Temporal implementation of a regional referral pathway in transthyretin cardiac amyloidosis: Emilia-Romagna experience.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and progressive cardiomyopathy caused by amyloid fibril deposition in myocardial tissue. Diagnostic challenges have historically hampered timely detection. Recent advances in noninvasive diagnostic techniques have facilitated ATTR-CA diagnosis. We aimed to examine the development of a regional network for the diagnosis and management of ATTR-CA and describe a cohort of patients with ATTR-CA, investigate diagnostic pathways and assess clinical outcomes according to diagnosis periods. METHODS: We performed a survey study analyzing answers from 11 cardiology centers and we conducted a retrospective study including patients with ATTR-CA attending a referral center between 1 January 2012 and 31 December 2022, and categorized by the period of diagnosis (2012-2016 and 2017-2022). RESULTS: Over the years, a growing number of patients reached a diagnosis and were treated in the surveyed nonreferral centers of the region. The retrospective study showed a more significant diagnostic delay in the earlier period rather than the later one [13.4 (5-30.2) vs. 10.6 (5.0-17.9) months, P = 0.04]. Patients diagnosed after 2017 showed a greater survival rate than those diagnosed earlier ( P = 0.02). In the multivariate analysis, the year of diagnosis from 2017 remained independently associated with mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.28-0.79; P = 0.005]. CONCLUSION: This study emphasized the shift toward noninvasive diagnostic criteria. It revealed a positive impact on patient survival and disease management with the use of disease-modifying therapies and diagnostic developments in more recent years. The findings underscore the importance of disease awareness and networking to reduce diagnostic delays and enhance patient journeys for ATTR-CA.

Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features.

Leucine zipper-like transcription regulator 1 (LZTR1) acts as a negative factor that suppresses RAS function and MAPK signaling; mutations in this protein may dysregulate RAS ubiquitination and lead to impaired degradation of RAS superfamily proteins. Germline LZTR1 variants are reported in Noonan syndrome, either autosomal dominant or autosomal recessive, and in susceptibility to schwannomatosis. This article explores the genetic and phenotypic diversity of the autosomal dominant LZTR1-related disorders, compiling a cohort of previously published patients (51 with the Noonan phenotype and 123 with schwannomatosis) and presenting two additional adult-onset cases: a male with schwannomatosis and Parkinson's disease and a female with Noonan syndrome, generalized joint hypermobility, and breast cancer. This review confirms that autosomal dominant LZTR1-related disorders exhibit an extreme phenotypic variability, ranging from relatively mild manifestations to severe and multi-systemic involvement, and offers updated frequences of each clinical feature. The aim is to precisely define the clinical spectrum of LZTR1-related diseases, using also two new emblematic clinical cases. Gaining insight into the mechanisms underneath this variability is crucial to achieve precision diagnostics and the development of therapeutic interventions.

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.

Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation.

BACKGROUND: Exercise echocardiography is used for assessment of pulmonary circulation and right ventricular function, but limits of normal and disease-specific changes remain insufficiently established. OBJECTIVES: The objective of this study was to explore the physiological vs pathologic response of the right ventricle and pulmonary circulation to exercise. METHODS: A total of 2,228 subjects were enrolled: 375 healthy controls, 40 athletes, 516 patients with cardiovascular risk factors, 17 with pulmonary arterial hypertension, 872 with connective tissue diseases without overt pulmonary hypertension, 113 with left-sided heart disease, 30 with lung disease, and 265 with chronic exposure to high altitude. All subjects underwent resting and exercise echocardiography on a semirecumbent cycle ergometer. All-cause mortality was recorded at follow-up. RESULTS: The 5th and 95th percentile of the mean pulmonary artery pressure-cardiac output relationships were 0.2 to 3.5 mm Hg.min/L in healthy subjects without cardiovascular risk factors, and were increased in all patient categories and in high altitude residents. The 5th and 95th percentile of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio at rest were 0.7 to 2.0 mm/mm Hg at rest and 0.5 to 1.5 mm/mm Hg at peak exercise, and were decreased at rest and exercise in all disease categories and in high-altitude residents. An increased all-cause mortality was predicted by a resting tricuspid annular plane systolic excursion to systolic pulmonary artery pressure <0.7 mm/mm Hg and mean pulmonary artery pressure-cardiac output >5 mm Hg.min/L. CONCLUSIONS: Exercise echocardiography of the pulmonary circulation and the right ventricle discloses prognostically relevant differences between healthy subjects, athletes, high-altitude residents, and patients with various cardio-respiratory conditions. (Right Heart International NETwork During Exercise in Different Clinical Conditions; NCT03041337).

sPAP/PAAT Ratio as a New Index of Pulmonary Vascular Load: A Study in Normal Subjects and Ssc Patients with and without PH.

In pulmonary hypertension (PH), the development of right ventricular (RV) dilatation and RV failure are signs of accelerated progression of the disease, resulting in an increased risk of cardiac death. Even the noninvasive assessment of systolic blood pressure in the pulmonary artery undertaken by echocardiography does not provide a measure of ventricle-pulmonary interaction. Some studies have shown the potential for echocardiography to indirectly evaluate pulmonary vascular resistance (PVR) and the acceleration time of pulmonary outflow (PAAT). We used systolic pulmonary artery pressure (sPAP) and pulmonary vascular resistance to develop an sPAP/PAAT ratio (strength/surface unit)/(time) for this study. From January 2017 to December 2018, 60 healthy subjects and 63 patients with systemic scleroderma (Ssc) (60 females, 3 males), 27 with PH and 36 without PH at two-dimensional echocardiographic/Doppler, were screened. In normal subjects, the mean sPAP/PAAT ratio was 0.26 ± 0.063, which indicated optimal pulmonary arterial ventricle coupling and biventricular function. The data derived from the analysis of the Ssc patients showed that those presenting pre-capillary PH at cardiac catheterization had an sPAP/PAAT ratio of 0.40 ± 0.05. There was a significant correlation between sPAP/PAAT with Walk Distance (WD) and PVR, but not with TAPSE. Interobserver variability was less than 5%. The sPAP/PAAT ratio is a new parameter that may indicate pulmonary vascular afterload and interaction, both in normal subjects and in patients with Ssc and PH.

The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19. MATERIALS AND METHODS: The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019. RESULTS: Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (p<0.001). A high level of attention is needed to avoid the potential risk of disease progression related to less aggressive escalation of treatment and the reduction in new PAH diagnoses compared with 2019. CONCLUSION: A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Severe hypertrophic cardiomyopathy in a patient with a homozygous MYH7 gene variant.

Background: Hypertrophic cardiomyopathy is an autosomal dominant disease. The main feature of this disorder is its occurrence in patients who present a left ventricular hypertrophy, unexplained by the loading conditions, usually asymmetric with greatest involvement most commonly of the interventricular septum.Case presentation During a sports medicine control, a ultrasound scan in a 17 years old patient has shown a concentric left ventricular parietal hypertrophy associated with a 23 mm mid- basal interventricular septum thickness. After genetic counselling, a positive family history for hypertrophic cardiac disease and parents' consanguineity was found. The genetic basis of the hypertrophic cardiomyopathy was investigated through a dedicated gene panel. The genetic test has revealed the presence of the variant c.3424G>A (p.Glu1142Lys) in the MYH7 gene in a homozygous state. Genotyping of the parents and of the two brothers revealed the presence of the MYH7 variant in heterozygosity in both parents and in the younger brother. In all of them, variable signs of hypertrophic cardiomyopathy were found. Conclusions: Our findings report the presence of a homozygous variant in a sarcomeric gene (MYH7) which gave rise to early HCM, whereas the variant in a heterozygous state was associated to much milder cardiac phenotypes in the affected relatives. The onset and the progression of the hypertrophic cardiomyopathy in the reported family is to be referred to the presence of the variant in hetero- or homo-zygosity in a gene dosage manner.

Chronic thromboembolic pulmonary hypertension risk score evaluation and validation (CTEPH SOLUTION): proposal of a study protocol aimed to realize a validated risk score for early diagnosis.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most serious long-term complication of acute pulmonary embolism (PE) though it is the only potentially reversible form of pulmonary hypertension (PH). Its incidence is mainly limited to the first 2 years following the embolic event, however it is often underdiagnosed or misdiagnosed. METHODS: This is a multicenter observational cross-sectional and prospective study. Patients with a prior diagnosis of PE will be enrolled and undergo baseline evaluation for prevalent PH detection through a clinical examination and an echocardiogram as first screening exam. All cases of intermediate-high echocardiographic probability of PH will be confirmed by right heart catheterization and then identified as CTEPH through appropriate imaging and functional examinations in order to exclude other causes of PH. A CTEPH Risk Score will be created using retrospective data from this prevalent cohort of patients and will be then validated on an incident cohort of patients with acute PE. RESULTS: One thousand retrospective and 218 prospective patients are expected to be enrolled and the study is expected to be completed by the end of 2021. Up to now 841 patients (620 retrospective and 221 prospective) have been enrolled. CONCLUSIONS: This study is the first large prospective study for the prediction of CTEPH development in patients with PE. It aims to create a comprehensive scoring tool that includes echocardiographic data which may allow early detection of CTEPH and the application of targeted follow-up screening programs in patients with PE.

Improved efficiency and cost reduction in the emergency department by replacing contemporary sensitive with high-sensitivity cardiac troponin immunoassay.

The Authors planned this study to evaluate the impact of replacing a contemporary-sensitive with HS cTnI immunoassay on hospital and laboratory workload. The authors say that, 'Despite some evidence, the clinicians are still hesitant to replace the former so-called contemporary-sensitive methods with HS-cTn techniques, justifying this reluctance with concerns of overutilization, possible over diagnosis of cardiac injuries, overcrowding of emer-gency departments (EDs), and excess of cardiac invasive testing. Several factors have lead clinicians to use terms such as "troponin leak", "false-positive" troponin elevation, or "troponinemia". The results of this study show substantial organizational and economic benefits by replacing con-temporary-sensitive with HS cTnI immunoassays. This is very important question because there are some areas such as acute non-ST elevation coro-nary syndromes (NSTEMI) and in elderly patients, the specificity is very low for the simultaneous presence of factors that can alter the dosage of HS-cTnI values.

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

PURPOSE: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork. METHODS: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured. RESULTS: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%. CONCLUSIONS: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

Left ventricular free-wall rupture, a potentially lethal mechanical complication of coronaric angioplasty : an unusual case report.

The incidence of complications of coronary perforation varied significantly among studies probably due to population heterogeneity and interventional techniques applied in each centre. Free wall rupture, cardiac tamponade and miocardial infarction are the most  feared. The treatment of perforation remains a challenge of every cath- lab team. The management strategies range from observation to urgent operation depending on patient's hemodynamic status, severity and location of the perforation, coronary anatomy, interventional practice and equipment in each centre and operators' skills on-site. In this case an extracorporeal circulation and cardioplegic arrest with anterograde hot blood cardioplegia was done. A composite Dacron with autologous pericardium patch was used for left ventricular free wall rupture repair and the geometry of the left ventricle was restored. Subsequently aorta was declamped; the patient was weaned from CEC and a good spontaneous hemodynamic was recovered.

Cardiac imaging in congenital heart disease during the coronavirus disease-2019 pandemic: recommendations from the Working Group on Congenital Heart Disease of the Italian Society of Cardiology.

: The recent outbreak of 2019 severe acute respiratory syndrome coronavirus-2 is having major repercussions on healthcare services provision in Italy and worldwide. Data suggest the virus has a strong impact on the cardiovascular system, and cardiac imaging will play an important role in patients affected by coronavirus disease-2019. Although paediatric patients are mildly affected, they represent a clear accelerator in spreading the virus, and healthcare workers are at higher risk of infection. The aim of this position paper is to provide clinical recommendation regarding the execution of imaging investigations for the cardiac diagnostic work-up of paediatric patients with suspected or confirmed infection.

Severe acute respiratory failure due to a multifactorial diffuse alveolar haemorrhage.

Diffuse alveolar haemorrhage (DAH) is a life-threatening syndrome caused by infection, coagulation disorders or autoimmune diseases. We here report the case of an 81-year-old male subject affected by a multifactorial DAH, in which the bleeding was related to the administration of clopidogrel and warfarin, both implicated in the context of a polycythaemia. He developed a severe acute respiratory failure treated with a ventilatory support by means of a continuous positive airway pressure (C-PAP) therapy. An improvement of patient's clinical conditions was observed only after clopidogrel and warfarin discontinuation.

Role of cardiac imaging in Anderson-Fabry cardiomyopathy.

The Anderson-Fabry disease (AFD, or simply Fabry Disease, FD; MIM #301500) is a rare X-linked lysosomal storage disorder (Xq22.1) characterized by progressive renal failure, leading to morbidity through cardio- and cerebro-vascular involvement. Despite the classic phenotype, only cardiac involvement (cardiac variant of AFD; MIM 301500) is frequent in about 40% of male and 28% of female AFD patients, as reported by the Fabry Registry ( https://www.registrynxt.com ). Morphologically, the cardiac characteristic of the disease, occurs as left ventricular hypertrophy, is accompanied by myocardial fibrosis. Cardiologists may come across these patients during clinical and instrumental evaluation in individuals with non-specific symptoms such as chest pain and arrhythmias, or after instrumental evidence of left ventricular hypertrophy/hypertrophic cardiomyopathy (HCM; MIM 192600). A comprehensive cardiological work-up, including a cardiological visit, a baseline electrocardiogram (ECG) and imaging by both echocardiography (ECHO) and magnetic resonance (MRI) enables identification of the cardiac involvement in patients with a proven diagnosis of AFD. The heart involvement is present in up to 75% of AFD patients irrespective of their sex. Involvement includes ECG and echocardiography features which suggest AFD and not HCM. Cardiac imaging plays an important role in detecting this sub-type of cardiomyopathy, which, since 2001, has benefited from the introduction of the enzyme replacement therapy (ERT) in symptomatic and pre-symptomatic patients.

Pulmonary Circulation on the Crossroads Between the Left and Right Heart in Systemic Sclerosis: A Clinical Challenge for Cardiologists and Rheumatologists.

Involvement of the right heart-pulmonary circulation system in systemic sclerosis is a typical feature, with critical prognostic implications. Pulmonary hypertension may occur in association with interstitial lung disease or as a result of an isolated pulmonary vascular disease that may affect both the precapillary arterioles and the postcapillary venules, as well as a consequence of left heart involvement. These apparently different phenotypes often underlie a significant pathophysiologic overlap, which makes the diagnosis and management of these patients highly complex and uncertain.

The Right Heart International Network (RIGHT-NET): Rationale, Objectives, Methodology, and Clinical Implications.

The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.

Role of Transesophageal 3D Echocardiography in Adult Cor Triatriatum Diagnosis.

Cor triatriatum is a very rare congenital abnormality, symptomatic during childhood;the non restrictive form is usually diagnosed as an incidental finding. We report the case of a 88 years old man referred to our hospital for elective endovascular repair of an aortic aneurysm; transthoracic cardiac bidimensional echocardiography showed an abnormal mass into the left atrium and a the diagnosis of cor triatriatum was fully made by a three dimensional transesophageal echocardiography. 3D echocardiography is an excellent noninvasive method that provides a rapid bedside diagnosis , without having to use ionizing radiation.

Transthoracic Echocardiography and Chest Computed Tomography Arteriography in Patients with Acute Pulmonary Embolism: A Two-Year Follow-Up Study.

BACKGROUND: Pulmonary hypertension (PH) is frequently found at the time of diagnosis of pulmonary embolism (PE). An incomplete resolution of PE can lead to chronic thromboembolic pulmonary hypertension (CTPH). Transthoracic echocardiogram (TTE) is the first step to diagnose an abnormality of the pulmonary vasculature. Based on computed tomography (CT), the Qanadli vascular obstruction index has been extensively used to assess acute PE. OBJECTIVES: Our aim was to ascertain whether at the time of diagnosis of an acute PE episode TTE variables and a Qanadli CT index score may be associated with CTPH 2 years later. METHOD: Patients with PE were prospectively enrolled. TTE was performed and the Qanadli CT obstruction index was calculated on admission to the hospital, while only TTE was repeated at the 2-year follow-up. The NYHA (New York Heart Association) functional classification was evaluated. Correlation analyses were performed. RESULTS: Twenty patients (11 males, median age 69.5 years) were considered for the study. There was no significant correlation between TTE parameters and the Qanadli CT obstruction index. A significant distribution (χ2 = 5.69, p = 0.017) was found in the analysis among patients with CTPH at 24 months and the Qanadli CT index, categorized by a receiver operating characteristic curve cutoff value of 42.5%. Additionally, a significant distribution (χ2 = 4.09, p = 0.043) was found in the analysis among patients with CTPH at 24 months and right ventricular systolic pressure on admission, categorized as PH (>31 mm Hg). CONCLUSION: Our study demonstrates that in patients with acute PE there is no relationship between the Qanadli CT obstruction index and TTE parameters on admission to the hospital. However, the occurrence of CTPH at the 24-month follow-up is associated with PH and with a high Qanadli CT obstruction index score.