Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.

Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

AIMS: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. METHODS AND RESULTS: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. CONCLUSION: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials.

An increasing awareness of the disease, new diagnostic tools and novel therapeutic opportunities have dramatically changed the management of patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Supportive therapies have shown limited benefits, mostly related to diuretics for the relief from signs and symptoms of congestion in patients presenting heart failure (HF). On the other hand, huge advances in specific (disease-modifying) treatments occurred in the last years. Therapies targeting the amyloidogenic cascade include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Tafamidis, a TTR stabilizer that demonstrated to prolong survival and improve quality of life in the ATTR-ACT trial, is currently the only approved drug for patients with ATTR-CM. The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen have been approved for the treatment of patients with hereditary ATTR polyneuropathy regardless of the presence of cardiac involvement, with patisiran also showing preliminary benefits on the cardiac phenotype. Ongoing phase III clinical trials are investigating another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR-CM. CRISPR-Cas9 represents a promising strategy of genome editing to obtain a highly effective blockade of TTR gene expression.

Right ventricular to pulmonary artery coupling and outcome in patients with cardiac amyloidosis.

AIMS: To investigate the prognostic value of the right ventricle-to-pulmonary artery (RV-PA) coupling in patients with either transthyretin (ATTR) or immunoglobulin light-chain (AL) cardiac amyloidosis (CA). METHODS AND RESULTS: Overall, 283 patients with CA from 3 Italian high-volume centres were included (median age 76 years; 63% males; 53% with ATTR-CA, 47% with AL-CA). The RV-PA coupling was evaluated by using the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. The median value of TAPSE/PASP was 0.45 (0.33-0.63) mm/mmHg. Patients with a TAPSE/PASP ratio <0.45 were older, had lower systolic blood pressure, more severe symptoms, higher cardiac troponin and N-terminal pro-B-type natriuretic peptide levels, greater left ventricular (LV) thickness, and worse LV systolic and diastolic function. A TAPSE/PASP ratio <0.45 was independently associated with a higher risk of all-cause death or heart failure (HF) hospitalization [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.32-2.96; P = 0.001] and all-cause death (HR 2.18, 95% CI 1.31-3.62; P = 0.003). The TAPSE/PASP ratio reclassified the risk of both endpoints [net reclassification index 0.46 (95% CI 0.18-0.74) P = 0.001 and 0.49 (0.22-0.77) P < 0.001, respectively], while TAPSE or PASP alone did not (all P > 0.05). The prognostic impact of the TAPSE/PASP ratio was significant both in AL-CA patients (HR for the composite endpoint 2.47, 95% CI 1.58-3.85; P < 0.001) and in ATTR-CA (HR 1.81, 95% CI 1.11-2.95; P = 0.017). The receiver operating characteristic curve showed that the optimal cut-off for predicting prognosis was 0.47 mm/mmHg. CONCLUSION: In patients with CA, RV-PA coupling predicted the risk of mortality or HF hospitalization. The TAPSE/PASP ratio was more effective than TAPSE or PASP in predicting prognosis.

Echocardiographic findings in subjects with an amyloidogenic apolipoprotein A1 pathogenic variant.

BACKGROUND: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available. METHODS: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening. RESULTS: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness (r = 0.484), LV mass index (r = 0.459), E/e' (r = 0.501), and right ventricular free wall thickness (r = 0.594) (all p < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death (p = 0.009), cardiovascular death (p = 0.001), cardiovascular death or heart failure (HF) hospitalisation (p < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival. CONCLUSIONS: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.

Left ventricular wall thickness and severity of cardiac disease in women and men with transthyretin amyloidosis.

AIMS: Cardiac amyloidosis (CA) is due to a deposition of amyloid fibrils in the heart causing an increase in wall thickness. A left ventricular (LV) wall thickness ≥12 mm plus at least one red flag should raise the suspicion of CA. As normal values of LV wall thickness are lower in women, the adoption or the same cut-off values for men and women could lead to underdiagnosis or delayed diagnosis in women. We investigated the relationship between LV wall thickness and the severity of cardiac involvement in women and men with transthyretin (ATTR) CA. METHODS AND RESULTS: We evaluated 330 consecutive patients diagnosed with ATTR-CA at three centres (Pisa, n = 232; Brescia, n = 69; Trieste, n = 29). Interventricular septum (IVS) and posterior wall (PW) thickness values were lower in women (n = 53, 16%) than men, but most differences were abolished when indexing by body surface area (BSA), height, or height2.7 , suggesting similar disease severity when accounting for the smaller body size of women. PW thickness indexed for height2.7 was even higher in women. We also searched for correlations between IVS and PW thickness and other indicators of the severity of cardiac disease. IVS values indexed by height2.7 displayed tighter associations with N-terminal pro-B-type natriuretic peptide values than non-indexed IVS values. Similarly, indexed values displayed closer relationships with relative wall thickness, E/e' ratio, and tricuspid annular plane systolic excursion. CONCLUSIONS: Indexed LV wall thickness values, particularly by height2.7 , reflect more accurately the severity of cardiac involvement than non-indexed values.

Value of the HFA-PEFF and H2 FPEF scores in patients with heart failure and preserved ejection fraction caused by cardiac amyloidosis.

AIMS: The HFA-PEFF and H2 FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their value in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated. METHODS AND RESULTS: We evaluated the diagnostic and prognostic value of the HFA-PEFF and H2 FPEF scores in 304 patients from three cohorts with HFpEF caused by transthyretin CA (n = 160, 53%) or immunoglobulin light-chain CA (n = 144, 47%). A diagnosis of HFpEF was more likely using the HFA-PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0-1), intermediate (2-4), or high (5, 6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0-1), intermediate (2-5), or high (6-9) probability of HFpEF using the H2 FPEF score. During a median follow-up of 19 months (interquartile range 8-40), 132 (43%) patients died. The HFA-PEFF score, but not the H2 FPEF score, predicted a high risk of all-cause death which remained significant after adjustment for age, AL-CA diagnosis, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and echocardiographic parameters, including left ventricular global longitudinal strain, left ventricular diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16-1.95, p = 0.002 for every 1-point increase in HFA-PEFF). CONCLUSIONS: The HFA-PEFF score has a higher diagnostic utility in HFpEF caused by CA and holds independent prognostic value for all-cause mortality, while the H2 FPEF score does not.

Aortic Valve Stenosis and Cardiac Amyloidosis: A Misleading Association.

The association between aortic stenosis (AS) and cardiac amyloidosis (CA) is more frequent than expected. Albeit rare, CA, particularly the transthyretin (ATTR) form, is commonly found in elderly people. ATTR-CA is also the most prevalent form in patients with AS. These conditions share pathophysiological, clinical and imaging findings, making the diagnostic process very challenging. To date, a multiparametric evaluation is suggested in order to detect patients with both AS and CA and choose the best therapeutic option. Given the accuracy of modern non-invasive techniques (i.e., bone scintigraphy), early diagnosis of CA is possible. Flow-charts with the main CA findings which may help clinicians in the diagnostic process have been proposed. The prognostic impact of the combination of AS and CA is not fully known; however, new available specific treatments of ATTR-CA have changed the natural history of the disease and have some impact on the decision-making process for the management of AS. Hence the relevance of detecting these two conditions when simultaneously present. The specific features helping the detection of AS-CA association are discussed in this review, focusing on the shared pathophysiological characteristics and the common clinical and imaging hallmarks.

COVID-19 Pneumonia, Takotsubo Syndrome, and Left Ventricle Thrombi.

Left ventricle thrombus is considered a rare complication of Takotsubo syndrome. However, both a stress condition predisposing to Takotsubo syndrome and coagulation abnormalities coexist in COVID-19. We describe a case of a patient with COVID-19 with Takotsubo syndrome. (Level of Difficulty: Intermediate.).

A giant interatrial mass: an unusual presentation of primary amyloidosis.

We report a patient with primary systemic amyloidosis who had a very unusual form of clinical and instrumental presentation.

Prognostic Significance of Change in the Left Ventricular Ejection Fraction After Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis and Left Ventricular Dysfunction.

Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis compared with patients with preserved LVEF. To evaluate the impact of early LVEF recovery in patients with baseline dysfunction on clinical outcomes after transcatheter aortic valve implantation (TAVI), we included all consecutive patients who underwent TAVI from the Italian ClinicalService registry with an LVEF of ≤45% at baseline who had 1-month LVEF data. Patients who experienced a previous coronary artery bypass graft, a previous valve replacement, or a previous myocardial infarction were excluded from the analysis. Therefore, 131 patients with an improvement in LVEF of <10% (no-R group) were compared with 121 patients with an improvement in LVEF of ≥10% (R group). The primary end point was the rate of death of any cause. Multivariable analysis was performed to determine independent predictors of lack in LVEF recovery. Early LVEF recovery occurred in 48% of the patients, generally before discharge. One-year all-cause mortality and major adverse cardiac and cerebrovascular events were significantly higher in the no-early recovery group (log rank test p = 0.005 and p = 0.003, respectively). Baseline severe left ventricular dysfunction and previous percutaneous coronary intervention were identified as independent predictors to warn the lack of improvement in LVEF. In conclusion, nearly 50% of patients with preoperative left ventricular dysfunction demonstrated a significant early improvement in LVEF after TAVI. Lack of early LVEF recovery is associated with a worse clinical outcome and is most likely among patients with a severely abnormal baseline LVEF and a previous percutaneous coronary intervention.

Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves.

Dilation of the ascending aorta (AA), which is disproportionate to associated valvular lesions, is a relatively well-recognized phenomenon in patients with a bicuspid aortic valve (BAV). The aim of this study was to evaluate the rate of changes in the AA dimensions and the outcome in patients with AA dilation and BAVs compared with patients with AA dilation and tricuspid aortic valves (TAVs). Serial transesophageal echocardiograms (>12 months apart) were performed in 113 consecutive patients (BAV, n=27 and TAV, n=86) with AA diameters of >or=40 and

Role of different vascular approaches on transcatheter aortic valve implantation outcome: a single-center study.

OBJECTIVE: To compare different vascular approaches on clinical outcome of patients undergoing transcatheter aortic valve implantation (TAVI) with self-expandable bioprosthesis. METHODS: We included all the patients undergoing CoreValve implantation at our institute between September 2007 and March 2014. They were divided into four groups based on the vascular approach: percutaneous transfemoral (pTF), cut-down transfemoral (cTF), transaxillary (TAx) and transaortic (TAo). Clinical outcomes were evaluated according to Valve Academic Research Consortium-2 recommendations. RESULTS: Out of 322 consecutive patients, 170 (53%) underwent pTF, 76 (23%) cTF, 32 (10%) TAx and 44 (14%) TAo approach. Although the TAx and TAo patients had a higher risk profile, they had a similar outcome compared with the pTF and cTF groups; in particular, there were no differences regarding cardiovascular and all-cause mortality at 30 days, 1 and 2 years, as well as stroke, myocardial infarction, bleeding, major vascular complications, permanent pacemaker implantation and acute kidney injury rates. The observed device success rate was higher in the TAo than in the other approaches (88.6 versus 65.9, 68.7 and 76.3% in the pTF, cTF and TAx groups, respectively; P = 0.019). No differences occurred regarding 30-day early safety and 1-year clinical efficacy across the four groups. Fluoroscopy time, amount of contrast medium used and minor vascular complications were significantly higher in pTF patients, as well as in-hospital stay in the TAo group. Atrial fibrillation and prosthetic valve regurgitation, but not the vascular approach, were independent predictors of all-cause mortality. CONCLUSION: A more invasive vascular approach, for CoreValve implantation, even in higher risk patients, does not affect early-term, mid-term and long-term outcomes.

Relationships between coronary flow vasodilator capacity and small artery remodelling in hypertensive patients.

BACKGROUND: Arterial hypertension is frequently associated with the presence of structural alterations in small arteries. Moreover, a reduced coronary flow reserve and vasodilator capacity has been observed in essential hypertensive patients, possibly due, at least in part, to microangiopathy of small coronary vessels. The aim of the present study was to evaluate a possible relationship between subcutaneous small artery structure and coronary flow reserve or vasodilator capacity in patients with essential hypertension. METHODS AND RESULTS: A total of 20 patients with mild to moderate essential hypertension were included in the study, and underwent a biopsy of the subcutaneous fat from the gluteal region. Small arteries were dissected and mounted on a micromyograph. The media thickness, the normalized internal diameter and the media:lumen ratio (M/L) were then calculated. In addition, a transesophageal Doppler echocardiographic study, which allows the measurement of coronary flow velocity before and during maximal pharmacological vasodilatation, was performed. Coronary flow reserve (CFR) was measured as the ratio of coronary flow velocity assessed during adenosine infusion and that measured in basal conditions. From blood pressure and coronary flow velocity during adenosine infusion, minimum coronary resistance was calculated. CFR as well as minimum coronary resistance were significantly correlated to both M/L and to normalized internal diameter of subcutaneous small arteries. CONCLUSIONS: Our results are consistent with the hypothesis of a generalized remodelling of small arteries in the body, including the coronary circulation; this remodelling may play an important role in the reduction of coronary vasodilator capacity in patients with mild to moderate essential hypertension.

The triple-orifice repair: a new technique for the treatment of mitral regurgitation in severe Barlow's disease.

We report a case of severe Barlow's disease with a very complex pathology, in which we applied the "edge-to-edge" technique, creating a triple-orifice mitral valve. Different techniques should be used to correct a similar valve defect; the combination of different surgical procedures and the valve pathology may influence the post-repair recurrence of regurgitation. We believe that it is better to perform a simple and reproducible repair than to carry on with combined complex procedures that could increase the risk of a suboptimal outcome.

Triple-orifice valve repair in severe Barlow disease with multiple-jet mitral regurgitation: report of mid-term experience.

OBJECTIVES: Barlow disease represents a surgical challenge for mitral valve repair (MR) in the presence of mitral insufficiency (MI) with multiple regurgitant jets. We hereby present our mid-term experience using a modified edge-to-edge technique to address this peculiar MI. METHODS: From March 2003 till December 2010, 25 consecutive patients (mean age 54 ± 7 years, 14 males) affected by severe Barlow disease with multiple regurgitant jets were submitted to MR. Preoperative transesophageal echo (TEE) in all the cases showed at least 2 regurgitant jets, involving one or both leaflets in more than one segment. In all the patients, a triple orifice valve (TOV) repair with annuloplasty was performed. Intra-operative TEE and postoperative transthoracic echocardiography (TTE) were carried out to evaluate results of the TOV repair. RESULTS: There was no in-hospital death and one late death (non-cardiac related). At intra-operative TEE, the three orifices showed a mean total valve area of 2.9 ± 0.1cm(2) (range 2.5-3.3 cm(2)) with no residual regurgitation (2 cases of trivial MI) and no sign of valve stenosis (mean transvalvular gradient 4.6 ± 1.5 mmHg). At follow up (mean 38 ± 22 months), TTE showed favourable MR and no recurrence of significant MI (6 cases of trivial and 1 of mild MI). Stress TTE was performed in 5 cases showing persistent effective valve function (2 cases of trivial MI at peak exercise). All the patients showed significant NYHA functional class improvement. CONCLUSIONS: This report indicates that the TOV technique is effective in correcting complex Barlow mitral valves with multiple jets. Further studies are required to confirm long-term applicability and durability in more numerous clinical cases.

Giant asymptomatic left atrial myxoma.

The classic triad of myxoma clinical presentation is characterized by intracardiac obstruction, embolisms, and constitutional symptoms with fever, weight loss, or symptoms resembling connective tissue disease. Giant myxoma without symptoms are very rare. We present a case of a 30-year-old female with a giant asymptomatic myxoma in the left atrium, discovered by echocardiography. The patient was asymptomatic.

Tricuspid valve myxoma in a patient with congestive heart failure.

Myxomas are the most frequent benign primary cardiac tumours (50% of benign heart tumours). This kind of tumour is most likely to be localized in the left atrium, followed by the right atrium, right ventricle and left ventricle. Quite exceptional is the presence of a myxoma originating from the tricuspid valve or from the Eustachian valve. We describe the case of a woman with moderate dyspnoea of unknown origin and the presence of tricuspid myxoma who underwent tricuspid valve curettage.

Coronary-to-bronchial anastomosis: an unusual cause of hemoptysis.

Coronary-to-bronchial anastomosis (CBA) is a rare anomaly. This vascular abnormality may be subclinical or be responsible for several pathophysiological events and symptoms involving the respiratory and/or the coronary system. We report the case of a patient with hemoptysis caused by this anomalous coronary-to-bronchial communication, who was concomitantly affected by aortic stenosis and coronary artery disease requiring surgical treatment. A coronary angiogram clearly demonstrated the abnormal vascular connection between the proximal right coronary artery and the bronchial arteries of the left inferior right lobe. The coronary branch was intra-operatively identified and ligated, in association with aortic valve replacement and coronary artery bypass, with an uneventful postoperative course and resolution of the respiratory symptoms. This case presents an unusual cause of hemoptysis due to CBA in patients with other cardiac comorbidities, which required surgical treatment, allowing direct ligation of the CBA. A review of the clinical and therapeutic characteristics of such a peculiar vascular abnormality is also provided.