From Atrial Fibrillation Management to Atrial Myopathy Assessment: The Evolving Concept of Left Atrium Disease in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiovascular disorder in adults and a significant cause of heart failure and sudden cardiac death. Historically, atrial fibrillation (AF) has been considered as a critical aspect in HCM patients as it is considered to be a marker of disease progression, escalates the frequency of heart failure hospitalisations, increases the risk of thromboembolic events, and worsens quality of life and outcome. Increasing evidence suggests that AF is the result of a subtle long-standing process that starts early in the history of HCM. The process of left atrial dilation accompanied by morphologic and functional remodelling is the quintessential prerequisite for the onset of AF. This review aims to describe the current understanding of AF pathophysiology in HCM, emphasising the role of left atrial myopathy in its development. In addition, we discuss risk factors and management strategies specific to AF in the context of HCM, providing insights into the complexities and challenges of treating this specific patient population.

The evolving paradigm and current perception of hypertrophic cardiomyopathy: Implications for management.

Recent evidence from imaging and genetic screening studies has clearly shown that hypertrophic cardiomyopathy (HCM) is more common than initially perceived, emphasizing the need to reassess its associated clinical and social burden. While clinical and academic efforts have long been focused on stratification of arrhythmic risk and management of intraventricular obstruction, progression of cardiac dysfunction and heart failure-related complications have emerged as most relevant from the epidemiological standpoint, delineating a major unmet need. Furthermore, a broader perspective of our patients' needs has become central in the care of individuals with HCM, addressing issues that are not strictly clinical but equally important to their wellbeing, such as quality of life, athletic participation, lifestyle and reproductive choices and psychological adaptation to a chronic condition often detected at a young age. The appropriate evaluation and objective assessment of disease burden associated with HCM are increasingly relevant not only to management but also to trial design and evaluation of the efficacy of emerging, targeted treatments. In this review, we discuss the evolving perception of HCM prevalence and natural history, as well as recent acquisitions regarding its true, often under-appreciated socio-economic and clinical burden.

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

PURPOSE: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. METHODS: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). RESULTS: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. CONCLUSION: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

The electrocardiogram in the diagnosis and management of patients with hypertrophic cardiomyopathy.

In an era of rapid technological development and evolving diagnostic possibilities, the electrocardiogram (ECG) is living an authentic "renaissance" in myocardial diseases. To date, the ECG remains an irreplaceable first step when evaluating patients with hypertrophic cardiomyopathy (HCM) and an abnormal ECG may be the only manifestation of disease at an early stage. In some instances, specific electrical anomalies may differentiate HCM from phenocopies such as cardiac amyloidosis and glycogen storage diseases. The exponential growth in knowledge of the complexity of HCM has led to new challenges in terms of early identification of the disease, differential diagnosis, risk stratification, and development of targeted therapies. In this scenario, the apparently "old fashioned" ECG and the array of ECG-based techniques, ranging from Holter monitoring and loop recorders to exercise testing, are as contemporary as ever. In the present review, we discuss the current role of the ECG in the diagnosis and management of HCM, focusing on various clinical settings where its appropriate use and interpretation can make a difference.

Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Background: A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers. Methods: Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints. Results: Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years. Conclusions: The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.

Cardiovascular screening in low-income settings using a novel 4-lead smartphone-based electrocardiograph (D-Heart®).

BACKGROUND: MHealth technologies are revolutionizing cardiovascular medicine. However, a low-cost, user-friendly smartphone-based electrocardiograph is still lacking. D-Heart® is a portable device that enables the acquisition of the ECG on multiple leads which streams via Bluetooth to any smartphone. Because of the potential impact of this technology in low-income settings, we determined the accuracy of D-Heart® tracings in the stratification of ECG morphological abnormalities, compared with 12-lead ECGs. METHODS: Consecutive African patients referred to the Ziguinchor Regional Hospital (Senegal) were enrolled (n=117; 69 males, age 39±11years). D-Heart® recordings (3 peripheral leads plus V5) were obtained immediately followed by 12 lead ECGs and were assessed blindly by 2 independent observers. Global burden of ECG abnormalities was defined by a semi-quantitative score based on the sum of 9 criteria, identifying four classes of increasing severity. RESULTS: D-Heart® and 12-lead ECG tracings were respectively classified as: normal: 72 (61%) vs 69 (59%); mildly abnormal: 42 (36%) vs 45 (38%); moderately abnormal: 3 (3%) vs 3 (3%). None had markedly abnormal tracings. Cohen's weighted kappa (kw) test demonstrated a concordance of 0,952 (p<0,001, agreement 98,72%). Concordance was high as well for the Romhilt-Estes score (kw=0,893; p<0,001 agreement 97,35%). PR and QRS intervals comparison with Bland-Altman method showed good accuracy for D-Heart® measurements (95% limit of agreement ±20ms for PR and ±10ms for QRS). CONCLUSIONS: D-Heart® proved effective and accurate stratification of ECG abnormalities comparable to the 12-lead electrocardiographs, thereby opening new perspectives for low-cost community cardiovascular screening programs in low-income settings.

Determinants of discrepancies between two-dimensional echocardiographic methods for assessment of maximal left atrial volume.

AIMS: The determinants of discrepancies among two-dimensional echocardiographic (2D-E) methods for left atrial volume (LAV) assessment are poorly investigated. METHODS AND RESULTS: Maximal LAV was measured in 613 individuals (282 healthy subjects,180 athletes, and 151 hypertensives; age 45 ± 20 years, 62% male) using the ellipsoid model (LAVEllips), the area-length method (LAVAL), and the Simpson's rule (LAVSimps). On the basis of a mathematical model, two left atrial (LA) geometry indexes were tested as predictors of discrepancies between methods: the ratio between LA medial-lateral diameter (MLD) and LA anteroposterior diameter (APD); and the ratio between LA area in the four-chamber view and that of an ellipse with the same diameters [deviation from ellipse (DE)-coefficient]. Discrepancies among methods were consistently present in the overall population and across all study groups. MLD/APD and the DE-coefficient together predicted 76 and 68% of differences between biplane LAVAL and LAVEllips, and between biplane LAVSimps and LAVEllips, respectively. The DE-coefficient was the only determinant of LAVAL/LAVSimps difference (ß = 0.167, P < 0.0001). Body mass index was the strongest predictor of discrepancies between single-plane and biplane approaches of LAVAL (ß = 0.427, P < 0.0001) and LAVSimps (ß = 0.424, P < 0.0001). In additional analyses, biplane LAVAL showed the best agreement with LAV obtained by three-dimensional echocardiography and the best reproducibility and repeatability. CONCLUSION: LA geometry is the main determinant of inconsistencies between 2D-E methods for measuring maximal LAV. Body mass index is the strongest determinant of differences between single-plane and biplane approaches. Different 2D-E methods cannot be used interchangeably for diagnosis and follow-up. The biplane area-length method should be preferred, particularly in overweight-obese subjects.

Dissecting functional impairment in hypertrophic cardiomyopathy by dynamic assessment of diastolic reserve and outflow obstruction: A combined cardiopulmonary-echocardiographic study.

BACKGROUND: Exercise limitation in hypertrophic cardiomyopathy (HCM) patients is often attributed to left ventricular outflow tract (LVOT) obstruction and diastolic impairment. However, these features assessed at rest fail to predict performance. To evaluate their variations and interplay during effort in HCM, we performed echocardiographic assessment of diastolic function and outflow obstruction during cardiopulmonary test (CPX). METHODS: We included 197 HCM patients (mean age 45±15years, 129 males), undergoing CPX. Diastolic dysfunction (DD) grade was measured at baseline and at peak exercise. Oxygen consumption (VO2 max) values <75% of maximum predicted were considered abnormal. RESULTS: One hundred-seven patients (54%) had DD grade II-III at rest (Rest DD), 40 (20%) showed preserved diastolic function (grade 0/I) both at rest and on effort (No DD). The remaining 50 patients (25%) had a grade 0/I pattern at rest but exhibited impaired diastolic reserve on exercise (Latent DD). Latent DD was associated with higher prevalence of patients with VO2<75% in both the non-obstructive and the latent-obstructive group: at multivariate regression analysis, left atrium volume index, LV obstruction at rest and rest or latent DD were significantly associated with lower peak VO2. Excluding rest-obstructive patients from the analysis, rest- or latent DD were the only determinants of exercise impairment (latent-obstructive, OR 8.9; 95% CI 1.5-18.8; p=0.012; non-obstructive, OR 2.2; 95% CI 1.0-5.8; p=0.03). CONCLUSION: Latent DD is a major determinant of exercise intolerance in HCM. Comprehensive assessment of outflow obstruction and diastolic reserve during cardiopulmonary test represents an important adjunct to clinical management.

Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in the United States.

Hypertrophic cardiomyopathy (HC) is the most common genetic heart disease and an important cause of sudden death and heart failure symptoms. The current prevalence for HC (1:500) is based on echocardiographic population studies in which a substantial proportion of affected subjects have not come to clinical recognition. Therefore, we sought to define the subset of patients with HC who are diagnosed in the US. A proprietary integrated claims database including medical condition International Classification of Diseases, Ninth Revision diagnostic codes for over 160 million individual patients in the US was interrogated for 2013 to identify the prevalence of clinically recognized HC. Patients with ≥1 claim for any of the HC International Classification of Diseases, Ninth Revision diagnosis codes from January to December 2013 were identified. The combined occurrence rate of HC was stratified by age and gender and multiplied by the 2013 United States population in the same age/gender categories to produce the final projected prevalence. The analysis was performed on 169,089,614 patients, of whom 59,009 unique patients were identified with ≥1 claim for HC. The projected estimated occurrence of diagnosed HC in the US in 2013 was 1:3,195 for a total of 98,958 subjects. Average age at HC diagnosis was in the fifth decade of life, with 43% of the cohort composed of women. In conclusion, leveraging a claims-based data analytic technique, about 100,000 patients are diagnosed clinically with HC in the US, an occurrence which is less than the prevalence reported in systematic population studies based on echocardiographic diagnosis. This observation supports the view that many patients with HC are undiagnosed throughout life and enhances our understanding of the burden of this genetic heart disease on the health care system.

Dynamic assessment of 'valvular reserve capacity' in patients with rheumatic mitral stenosis.

AIMS: Mitral stenosis (MS) may exhibit a dynamic valvular reserve. When resting gradients and systolic pulmonary pressure (sPAP) do not reflect the real severity of the disease, a dynamic evaluation becomes necessary. The aim of the study was to assess the clinical utility of exercise echocardiography in symptomatic patients with apparently subcritical MS. METHODS AND RESULTS: One hundred and thirty consecutive patients were referred for symptomatic MS. Patients with unimpressive resting MVA (>1-1.5 cm(2)) and mean PG (≥5-9 mmHg) underwent exercise echocardiography. Cardiac performance and mitral indices (MVA, peak/mean PG, sPAP) were measured. Exhaustion of valvular reserve capacity under exercise was defined as appearance of symptoms and sPAP > 60 mmHg. Forty-six patients (35%) (age: 53 ± 10 years; 74%, female) with resting MVA (1.2 ± 0.36 cm(2)), mean PG (6.8 ± 2.7 mmHg), and sPAP (38 ± 7 mmHg) inconsistent with symptoms underwent stress echocardiography. Exercise was stopped for dyspnoea (76%) or fatigue (24%). At peak workloads (57.2 ± 21.8 Watts), increased mean PG (17.2 ± 4.8 mmHg, P< 0.001) and sPAP (67.4 ± 11.4 mmHg; P< 0.0001) were observed, without change in MVA (1.25 ± 0.4 cm(2); P= n.s.). At univariate analysis, predictors of adaptation to exercise were age (-0.345; P = 0.024), mean PG (0.339; P= 0.023), and sPAP (0.354; P= 0.024); at multivariate analysis, best predictor was resting mean PG, although correlation was poor (-0.339; P= 0.015). CONCLUSION: In MS with limiting symptoms despite unimpressive findings at rest, valvular capacity exhaustion should be tested on a dynamic background, as no single resting index can predict potential haemodynamic adaptation to exercise. In such context, the contribution of exercise echocardiography remains extremely valuable.

Echocardiography in patients with hypertrophic cardiomyopathy: usefulness of old and new techniques in the diagnosis and pathophysiological assessment.

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiomyopathy. The identification of patients with HCM is sometimes still a challenge. Moreover, the pathophysiology of the disease is complex because of left ventricular hyper-contractile state, diastolic dysfunction, ischemia and obstruction which can be coexistent in the same patient. In this review, we discuss the current and emerging echocardiographic methodology that can help physicians in the correct diagnostic and pathophysiological assessment of patients with HCM.

Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

OBJECTIVES: Our aim was to assess the distribution and clinical significance of left ventricular (LV) mass in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Hypertrophic cardiomyopathy is defined echocardiographically by unexplained left ventricular wall thickening. Left ventricular mass, quantifiable by modern cardiovascular magnetic resonance techniques, has not been systematically assessed in this disease. METHODS: In 264 HCM patients (age 43 +/- 18 years; 75% men), LV mass by cardiovascular magnetic resonance was measured, indexed by body surface area, and compared with that in 606 healthy control subjects. RESULTS: The LV mass index in HCM patients significantly exceeded that of control subjects (104 +/- 40 g/m(2) vs. 61 +/- 10 g/m(2) in men and 89 +/- 33 g/m(2) vs. 47 +/- 7 g/m(2) in women; both p < 0.0001). However, values were within the normal range (< or = mean +2 SDs for control subjects) in 56 patients (21%), and only mildly increased (mean +2 to 3 SDs) in 18 (16%). The LV mass index showed a modest relationship to maximal LV thickness (r(2) = 0.38; p < 0.001), and was greater in men (104 +/- 40 g/m(2) vs. 89 +/- 33 g/m(2) in women; p < 0.001) and in patients with resting outflow obstruction (121 +/- 43 g/m(2) vs. 96 +/- 37 g/m(2) in nonobstructives; p < 0.001). During a 2.6 +/- 0.7-year follow-up, markedly increased LV mass index proved more sensitive in predicting outcome (100%, with 39% specificity), whereas maximal wall thickness >30 mm was more specific (90%, with 41% sensitivity). CONCLUSIONS: In distinction to prior perceptions, LV mass index was normal in about 20% of patients with definite HCM phenotype. Therefore, increased LV mass is not a requirement for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness, and proved more sensitive in predicting outcome.

Systemic arterial waveform analysis and assessment of blood flow during extracorporeal circulation.

BACKGROUND: The pressure recording analytical method (PRAM) is a method for real-time beat-to-beat quantification of peripheral blood flow based on the analysis of arterial waveform morphology. Since PRAM can be implemented in any conditions of flow, whether physiological or artificial, we assessed its accuracy in patients undergoing cardiac surgery during extracorporeal circulation (ECC), using the roller-pump device as the reference gold standard. METHODS: We prospectively studied 32 patients undergoing elective coronary surgery. Flow values obtained by PRAM from the radial artery were compared with simultaneous values by thermodilution in physiological conditions of flow and with the roller-pump device readings during ECC. RESULTS: Before and after ECC, the overall estimates of flow measured by PRAM closely agreed with thermodilution (mean difference 0.07 +/- 0.40 L/min). During ECC, PRAM estimates of flow also closely correlated with simultaneous pump readings (mean difference 0.11 +/- 0.33 L/min). At time of weaning from ECC, two patterns of hemodynamic adaptation were documented by PRAM following resumption of cardiac contraction: in most patients (n =26; 80%), cardiac output (CO) was stable (reduction < or = 10% compared to the steady ECC phase); six patients (20%) showed a fall in CO exceeding 10% and up to 38%. CONCLUSIONS: PRAM provided accurate, continuous quantification of peripheral blood flow during each phase of cardiac surgery, including ECC, and allowed early recognition of patients with low CO during weaning from the pump.

The epidemiologic evolution and present perception of hypertrophic cardiomyopathy.

Patients with rare diseases are confronted by limited attention from the scientific community, a delayed diagnosis, a limited availability of resources and high costs of treatment. Although hypertrophic cardiomyopathy (HCM) does not meet the criteria for rare diseases, many physicians are uncomfortable with the disease, and patients still pay a price for the perceived "rarity" of HCM. In the year 2000, as part of a large research project on cardiovascular disease prevention (Progetto Cuore), the Italian Institute of Health has approved and funded a National Registry of HCM. The aims of the registry included: the collection of clinical data for HCM patients in different geographical areas; the creation of a network of cardiologists involved in the care of HCM patients; and an improved access of patients to the most advanced treatment options. It is our hope that the registry will be imitated by other countries, and that it will contribute to overcome the limitations of "rarity" in HCM research.

Effectiveness of a multidisciplinary chest pain unit for the assessment of coronary syndromes and risk stratification in the Florence area.

BACKGROUND: In patients seen at the emergency department (ED) with chest pain (CP), noninvasive diagnostic strategies may differentiate patients at high or intermediate risk from those at low-risk for cardiovascular events and optimize the use of high-cost resources. However, in welfare healthcare systems, the feasibility, accuracy, and potential benefits of such management strategy need further investigation. METHODS: A total of 13,762 consecutive patients with CP were screened, and their conditions were defined as high, intermediate, and low risk for short-term cardiovascular events. Patients at high and intermediate risk were admitted. Patients at low risk were discharged from the ED if first line (<6 hours, including electrocardiogram, troponins, and serum cardiac markers) or second line short-term evaluation (<24 hours, including echocardiogram, rest or stress 99m-Tc myocardial scintigraphy, exercise tolerance test, or stress-echocardiography) had negative results. Patients with a diagnosis of coronary artery disease (CAD) were admitted. Patients without evidence of cardiovascular disease underwent screening for psychiatric and gastroesophageal disorders. Inhospital mortality rate was assessed in all patients. RESULTS: Among patients at high and intermediate risk (n = 9335), 2420 patients had acute myocardial infarction (26%, 10.6% mortality rate), 3764 had unstable angina (40%, 1.1% mortality rate), 129 had aortic dissection (1.4%, 23.3% mortality rate), and 408 had pulmonary embolism (4%, 27.6% mortality rate). The remaining 2614 had chronic coronary heart disease in the context of multiple pathology (n = 2256) or pleural or pericardial diseases (n = 358). Among patients at low risk (n = 4427), 2672 were discharged at <6 hours (60%, 0.2% incidence rate of nonfatal CAD at 6 months) and 870 patients were discharged at <24 hours (20%, no CAD at follow-up). The remaining 885 patients were recognized as having CAD (20%, 1.1% inhospital mortality rate). Finally, half of the patients without CAD had active gastroesophageal or anxiety disorders. CONCLUSION: An effective screening program with an observation area inside the ED (1) could be implemented in a public healthcare environment and contribute significantly to the reduction of admissions, (2) could optimize the management of patients at high and intermediate risk and succeed in recognizing CAD in 20% of patients at low risk, and (3) could allow screening for alternative causes of CP in patients without evidence of CAD.