors.

Sudden death screening

SCD is a tragic-event that rarely affects exercising individuals. It is important for the practitioner to recognize the normal physiologic changes that occur in the exercising athlete that correspond to AHS so as to differentiate them from conditions placing an athlete at risk for SCD. Different clinical entities account for SCD in athletes under age 30 as opposed to over age 30, although there is some overlap. Comprehensive and expensive screening tests have not proved to be cost-effective, nor are they able consistently to identify athletes at risk. A quality history and thorough cardiac screening examination are the best means to identify athletes at risk for SCD and lead to a cost-effective means to pursue further workup. Table 7 lists a screening battery of tests and what the tests detect and miss. In general, a history and physical examination detect aortic stenosis and a portion of HCM and Marfan's syndrome. If the physical examination is suggestive of Marfan's syndrome and a chest roentgenogram is done, a larger portion of cystic medial necrosis will be found. When an ECG is added to the series, most of the HCM patients at risk for SCD can be diagnosed. In addition, if echocardiography is added, most patients with HCM and cystic medial necrosis can be identified. If an exercise stress test is then performed, 20% of coronary artery disease and congenital artery anomalies are identified. Additional studies, including Holter monitoring, electrophysiologic studies, and thallium scintigraphy, can be added to identify further at-risk patients. Because some asymptomatic patients present with SCD, it is virtually impossible to identify comprehensively all patients at risk. By knowing what questions to ask, performing a thorough cardiac screening examination, and being more aware of potential diagnostic clues, the practitioner can feel comfortable in identifying most patients at risk for SCD. Specific history and physical examination guidelines regarding screening for competition are included. Supplemental information is found in the 16th Bethesda Conference. In addition, a well-outlined emergency plan needs to be established when physicians, athletic trainers, or coaches are working with athletes. Proper recognition of cardiac symptoms is a key point. Appropriate education including basic first aid and cardiopulmonary resuscitation training should be encouraged for anyone working extensively with athletes. The emergency plan should include on-site treatment, mechanism to contact emergency personnel, and proper transport to a qualified facility.

DEVELOPMENT OF AN EXPERIMENTAL APPARATUS TO STUDY HYPERTROPHIC CARDIOMYOPATHY (HCM)

An experimental apparatus to model the systolic phase of a heartbeat has been developed to investigate the controversy surrounding the cause of high intraventricular pressures for HCM patients. The model, which is two-dimensional, has approximately seven times the volume of an average human heart and operates at Reynolds numbers which are similar to those measured in the left ventricle/aortic arch. Preliminary tests of the model show pressure time relationships similar to those found in vivo.

Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy: assessment with proton-decoupled P-31 MR spectroscopy.

Proton-decoupled phosphorus-31 heart spectroscopy was performed in healthy subjects (n = 9) and patients with dilated cardiomyopathy (DCM, n = 9) or hypertrophic cardiomyopathy (HCM, n = 8). The phosphocreatine (PCr)-to-adenosine triphosphate ratio (+/- one standard deviation) after correction for blood contribution and partial saturation was significantly lower in HCM patients relative to the control subjects (1.32 +/- 0.29 vs 1.65 +/- 0.26, P < .05) but not in DCM patients (1.52 +/- 0.58 vs 1.65 +/- 0.26). The inorganic phosphate (Pi) peak was resolved only in patients with the highest spectral quality. Myocardial pH was lower in HCM patients (n = 6) relative to control subjects (n = 4) (7.07 +/- 0.07 vs 7.15 +/- 0.03, P < .05). The Pi/PCr ratio was higher in DCM (n = 3) and HCM (n = 6) patients relative to control subjects (n = 4) (0.29 +/- 0.06 and 0.20 +/- 0.04, respectively, vs 0.14 +/- 0.06; P < .05). Elevated phosphodiester signal in DCM patients correlated with 2,3-diphosphoglycerate signal (r = .94), reflecting blood pool contamination. P-31 spectroscopy enabled detection of abnormalities in cardiac metabolism and determination of pH in patients with HCM and DCM.

Vibration Analysis of the Human Left Ventricular Posterobasal Wall at the Moment of the First Heart Sound Emission.

We examined whether human left ventricular (LV) wall vibration at the first heart sound emission (LVvibr) could be a potential source of information about the left ventricular physical properties, as has been demonstrated by experimental forced vibration studies. LV posterobasal wall vibration in 51 subjects characterized by functional murmur (n = 13), mitral stenosis (n = 8), hypertrophic cardiomyopathy (HCM, n = 8), ischemic heart disease with old myocardial infarction (n = 12) and without prior infarction (n = 10), was detected with a miniature intraesophageal vibration sensor. Peak frequency, sharpness and peak power of LVvibr in patients with functional murmur and mitral stenosis were linearly related to the Q-vibration interval. HCM patients showed a higher peak frequency and sharper configuration in the power spectrum. However, differing from previous reports, we found no characteristic difference in configuration of power spectrum in patients with ischemic heart disease. These results suggest that human LVvibr possibly includes information demonstrated by experimental forced vibration analysis.

Significance of ultrafast computed tomography in cardiac imaging: usefulness in assessment of myocardial characteristics and cardiac function.

The usefulness of cardiac ultrafast computed tomography (CT) is discussed in this article. Thirty-three patients with ischemic heart disease and 15 patients with hypertrophic cardiomyopathy were assessed for myocardial characteristics, while 30 patients with various heart diseases were assessed for cardiac function. Volume mode (100 msec scan) and cine mode (50 msec scan) studies were applied. As the findings of abnormal myocardial characteristics, early defect (ED) and late enhancement (LE) of the left ventricular (LV) wall were observed after injection of contrast medium. In ischemic heart disease, all 27 patients with myocardial infarction (MI) and all 16 MI sites showed LE, while 25 ED sites were well correlated with MI or significant coronary stenosis. LE was quite sensitive for MI and ED was highly predictive for ischemia. Seven of 15 HCM patients (47%) also showed LE, indicating that LE occurs in tissues with a different capillary architecture from that observed in normal myocardium. For evaluation of cardiac function, ventricular volumetry was performed by summation of a sliced area of the ventricles. End-diastolic volume and LV ejection fraction calculated by this means correlated excellently with the values obtained using left ventriculography (R = 0.97 and 0.96). The stroke volumes for both ventricles were nearly equal when calculated using ultrafast CT. Consequently, the study of cardiac volumetry using ultrafast CT was thought to be reliable and utilizable in clinical practice.

VT and sudden death in HCM patients.

VT and sudden death in HCM patients.