Search Results (15)

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, caused by either sarcomere protein or other gene mutations. It is a complex and highly heterogeneous disorder, with phenotypes ranging from asymptomatic to severe disease, characterized by asymmetric left ventricular (LV) hypertrophy unexplained by loading conditions, which is also associated with myocardial fiber disarray, and preserved or increased ejection fraction without LV dilation. Comprehensive personal and family history, physical examination, and ECG testing raise suspicion of HCM, and echocardiogram represents the first-line imaging modality for confirming a diagnosis. Moreover, contrast-enhanced cardiac magnetic resonance (CMR) imaging has increasingly emerged as a fundamental diagnostic and prognostic tool in HCM management. This article reviews the role of CMR in HCM identification and differentiation from phenotypic mimics, characterization of HCM phenotypes, monitoring of disease progression, evaluation of pre- and post-septal reduction treatments, and selection of candidates for implantable cardioverter-defibrillator. By providing information on cardiac morphology and function and tissue characterization, CMR is particularly helpful in the quantification of myocardial wall thickness, the detection of hypertrophy in areas blind to echocardiogram, subtle morphologic features in the absence of LV hypertrophy, myocardial fibrosis, and apical aneurysm, the evaluation of LV outflow tract obstruction, and the assessment of LV function in end-stage dilated HCM. Full article

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder marked by myocardial hypertrophy, leading to diastolic and systolic dysfunction and heart failure. Traditionally, the burn-out stage is defined by systolic dysfunction, but we propose expanding its definition to include advanced diastolic dysfunction. Methods: We retrospectively analyzed HCM patients (2004–2023) with either systolic dysfunction (left ventricular ejection fraction [LVEF] < 50%) or advanced diastolic dysfunction (preserved LVEF with left atrial enlargement and elevated filling pressures: E/A ≥ 2 or E/e′ ≥ 14). Both subgroups were included under the term “end-stage HCM” and compared to HCM controls with preserved LVEF and impaired relaxation. Results: Of 696 HCM patients, 94 had end-stage HCM (23 with systolic dysfunction, 71 with advanced diastolic dysfunction). Median age was 56.5 years, and 55.3% were male. End-stage HCM patients were more symptomatic at follow-up than controls (91.5% vs. 75.0%, p-value = 0.006), with higher rates of dyspnea and advanced heart failure (38.3% vs. 6.3%, p-value < 0.001). Advanced diastolic dysfunction was associated with a more symptomatic profile (p-value = 0.013) and a high annual mortality rate (2.34%, p = 0.014). Male sex, older age, lower LVEF, and higher E/A predicted systolic dysfunction. Conclusions: Advanced diastolic dysfunction represents an alternative progression pathway in burn-out HCM, requiring distinct management strategies alongside systolic dysfunction. Full article

Hypertrophic cardiomyopathy (HCM) is a complex and heterogeneous cardiac disorder, often complicated by cardiogenic shock, a life-threatening condition marked by severe cardiac output failure. Managing cardiogenic shock in HCM patients presents unique challenges due to the distinct pathophysiology of the disease, which includes dynamic left ventricular outflow tract obstruction, diastolic dysfunction, and myocardial ischemia. This review discusses current and emerging therapeutic strategies tailored to address the complexities of HCM-associated cardiogenic shock and other diseases with similar pathophysiology that provoke left ventricular outflow tract obstruction. We explore the role of pharmacological interventions, including the use of vasopressors and inotropes, which are crucial in stabilizing hemodynamics but require careful selection to avoid exacerbating the outflow obstruction. Additionally, the review highlights advancements in mechanical circulatory support devices such as extracorporeal membrane oxygenation (ECMO) and left ventricular assist devices (LVADs), which have become vital in the acute management of cardiogenic shock. These devices provide temporary support and bridge patients to recovery, definitive therapy, or heart transplantation, which remains a critical option for those with end-stage disease. Furthermore, the review delves into the latest research and clinical trials that are refining these therapeutic approaches, ensuring they are optimized for HCM patients. The impact of these treatments on patient outcomes, including survival rates and quality of life, is also critically assessed. In conclusion, this review underscores the importance of a tailored therapeutic approach in managing cardiogenic shock in HCM patients, integrating pharmacological and mechanical support strategies to improve outcomes in this high-risk population. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a broad spectrum of clinical manifestations, including severe complications, such as end-stage renal disease, hypertrophic cardiomyopathy, and cerebrovascular disease. Enzyme replacement therapy (ERT), when initiated early, has been shown to reduce the incidence of severe events and slow disease progression. In the classic form, characterized by the absence of α-galactosidase A (α-Gal A) enzyme activity, diagnosis is straightforward. However, when residual activity is present, the delayed and less obvious presentation can make diagnosis more challenging. Ophthalmological alterations, which can be detected through non-invasive examinations may play a crucial role in correctly assessing the patient in terms of diagnosis and prognosis, particularly in these atypical cases. Recognizing these ocular signs allows for timely intervention with ERT, leading to improved patient outcomes. This review highlights the importance of ophthalmological findings in FD, emphasizing their role in diagnosis and treatment planning. By raising awareness among ophthalmologists and healthcare specialists, this review aims to improve disease management, offering tools for early detection and better long-term prognosis in patients with FD. Full article

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George’s Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. “Discrete” subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald–Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term “functional subaortic stenosis” was used in 1959 and “idiopathic hypertrophic subaortic stenosis” in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy’s Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989–1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled “HCM without hypertrophy”. Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death. Full article

Apical sparing is an echocardiographic pattern where myocardial strain is preserved at the apex compared to the basal segments. In a normal heart, longitudinal strain shows a gradient with lower values at the base and higher at the apex. This gradient becomes more pronounced in pathological states, such as cardiac amyloidosis, resulting in a relative apical sparing effect. This study explores cardiac conditions associated with apical sparing and the underlying mechanisms. We reviewed echocardiography examinations reporting apical sparing from 2021 to 2024 in our hospital database. Relevant echo exams and clinical data were retrieved and analyzed. Apical sparing was identified in 74 patients. Cardiac amyloidosis was diagnosed in 12 patients (16.2%). Other cardiac pathologies potentially contributing to apical sparing included hypertrophic cardiomyopathy, left ventricular hypertrophy due to hypertension, end-stage renal disease, coronary artery disease (involving the right coronary artery and left circumflex), reversed Takotsubo syndrome, and chemotherapy-induced cardiomyopathy. The clinical context of echocardiography was crucial in guiding the diagnostic work-up. Apical sparing is a nonspecific echocardiographic finding associated with various cardiac conditions. Its diagnostic value depends heavily on the clinical context. Understanding the broader clinical picture is essential for accurate interpretation and diagnosis. Full article

Introduction: The aim of this study was to evaluate the age at onset, clinical course, and patterns of left ventricular (LV) remodelling during follow-up in children and young patients with hypertrophic cardiomyopathy (HCM). Methods: We included consecutive patients with sarcomeric or non-syndromic HCM below 18 years old. Three pre-specified patterns of LV remodelling were assessed: maximal LV wall thickness (MLVWT) thickening; MLVWT thinning with preserved LV ejection fraction; and MLVWT thinning with progressive reduction in LV ejection fraction (hypokinetic end-stage evolution). Results: Fifty-three patients with sarcomeric/non-syndromic HCM (mean age 9.4 ± 5.5 years, 68% male) fulfilled the inclusion criteria. In total, 32 patients (60%) showed LV remodelling: 3 patients (6%) exhibited MLVWT thinning; 16 patients (30%) showed MLVWT thickening; and 13 patients (24%) progressed to hypokinetic end-stage HCM. Twenty-one patients (40%) had no LV remodelling during follow-up. In multivariate analysis, MLVWT was a predictor of the hypokinetic end-stage remodelling pattern during follow-up (OR 1.17 [95%CI 1.01–1.36] per 1 mm increase, p-value 0.043), regardless of sarcomeric variants and New York Heart Association class. Two patients with sarcomeric HCM, showing a pattern of MLVWT regression during childhood, experienced progression during adolescence. Conclusions: Different patterns of LV remodelling were observed in a cohort of children with sarcomeric/non-syndromic HCM. Interestingly, a pattern of progressive MLVWT thinning during childhood, with new progression of MLVWT during adolescence, was noted. A better understanding of the remodelling mechanisms in children with sarcomeric HCM may be relevant to defining the timing and possible efficacy of new targeted therapies in the preclinical stage of the disease. Full article

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease. Full article

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic disorder, most often caused by sarcomeric gene mutations, with a small proportion due to variants in non-sarcomeric loci. Phospholamban (PLN) is a phosphoprotein associated with the cardiac sarcoplasmic reticulum, a major determinant of cardiac contractility and relaxation. We conducted a retrospective study to determine the prevalence, phenotypical spectrum and clinical course of patients carrying the PLN p.Leu39* variant. A cohort including 11 PLN patients was identified among all patients with HCM (9/189, 4.8%) and DCM (2/62, 3.2%) who underwent genetic testing from two tertiary centers and five more were detected through cascade screening. Complete phenotyping was performed. PLN p.Leu39* variant-driven cardiomyopathy presented mostly as hypertrophic, with frequent progression to end-stage dilated HCM. We proceeded to compare these results to a similar analysis of a control cohort consisting of age-matched individuals that inherited pathogenic or likely pathogenic variants in common sarcomeric genes (MYBPC3/MYH7). Overall, the clinical characteristics and examination findings of patients carrying PLN p.Leu39* were not different from patients with cardiomyopathy related to sarcomeric mutations except for the presence of pathological Q waves and the incidence of non-sustained ventricular arrhythmias, which were higher in PLN patients than in those with MYBPC3/MYH7-related diseases. Full article

Cardiac hypertrophy resulting from sympathetic nervous system activation triggers the development of heart failure. The transcription factor Y-box binding protein 1 (YB-1) can interact with transcription factors involved in cardiac hypertrophy and may thereby interfere with the hypertrophy growth process. Therefore, the question arises as to whether YB-1 influences cardiomyocyte hypertrophy and might thereby influence the development of heart failure. YB-1 expression is downregulated in human heart biopsies of patients with ischemic cardiomyopathy (n = 8), leading to heart failure. To study the impact of reduced YB-1 in cardiac cells, we performed small interfering RNA (siRNA) experiments in H9C2 cells as well as in adult cardiomyocytes (CMs) of rats. The specificity of YB-1 siRNA was analyzed by a miRNA-like off-target prediction assay identifying potential genes. Testing three high-scoring genes by transfecting cardiac cells with YB-1 siRNA did not result in downregulation of these genes in contrast to YB-1, whose downregulation increased hypertrophic growth. Hypertrophic growth was mediated by PI3K under PE stimulation, as well by downregulation with YB-1 siRNA. On the other hand, overexpression of YB-1 in CMs, caused by infection with an adenovirus encoding YB-1 (AdYB-1), prevented hypertrophic growth under α-adrenergic stimulation with phenylephrine (PE), but not under stimulation with growth differentiation factor 15 (GDF15; n = 10–16). An adenovirus encoding the green fluorescent protein (AdGFP) served as the control. YB-1 overexpression enhanced the mRNA expression of the Gq inhibitor regulator of G-protein signaling 2 (RGS2) under PE stimulation (n = 6), potentially explaining its inhibitory effect on PE-induced hypertrophic growth. This study shows that YB-1 protects cardiomyocytes against PE-induced hypertrophic growth. Like in human end-stage heart failure, YB-1 downregulation may cause the heart to lose its protection against hypertrophic stimuli and progress to heart failure. Therefore, the transcription factor YB-1 is a pivotal signaling molecule, providing perspectives for therapeutic approaches. Full article

Hypertrophic cardiomyopathy (HCM) is an inherited primary myocardial disease characterized by asymmetrical/symmetrical left ventricle (LV) hypertrophy, with or without LV outflow tract (LVOT) dynamic obstruction, and poor prognosis. Cardiac resynchronization therapy (CRT) has emerged as a minimally invasive tool for patients with heart failure (HF) with decreased LV ejection fraction (LVEF) and prolonged QRS duration of over 120 ms with or without left bundle branch block (LBBB). Several HCM patients are at risk of developing LBBB because of disease progression or secondary to septal myomectomy, while others might develop HF with decreased LVEF, alleged end-stage/dilated HCM, especially those with thin myofilament mutations. Several studies have shown that patients with myectomy-induced LBBB might benefit from left bundle branch pacing or CRT to relieve symptoms, improve exercise capacity, and increase LVEF. Otherwise, patients with end-stage/dilated HCM and prolonged QRS interval could gain from CRT in terms of NYHA class improvement, LV systolic performance increase and, to some degree, LV reverse remodeling. Moreover, several electrical and imaging parameters might aid proper selection and stratification of HCM patients to benefit from CRT. Nonetheless, current available data are scarce and further studies are still required to accurately clarify the view. This review reassesses the importance of CRT in patients with HCM based on current research by contrasting and contextualizing data from various published studies. Full article

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets. Full article

While most patients with hypertrophic cardiomyopathy (HCM) show a relatively stable morphologic and clinical phenotype, in some others, progressive changes in the left ventricular (LV) wall thickness, cavity size, and function, defined, overall, as “LV remodeling”, may occur. The interplay of multiple pathophysiologic mechanisms, from genetic background to myocardial ischemia and fibrosis, is implicated in this process. Different patterns of LV remodeling have been recognized and are associated with a specific impact on the clinical course and management of the disease. These findings underline the need for and the importance of serial multimodal clinical and instrumental evaluations to identify and further characterize the LV remodeling phenomenon. A more complete definition of the stages of the disease may present a chance to improve the management of HCM patients. Full article

Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocardial disarray, small vessel disease (SVD), and fibrosis. The relationship between SVD and replacement-type fibrosis is still unclear. Methods: Histopathologic assessment of replacement-type fibrosis and SVD in HCM patients with either end-stage heart failure (HF) or sudden cardiac death (SCD). Chronic ischemic heart disease (IHD) patients served as controls. Results: Forty HCM hearts, 10 HF and 30 SCD, were studied. Replacement-type fibrosis was detected in all HF and in 57% of SCD cases. In SCD, replacement-type fibrosis was associated with older age, greater septal thickness, SVD prevalence, and score (all p < 0.05). Prevalence of SVD did not show significant differences among SCD, HF, and IHD (73%, 100% and 95%, respectively), while SVD score was higher in HF than IHD and SCD (2.4, 1.95, and 1.18, respectively) and in areas with replacement-type fibrosis vs. those without in HF (3.4 vs. 1.4) and SCD (1.4 vs. 0.8) (all p < 0.05). Conclusions: SVD is a frequent feature in HCM independent of the clinical presentation. A higher SVD score is observed in HCM-HF and in areas with replacement-type fibrosis. Although SVD is part of the HCM phenotype, further remodeling of the microcirculation might occur secondarily to fibrosis. Full article

A 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage evolution). She was recently diagnosed elsewhere because of palpitations. Her 7-year-old daughter underwent familiar screening and she was diagnosed with classic HCM. She was completely asymptomatic without extracardiac or systemic manifestations. During the following years, they both experienced a similar clinical course with worsening dyspnoea and progressive deterioration of LV systolic function. They both underwent heart transplantation, the mother at the age of 47 and the daughter at the age of 23, respectively. Many diagnostic hypotheses, including sarcomeric HCM, Anderson-Fabry disease, glycogen storage diseases and mitochondrial cardiomyopathies have been taken into account. The diagnostic work-up included serial electrocardiogram and echocardiographic assessments, pathologic evaluation of the explanted hearts and genetic analysis of 8 sarcomeric and 3 metabolic genes. Even if a shared HCM phenotype (LV systolic dysfunction in two first-degree female family members associated with a likely autosomal dominant inheritance and absence of extracardiac or multisystemic manifestations) could support a temptative diagnosis of sarcomeric HCM, a definitive diagnosis could not be reached, due to the lack of genetic analysis to confirm such diagnosis. Full article