Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

SCN5A mutation is associated with a higher Shanghai Score in patients with type 1 Brugada ECG pattern.

AIMS: Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history. METHODS: The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R). RESULTS: The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (P = 0.006) and QRS (P = 0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system. CONCLUSION: Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients.

TeleNEwCARe: An Italian case-control telegenetics study in patients with Hereditary NEuromuscular and CARdiac diseases.

Telemedicine provides healthcare services remotely and represents a fundamental resource for the management of rare and fragile patients. Tele-health implementation is a main objective of the European Reference Networks (ERNs) mission to accelerate diagnosis for rare diseases. TeleNewCARe is a pilot case-control project which evaluates the efficacy and satisfaction of telegenetics for neuromuscular and cardiac adult patients, compared to face-to-face genetic counselling. The virtual sessions were co-hosted by a medical geneticist and a neurologist/cardiologist. Specific questionnaires (Clinical Genetics Satisfaction Questionnaire (CGS), Telemedicine Satisfaction Questionnaire (TSQ) and a Satisfaction Questionnaire for medical geneticists) were used to assess the effectiveness and fulfilment of telecounselling, both for patients and health care providers. Satisfaction expressed for telegenetics did not significantly differ from face-to-face counselling. The virtually enrolled patients declared they had the possibility to relate confidentially with the specialists, to share information and to be informed in an exhaustive way about their disease. Almost all patients declared themselves willing to reuse the telecounselling in the future. The multidisciplinary care was perceived as a significant added value. No overt technical problems were reported although the need for digital skills and tools can limit patients' compliance. Our experience supports telegenetics as a valid alternative to traditional genetic counselling in cardiac and neuromuscular patients. This innovative approach facilitates multidisciplinary care, grants a periodical follow up, without forcing patients to discomfortable travelling, and allows to maintain expert care. This result meets the ERNs needs to reduce patients' burden to access and monitor their healthcare.

[Acute aortic dissection: a challenging pitfall on the acute coronary syndrome pathway]. / Dissezione aortica acuta: un trabocchetto insidioso nel percorso della sindrome coronarica acuta.

Acute aortic dissection is a life-threatening condition that is challenging and difficult to recognize since symptoms may mimic other time-dependent conditions like acute coronary syndrome, acute pulmonary embolism or abdominal conditions. We here describe the case of a middle-aged male with thoraco-abdominal pain, positive ECG and troponin tests that demonstrated a large type A aortic dissection at echocardiography done as part of the acute coronary syndrome work-up. This case report reminds clinicians that acute aortic dissection, although rare, should be considered as a differential diagnosis in the work-up of acute coronary syndrome to avoid critical pitfalls, and echocardiography is crucial to rule out it.

Interactions between cardiovascular and cerebrovascular disease.

OPININION STATEMENT: All patients with ischemic stroke should undergo a comprehensive assessment of cardiovascular risk. Patients with carotid artery disease, symptoms of cerebral ischemia and high cardiovascular risk profiles should be considered for noninvasive testing for coronary artery disease (CAD). Routine testing for CAD before carotid endarterctomy is not recommended. Patients with coexisting coronary and carotid artery disease should be more aggressively treated for reducing their "very high" risk of cardiovascular events. In patients candidates to carotid revascularization, a preoperative coronary angiography and coronary revascularization are not recommended. Warfarin is recommended in all patients with moderate to high risk of stroke. Novel oral anticoagulants represent an attractive alternative to warfarin. However, their place in therapy in clinical practice is not yet established. Percutaneous closure of the left atrial appendage for stroke prophylaxis may be considered in selected patients with atrial fibrillation and contraindications for oral anticoagulant therapy. Warfarin is not indicated in patients with heart failure who are in sinus rhythm. Percutaneous closure of patent foramen does not seem to be superior to medical therapy for the prevention of recurrences in patients with cryptogenic stroke.

[Electrocardiographic diagnosis of acute myocardial infarction in the aera of primary percutaneous coronary intervention and hub and spoke networks]. / La diagnosi elettrocardiografica di infarto miocardico acuto nell'era dell'angioplastica primaria e delle reti hub and spoke.

More than a century after it was invented, standard ECG is enjoying a renaissance of sorts. With regard to acute ischemic heart disease, this phenomenon is due mainly to the availability of large databases that in an ordered and predefined manner collect patient ECG patterns along side their clinical and coronary angiography details as well as outcome data. The present review critically analyses the diagnostic role of standard ECG in acute coronary syndromes with or without ST-segment elevation (STEMI and NSTEMI, respectively) and focuses on interpretation pitfalls and patterns that can contribute to therapeutic decision-making. In front of a patient with a clinical presentation suggestive of acute myocardial infarction the ECG can help answer many questions. In case a STEMI is suspected: are we sure we can exclude an infarction? (the problem of false negatives); are we sure it is a real infarction and not a false positive? Which is the obstructed coronary artery and at what level? Has there been reperfusion? In case an NSTEMI is suspected: are we sure it is a real myocardial infarction, rather than a pulmonary embolism or an aortic dissection? Are we sure it is NSTEMI rather than a "masked" dorsal STEMI? Which coronary substrate and what ischemia extension can we hypothesize in this patient? In particular, is the substrate of such high risk suggesting an emergency invasive approach?

[Epidemiology of acute coronary syndromes in Italy]. / Epidemiologia delle sindromi coronariche acute in Italia.

Acute coronary syndromes (ACS) represent the most common cause of death in the western world and determine high morbidity. The objective of this review is to describe the epidemiology of ACS in the Italian setting, using administrative data, clinical surveys and registries. The prevalence of patients with myocardial infarction without persistent ST-segment elevation (NSTE) has increased in comparison with myocardial infarction with persistent ST-segment elevation patients. Females are about 30%, one third of patients is >75 years old, one quarter is affected by diabetes, patients with NSTE ACS show a higher risk profile. The mortality rate of patients with ACS has decreased over the last 10 years as a consequence of new therapeutic strategies. In order to offer primary coronary angioplasty to all ST-elevation myocardial infarction patients, a network between tertiary and peripheral hospitals is under development and implementation. Early experiences show a significant increase in the number of patients treated with reperfusion therapy and a decrease in mortality and morbidity. It has been demonstrated that management of NSTE patients, based on potent antithrombotic medication and coronary angioplasty, is primarily driven by resource availability rather than by clinical predictors of worse outcome. The reduction in recurrent ischemic events was obtained at the cost of an increased rate of major bleeding, which is associated with worse clinical outcomes. Therefore, it is essential the balance between the ischemic and hemorrhagic risk.

Myocardial rupture with left ventricle to coronary sinus communication: an unusual post-infarction mechanical complication.

We describe a rare case of post-infarction myocardial rupture leading to communication between the left ventricle and coronary sinus, which eventually led to a left-to-right shunt. The observation was made in an elderly woman with subacute infero-posterior myocardial infarction. Diagnosis was initially made by transthoracic echocardiography (elicited by the finding of high-velocity flow within a dilated coronary sinus), and was confirmed in greater detail at cardiac magnetic resonance. This description adds to the list of known post-infarction mechanical complications. The finding of high-velocity flow within the coronary sinus after myocardial infarction suggests the possibility of myocardial rupture leading to left ventricle to coronary sinus communication; an unusual but potentially treatable complication.

Gender-related risk of myocardial involvement in systemic amyloidosis.

To investigate associations between gender and myocardial involvement in systemic amyloidosis, we reviewed all patients presenting between 1994 and September 2006 in our institutional network (100 AL and 98 familial transthyretin-related amyloidosis (ATTR) patients, plus 12 elderly men with senile systemic amyloidosis). We focused on echocardiographic descriptors of myocardial involvement (height-indexed mean left ventricular (LV) wall thickness, LV mass index), and baseline LV function. Among familial ATTR patients, female prevalence was lower within the highest tertile of either echocardiographic indicator of myocardial involvement. Gender was independently associated with height-indexed mean LV wall thickness (as were gene mutations). Female prevalence appeared rather similar across the different neurological stages. Within the subgroup of familial ATTR patients with amyloidotic cardiomyopathy, women tended to display a considerably less severe morphological and functional echocardiographic profile. We explored the possible role of female sex hormones by considering menopausal status: women in the highest tertile of mean LV wall thickness index were more often postmenopausal than those in the other two tertiles and had a much higher ( approximately 15 years) mean age; analogous age-related associations were not observable for men. In conclusion, these findings raise the hypothesis that some biological characteristic associated with female gender protects against myocardial involvement in familial ATTR.

Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: towards tailoring of therapeutic strategies?

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8-120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart-liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.

Different types of cardiomyopathy associated with isolated ventricular noncompaction.

Although mainly described in the context of dilated and hypokinetic left ventricles, it is unclear whether isolated ventricular noncompaction (IVNC) is a distinct cardiomyopathy, a subtype of dilated cardiomyopathy, or a morphogenetic disorder. To investigate the spectrum of cardiomyopathies associated with IVNC, children and adults with stringent echocardiographic diagnoses of IVNC were reviewed. Seventy-three patients (12 children aged <15 years) seen since 1994 satisfied stringent echocardiographic criteria for IVNC. Sixty-five patients (89%; 11 children) had dilated cardiomyopathy, 2 adults had clear-cut hypertrophic cardiomyopathy, 1 adult had restrictive cardiomyopathy (to the investigators' knowledge, the first reported example of this particular association), and 5 patients (1 child) had normal left ventricular morphology and function. In conclusion, knowledge that IVNC can co-exist with restrictive and hypertrophic cardiomyopathy (in addition to the dilated form) supports the concept that IVNC is a morphologic trait rather than a distinct cardiomyopathy. This knowledge should be taken into account during echocardiographic examination and encourage the use of contrast echocardiography (and magnetic resonance) and could also orient molecular biology studies.

[Atheromatosis of the thoracic aorta and risk of stroke]. / Aterosclerosi dell'aorta toracica e rischio di ictus.

Atrial fibrillation and severe carotid artery stenosis are the most common causes of stroke. However, several patients recognize unusual cause for their cerebral ischemia. At the beginning of the last decade after the introduction of transesophageal echocardiography (TEE) and other imaging techniques, atheromatosis of the thoracic aorta has been recognized as an important source of stroke or systemic embolism. Formerly in the pre-TEE era, this entity was included into cryptogenic strokes. Notably, aortic atheromas are found in about one quarter of patients presenting with embolic events and their grading by TEE correlates with the risk of future embolism, especially if mobile lesions or superimposed thrombi are present. Unfortunately, the diagnosis of aortic atheroma is mostly established when an embolic event has already occurred. The aim of this paper is to review the current evidence for aortic atheroma as an important independent risk factor for stroke, and to discuss the potential therapeutic options. Unfortunately, randomized studies addressing the treatment of patients with severe aortic atheroma are not yet completed. Furthermore, although warfarin and statins look promising in several retrospective series, their results are by most controversial so far. In conclusion, although the diagnostic criteria and the negative prognostic significance of aortic atheroma are almost defined, its therapeutic options are far to be clear. Therefore, clinical trials addressing this relevant pathologic condition are urgently needed.

Paradoxical contributions of non-compacted and compacted segments to global left ventricular dysfunction in isolated left ventricular noncompaction.

The pathophysiologic mechanisms of left ventricular (LV) dysfunction in isolated ventricular noncompaction (IVNC) remain unclear. Evaluating global and segmental systolic LV function in 65 patients with IVNC, this study found that normal wall motion was more common in noncompacted than in compacted segments. The number of noncompacted segments per patient correlated positively with the LV ejection fraction and negatively with LV end-diastolic volume index. These paradoxical findings support the concept that noncompaction represents a marker of a more generalized (cardio)myopathy rather than the direct pathophysiologic substrate of this still little-understood disease.

Dilated-hypokinetic evolution of hypertrophic cardiomyopathy: prevalence, incidence, risk factors, and prognostic implications in pediatric and adult patients.

OBJECTIVES: This study sought to investigate the incidence, risk factors, and prognosis of dilated-hypokinetic evolution in a large cohort of patients with hypertrophic cardiomyopathy (HCM) followed up at a cardiology center serving both the pediatric and the adult population. BACKGROUND: The available data on this evolution of HCM mainly regards prevalence (rather than incidence) in adults, with very little being known about the pediatric population. METHODS: A total of 222 consecutive HCM patients (65% men, 19% < or =18 years old) were prospectively evaluated for a mean follow-up of 11 +/- 9 years. RESULTS: A diagnosis of dilated-hypokinetic HCM was made in 12 patients at first evaluation (11 without previous septal myectomy surgery; prevalence, 4.9%). Twelve of the 210 patients with classic HCM at first evaluation underwent dilated-hypokinetic evolution (incidence, 5.3/1,000 patient-years). Patients with prevalent/incident dilated-hypokinetic evolution were younger at first evaluation (32 +/- 14 years vs. 41 +/- 21 years, p = 0.04) and more often had a family history of HCM (61% vs. 26%, p = 0.002) or sudden death (43% vs. 19%, p = 0.01) with respect to patients who maintained classic HCM. Moreover, they showed greater interventricular septum (23 +/- 3 mm vs. 19 +/- 6 mm, p = 0.004) and posterior wall (15 +/- 3 mm vs. 13 +/- 4 mm, p = 0.006) thickness. Cardiovascular death-free survival was lower among patients with dilated-hypokinetic HCM (p < 0.04). Cox proportional hazards regression analysis identified left ventricular wall thickness (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 1.01 to 1.14; p = 0.03) and end-diastolic diameter (HR = 1.08; 95% CI 1.04 to 1.11; p = 0.0001) as independent predictors of cardiovascular death. CONCLUSIONS: Dilated-hypokinetic evolution is rare but not exceptional in HCM. Young age at diagnosis, family history of HCM, and greater wall thickness are incremental risk factors for dilated-hypokinetic HCM, which carries an ominous prognosis.