Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining.

BACKGROUND: Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly. RESULTS: Three TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis. CONCLUSION: Multiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.

Treatment of amyloid light chain cardiac amyloidosis: systematic review and future directions.

BACKGROUND: Several treatment strategies for amyloid light chain cardiac amyloidosis (AL-CA) have been described in the literature; however, there is no consensus about the optimal approach to AL-CA. OBJECTIVE: We conducted this systematic review to summarize current evidence from published studies about the safety and efficacy of various treatment regimens for patients with AL-CA, mainly focusing on autologous stem cell transplant (ASCT) and heart transplant. METHODS: An electronic literature search of PubMed, Web of Science, Scopus, EBSCO, and CINAHL Plus was conducted through December 2019 using the relevant keywords and prespecified MeSH terminology. Records were screened, and eligible studies were selected and narratively discussed. Data on the hematologic and cardiac responses as well as the safety of the treatment regimens were extracted and synthesized narratively in the context of the systematic review. RESULTS: Thirty published articles were included in this systematic review. The most commonly used first-line treatment in the included studies was bortezomib-based therapy followed by high-dose melphalan and ASCT, with recent evidence of improved outcome with the addition of daratumumab. Heart transplant was found to extend survival for selected patients who were not eligible for ASCT; however, it was found to affect the patients' tolerance of further chemotherapy in some studies. Published data on longterm outcomes with immunomodulatory agents were scarce. CONCLUSION: Current evidence suggests several possible regimens for the treatment of AL-CA. Effective treatment approaches for AL-CA include induction therapy with bortezomib-based or immunotherapy-based combinations in moderate/severe forms of cardiac involvement, followed by high-dose melphalan and ASCT in eligible patients, and heart transplant for selected severe cases. Therefore, we highlight the necessity of conducting well-designed, randomized controlled trials to provide evidence about the efficacy of these drugs with respect to ASCT.

Constrictive pericarditis following heart transplantation: Reality or fiction?

Constrictive pericarditis (CP) is a curable cause of diastolic heart failure with prior cardiac surgery being a recognizable etiology. We report a patient who developed CP one year following heart transplantation. Several clinical and imaging related factors may lead to diagnostic delays in similar patients, including the mistaken belief that transplanted hearts are devoid of pericardium and thus do not develop constriction. Post-transplantation pericardial effusion, mediastinitis, and cardiac rejection predispose to future CP. Caretakers should consider this entity in allograft recipients who develop heart failure symptoms of unclear etiology.

Comparison of echocardiographic parameters in Fabry cardiomyopathy and light-chain cardiac amyloidosis.

BACKGROUND: Fabry cardiomyopathy (FC) and light-chain amyloid cardiomyopathy (AL) present with concentric left ventricular (LV) hypertrophy/remodeling and diastolic rather than systolic dysfunction. Direct comparisons are difficult due to rarity and confounded by variability of LV thickness. AIMS: To compare LV diastolic and systolic properties between patients with FC and AL in a cohort matched for interventricular septal thickness (IVS). METHODS: A two-center echocardiographic analysis was performed, comprising 118 patients with IVS ≥12 mm (FC and AL 59 patients each) matched by IVS. RESULTS: Fabry cardiomyopathy patients had larger LV end-diastolic diameter (47.7 [44.0-50.9] vs 45.0 [41.5-49.0] mm, P = 0.002), better LV ejection fraction (EF 68.7 [63.4-74.0] vs 63.0 [54.0-70.0]%, P = 0.001) and midwall fractional shortening (midFS 14.8 [13.0-16.1] vs 12.1 [8.9-15.0]%, P = 0.006). LV EF <40% was rare in both (2% vs 7%, P = 0.17). AL patients expressed higher LV diastolic dysfunction grade (III in 26% vs 4%, II in 21% vs 12% and I in 54% vs 84%, P = 0.004), with higher E/e' ratio (13.6 [10.2-18.8] vs 9.8 [7.5-12.3], P < 0.0001). Average E/e' ratio and midFS were significantly associated with NYHA severity in both groups (P < 0.05 for all). CONCLUSIONS: Matched AL patients had worse LV diastolic function than FC, driven by E/e'. Significant LV systolic dysfunction was rare overall. MidFS and E/e' were associated with heart failure severity in both groups.

Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?

BACKGROUND: Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated. AIMS: To describe patients with concomitant AS and TTR-CA. METHODS: Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years. RESULTS: Sixteen patients were included. Mean ± SD age was 79 ± 6 years, 81% were men. Sixty per cent were NYHA III-IV, 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1;Q4) NT-proBNP was 4382 (2425;4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n = 14/16), of whom 86% (n = 12) had low-gradient AS. Mean ± SD interventricular septum thickness was 18 ± 4 mm. Mean left ventricular ejection fraction and global LS were 50 ± 13% and -7 ± 4%, respectively. Diagnosis of TTR-CA was histologically proven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n = 13), one had mutated Val122I and 19% did not had genetic test (n = 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16;65) months. Mortality was of 44% (n = 7) during the whole follow-up period. CONCLUSIONS: Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management.

Spectral Doppler of the Hepatic Veins in Rate, Rhythm, and Conduction Disorders.

Doppler interrogation of blood flow in the hepatic veins (HVs) provides valuable information regarding a wide spectrum of pathological processes that affect the right heart. Systematic analysis of the direction, velocity, and phasicity of the HV waveforms allows one to distinguish normal from abnormal patterns and provides important diagnostic information. Abnormalities in heart rate, rhythm, and intracardiac conduction are commonly encountered during echocardiographic studies. Sinus bradycardia and tachycardia, bradyarrhythmias and tachyarrhythmias as well as atrioventricular conduction disturbances influence the flow pattern in the HVs and may pose a challenge to the correct interpretation of the HV Doppler. Alterations in HV flow that are induced by the electrical abnormalities may mimic right heart pathology. Awareness of these alterations allows one to avoid misinterpretation of the HV signal, helps diagnose the underlying rhythm or conduction abnormality, and permits assessment of the impact on right heart hemodynamics.

The Echocardiographic "Spike and Dome"--Obstruction It Is But Where?

Spectral Doppler interrogation of the descending thoracic and abdominal aorta provides valuable information regarding cardiac and vascular hemodynamics. An abnormal aortic Doppler profile is encountered in pathological conditions that affect the aorta and its branches, the aortic valve, the left ventricle, and the pericardium. Characteristic findings on Doppler interrogation of the aorta are often noted in individuals with obstructive atherosclerotic disease of the aorto-iliac system including severe stenosis or occlusion of the distal aorta and/or iliac arteries. In this manuscript, we highlight the findings on spectral Doppler that led to the identification of occlusive disease in the distal aorta.

Prevalence and long-term outcome of aortic prosthesis-patient mismatch in patients with paradoxical low-flow severe aortic stenosis.

BACKGROUND: Patients with severe aortic stenosis (AS) and paradoxical low flow (PLF) have worse outcome compared with those with normal flow. Furthermore, prosthesis-patient mismatch (PPM) after aortic valve replacement is a predictor of reduced survival. However, the prevalence and prognostic impact of PPM in patients with PLF-AS are unknown. We aimed to analyze the prevalence and long-term survival of PPM in patients with PLF-AS. METHODS AND RESULTS: Between 2000 and 2010, 677 patients with severe AS, preserved left ventricular ejection fraction, and aortic valve replacement were included (74±8 years; 42% women; aortic valve area, 0.69±0.16 cm(2)). A PLF (indexed stroke volume ≤35 mL/m(2)) was found in 26%, and after aortic valve replacement, 54% of patients had PPM, defined as an indexed effective orifice area ≤0.85 cm(2)/m(2). The combined presence of PLF and PPM was found in 15%. Compared with patients with noPLF/noPPM, those with PLF/PPM were significantly older, with more comorbidities. They also received smaller and biological bioprosthesis more often (all P<0.01). Although early mortality was not significantly different between groups, the 10-year survival rate was significantly reduced in case of PLF/PPM compared with noPLF/noPPM (38±9% versus 70±5%; P=0.002), even after multivariable adjustment (hazard ratio, 2.58; 95% confidence interval, 1.5-4.45; P=0.0007). CONCLUSIONS: In this large catheterization-based study, the coexistence of PLF-AS before surgery and PPM after surgery is associated with the poorest outcome.

Spectral Doppler interrogation of mitral regurgitation -spot diagnosis.

Mitral regurgitation (MR) is one of the most common valvular lesions that are readily identified by transthoracic echocardiography. Color Doppler imaging is the modality of choice for the recognition of MR, and it plays an important role in the assessment of regurgitation severity. Continuous wave (CW) Doppler is commonly used to interrogate the MR signal, and this modality can provide highly useful data regarding several physiological and pathological parameters. In this manuscript, we present a series of cases that illustrate the various hemodynamic parameters that can be derived from analysis of the CW Doppler signal of MR.

Spectral Doppler of the hepatic veins in pulmonary hypertension.

Pulsed-wave Doppler interrogation of the hepatic veins (HVs) provides a window to right heart hemodynamics and function. Various pathologies that involve the right heart are manifested on the HV Doppler depending on the location and severity of the involvement and its hemodynamic consequences. Pulmonary hypertension (PHTN), a common finding on echocardiographic studies, imparts changes on the HV Doppler that are important to recognize. In this article, we provide a review of the main abnormalities that are encountered on the HV Doppler in patients with PHTN.

Spectral Doppler interrogation of the pulmonary veins in atrial septal defect.

The various components of the pulmonary venous (PV) flow are linked to physiological and pathological changes that predominantly occur in the left heart. Thus, spectral Doppler interrogation of the PVs provides hemodynamic insight mainly into left-sided cardiac function. An exception to the dependence of PV flow on left heart events occurs in the setting of an atrial septal defect (ASD). The latter causes a portion of the PV blood flow, intended to cross the mitral valve, to be channeled into the more compliant right heart. This phenomenon makes the PV flow more dependent on the left-to-right interatrial shunt. The identification on the PV Doppler of a pattern that suggests uncoupling with left heart hemodynamics should raise the suspicion of an underlying ASD.

The various hemodynamic profiles of the patent ductus arteriosus in adults.

The patent ductus arteriosus (PDA) has diverse clinical and hemodynamic manifestations depending on its size and the degree of the ensuing left-to-right shunt. A small PDA that causes minor shunting has no major hemodynamic consequences. Conversely, a large PDA with a significant left-to-right shunt may lead to various hemodynamic abnormalities. These include left-sided volume overload that may result in heart failure and/or pulmonary hypertension, the latter being a flow-dependent and mostly reversible phenomenon. The most feared complication is the development of severe and irreversible pulmonary hypertension (Eisenmenger physiology). In this manuscript, we provide examples of the various hemodynamic profiles of PDA as assessed by echocardiography in the adult population.

Spectral Doppler interrogation of the patent foramen ovale-a window to left heart hemodynamics.

Spectral Doppler interrogation of flow across a patent foramen ovale (PFO) allows recording of the instantaneous pressure gradient between left and right atrium (RA). The assessment of RA pressure using the size and collapsibility of the inferior vena cava would thus allow estimation of left atrial (LA) pressure. In this article, we illustrate the value of spectral Doppler interrogation of flow across the PFO by transthoracic echocardiography as a novel and simple tool for the assessment of LA pressure and left cardiac hemodynamics in addition to the conventional noninvasive parameters.

Spectral Doppler of the hepatic veins in tricuspid valve disease.

Spectral Doppler recording of the hepatic veins (HV) provides a semiquantitative assessment of tricuspid regurgitation (TR) severity. It complements findings on two-dimensional echocardiography and color Doppler imaging and helps to discriminate between hemodynamically significant and nonsignificant degree of regurgitation. In this manuscript, we discuss the usefulness of the HV Doppler for the diagnosis of tricuspid valve (TV) disease and provide examples of the various spectral Doppler patterns that assist in the quantification of TR.

Outcome and impact of surgery in paradoxical low-flow, low-gradient severe aortic stenosis and preserved left ventricular ejection fraction: a cardiac catheterization study.

BACKGROUND: The clinical relevance and management of paradoxical low-flow, low-gradient aortic stenosis (LFLG-AS) with preserved left ventricular ejection fraction remain debated. The aim of this study is to determine the features and outcome of LFLG-AS assessed using cardiac catheterization. METHODS AND RESULTS: Between 2000 and 2010, 768 patients with preserved left ventricular ejection fraction (>50%) and severe AS (valve area ≤ 1 cm(2)) without other valvular disease underwent cardiac catheterization. Mean age was 74 ± 8 years, 42% were women, and 46% had associated coronary artery disease. The prevalence of LFLG (indexed left ventricular stroke volume <35 mL/m(2) and mean gradient <40 mm Hg), normal flow high gradient, normal flow low gradient, and low flow high gradient were 13%, 50%, 22%, and 15%, respectively. Compared with patients with normal flow high gradient, those with LFLG were significantly older, with significantly reduced systemic arterial compliance and vascular resistances and increased valvulo-arterial impedance (all P<0.05). Ten-year survival was reduced in LFLG-AS (32 ± 9%) compared with normal flow high gradient (66 ± 4%; P=0.0002). After adjustment for other risk factors, LFLG-AS was independently associated with reduced long-term survival (hazard ratio, 1.85; 95% confidence interval, 1.08-3.07; P=0.02). However, despite higher operative mortality, patients with LFLG-AS undergoing aortic valve replacement seemed to have better long-term survival than those managed conservatively (5-year survival rate: 63 ± 6% versus 38 ± 15%; P=0.007; hazard ratio, 0.23; 95% confidence interval, 0.09-0.59; P=0.002). CONCLUSIONS: This large cardiac catheterization-based study reports that the LFLG-AS entity is not rare and is associated with worse outcome whether treated medically or surgically. However, these patients may have better long-term survival if treated surgically. Further prospective studies are needed to confirm this finding.

Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III).

Bortezomib is an active agent in AL amyloidosis and responses to this drug in combination with cyclophosphamide and dexamethasone are both rapid and deep. Here we present an international, multicenter series of 60 patients with Mayo Clinic stage III cardiac amyloidosis to assess the impact of this regimen in improving outcomes in this poor-risk group. The median follow-up for the entire cohort is 11.8 months. The overall response rate was 68%. In a landmark analysis, examining patients who survived more than 3 months, the overall response rate was 86%. A cardiac response was seen in 32% of patients. The estimated 1-year survival rate for the whole cohort was 57% and 24 patients (40%) died while on therapy. Although unable to save the poorest risk patients, the combination of bortezomib, cyclophosphamide and dexamethasone can achieve a high number of hematologic and cardiac responses, likely improving overall survival and justifying a prospective trial.

First report of the clinical characteristics and outcomes of cardiac amyloidosis in Saudi Arabia.

AIMS: Cardiac amyloidosis (CA) is a potentially fatal multisystemic disease that remains significantly underdiagnosed, particularly in the Middle East. This study aims to evaluate the prevalence and clinical characteristics of CA in a high-risk population at a tertiary centre in Saudi Arabia. METHODS: This cross-sectional, retrospective, single-centre study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. We reviewed the medical records of heart failure patients seen between August 2018 and July 2022 who exhibited red flags for CA and subsequently underwent CA screening. Red flags that prompted the workup included at least two of the following factors: the presence of unilateral or bilateral carpal tunnel syndrome, a family history of transthyretin amyloid (ATTR) amyloidosis and specific electrocardiographic features (relative/absolute low QRS voltage, pseudoinfarct pattern and atrioventricular/interventricular conduction abnormalities). Echocardiographic red flags included mainly increased wall thickness (≥12 mm), significant diastolic dysfunction, reduced left ventricular (LV) longitudinal function, right ventricular (RV) dysfunction and elevated right atrial (RA)/pulmonary artery (PA) pressure. Cardiac magnetic resonance (CMR) red flags included aspects similar to those in an echocardiogram as well as a subendocardial or transmural late gadolinium enhancement (LGE) pattern. These patients were assessed for CA through technetium-99m pyrophosphate ([99mTc]Tc-PYP) bone scintigraphy, serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. RESULTS: A total of 177 patients were screened, of which 21.0 (11.9%) patients were diagnosed with transthyretin amyloid CA (ATTR-CA) and 13 (7.3%) patients were diagnosed with light chain CA (AL-CA). Compared with patients with negative/equivocal [99mTc]Tc-PYP scans (grades 0-1), patients with positive [99mTc]Tc-PYP scans (grades 2-3) were older (78.0 vs. 68.0 years, P < 0.001), had higher levels of troponin (P = 0.003) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P < 0.001), had a higher LV mass index (P < 0.001), displayed a more depressed global longitudinal strain (GLS) (P < 0.001) with a greater prevalence of a relative apical sparing pattern (P < 0.001) and demonstrated a higher incidence of first-degree atrioventricular block (P = 0.008) and low voltage patterns on electrocardiography (P < 0.001). Patients with ATTR-CA and AL-CA were more likely to have a subendocardial or transmural LGE pattern on CMR (P < 0.001) and had a significantly lower overall survival (P < 0.001) when compared with other heart failure aetiologies. CONCLUSIONS: This is the first study to describe the clinical characteristics and outcomes of CA in the Middle East and Saudi Arabia. The prevalence of CA among screened heart failure patients here aligns with major international studies, suggesting significant underdiagnosis in the region. Therefore, larger multicentric studies and regional screening programmes are urgently needed to accurately characterize the epidemiology and outcomes of CA in the Middle East.

Differences in heart failure with preserved ejection fraction management between care providers: an international survey.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by growing incidence and poor outcomes. A large majority of HFpEF patients are cared by non-cardiologists. The availability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as recommended therapy raises the importance of prompt and accurate identification and treatment of HFpEF across diverse healthcare settings. We evaluated HFpEF management across specialties through a survey targeting cardiologists, HF specialists, and non-cardiologists. METHODS AND RESULTS: An independent web-based survey was distributed globally between May and July 2023. We performed a post-hoc analysis, comparing cardiologists, HF specialists, and non-cardiologists. A total of 1460 physicians (61% male, median age 41[34-49]) from 95 countries completed the survey; 20% were HF specialists, 65% cardiologists, and 15% non-cardiologists. Compared with HF specialists, non-cardiologists and cardiologists were less likely to use natriuretic peptides (p = 0.003) and HFpEF scores (p = 0.004) for diagnosis, and were also less likely to have access to or consider specific echocardiographic parameters (p < 0.001) for identifying HFpEF. Diastolic stress tests were used in less than 30% of the cases, regardless of the specialty (p = 1.12). Multidrug treatment strategies were similar across different specialties. While SGLT2i and diuretics were the preferred drugs, angiotensin receptor blockers and angiotensin receptor-neprilysin inhibitors were the least frequently prescribed in all three groups. However, when constrained to choose one drug, the proportion of physicians favoring SGLT2i varied significantly among specialties (66% HF specialists, 52% cardiologists, 51% non-cardiologists). Additionally, 10% of non-cardiologists and 8% of cardiologists considered beta blocker the drug of choice for HFpEF. CONCLUSION: Significant differences among specialty groups were observed in HFpEF management, particularly in the diagnostic work-up. Our results highlight a substantial risk of underdiagnosis and undertreatment of HFpEF patients, especially among non-HF specialists.

Diagnostic and therapeutic practice for Heart Failure with preserved ejection fraction around the world: An international survey.

BACKGROUND AND AIMS: There is a gap in knowledge about implementing diagnostic tools and therapy for heart failure with preserved ejection fraction (HFpEF) in clinical practice. This survey aimed to assess real-world practice in HFpEF diagnosis and treatment in the international medical community. METHODS: An independent academic web-based 29-question survey was designed by a group of heart failure specialists and posted by email and through scientific societies and social networks to a broad community of physicians worldwide. RESULTS: 1.460 physicians from 95 countries answered the survey, with a mean age of 42.2±10.4 years, 39.4 % females, and 85.1 % were cardiologists. The left ventricular ejection fraction cut-off value selected for HFpEF diagnosis was 50 % for 89 % of participants. The scores for the probability of diagnosis of HFpEF were used only by 47.2 %, and H2FPEF was the most used score (31 %). Natriuretic peptides were used by 87.4 % of participants for the diagnostic workup, while the diastolic stress test was only used by 26.2 %. 54.4 % of participants chose SGLT2 inhibitors as their first drug treatment, followed by diuretics (18.6 %) and ACE inhibitors (8.4 %). CONCLUSIONS: In an international academic survey on HFpEF management, the criteria for screening and diagnosis of HFpEF patients remain aligned with classic international guidelines with a low use of diagnostic scores. SGLT2i is the leading therapeutic drug class used for this heterogeneous patient population. These results raise the need to improve education and awareness on diagnosing and managing HFpEF patients.