Abstract
Introduction
Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both ...physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions.
Purpose
We developed and validate a free digital support tool in the form of an App to provide support and to guide the physician in the differential diagnostic process of patients presenting with primary LVH.
Methods
We studied 210 consecutively genotyped patients (54±21 years, 118 (56% males) referred to our center for the suspicion of primary LVH. A systematic literature analysis was conducted to classify disease specific red-flags (RFs) associated with sarcomeric and non sarcomeric hypertrophic cardiomyopathy (HCM). RFs were categorized into two subgroups: extremely specific RFs (features only described associated to the given disease) and specific RF (characteristics typical for the disease but also associated with other conditions). Pre-specified RF were categorized into four domains: family history; signs/symptoms; electrocardiography and imaging. The outcome of the digital support tool was categorized as follows: (a) most likely diagnosis (if contemplated age range for the condition, at least 1 extremely specific RFs or more than 1 specific RF were satisfied); (b) possible diagnosis (if contemplated age range for the condition, 1 specific RF were satisfied); (c) less likely diagnosis (outside age range for disease and no RF selected).
Results
Of the 210 patients, 84 (40%) were diagnosed with sarcomeric HCM, 56 (27%) with TTR amyloidosis, 44 (21%) with Fabry disease (FD), 7 (4%) with a mitochondrial disease, 4 (2%) with Pompe disease, 4 (2%) with PRKAG2 cardiomyopathy, 3 (1%) with Noonan, 3 (1%) with Friederich's Ataxia, 3 (1%) with LEOPARD and 2 (1%) with Danon disease. A total of 942 RFs has been identified in the cohort, of which 327 were extremely specific RFs (41 from family history; 107 from signs/symptoms; 111 from electrocardiography and 113 from imaging sections). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and >55yo. One-hundred-ninety-five patients (92%) were correctly categorized in the most likely and possible diagnosis section. The App proved to be sensible for sarcomeric HCM, FD (0.99 and 0.91, NPV 0.98 and 0.83) and extremely capable in the identification of rare causes of LVH (Danon, Friederich's ataxia, LEOPARD, Pompe, Noonan and PRKAG2 diseases). By design, specificity was not high, in particular for sarcomeric HCM and FD.
Conclusions
The present free digital support tool in the form of an App proved to be extremely sensible in providing the support to the screening of different causes of primary LVH in patients presenting with a HCM phenotype. Further external and multicenter validation is warranted.
Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Amicus therapeutics
Abstract
Introduction
For patients presenting with primary Left Ventricular Hypertrophy (LVH), the ESC recommends systematic search for diagnostic clues or “red flags” (cardiac and non-cardiac) that ...can identify particular treatable disorders and guide rational selection of diagnostic tests. To date, a systematic evaluation of this recommendation has not been performed
Purpose
We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM).
Methods
We studied 210 consecutively genotyped patients (54±21 years, 118 (56% males) referred to our center for the suspicion of primary LVH. Pre-specified RF were categorized into four domains: family history; signs/symptoms; electrocardiography and imaging.
Results
Of the 210 patients, 84 (40%) were diagnosed with sarcomeric HCM, 56 (27%) with TTR amyloidosis, 44 (21%) with Fabry disease (FD), 7 (4%) with a mitochondrial disease, 4 (2%) with Pompe disease, 4 (2%) with PRKAG2 cardiomyopathy, 3 (1%) with Noonan, 3 (1%) with Friederich's Ataxia, 3 (1%) with LEOPARD and 2 (1%) with Danon disease. A total of 942 RF has been identified in the cohort. Concerning family history, autosomal dominant pattern was specific for sarcomeric HCM (66/84, 79%), whereas X-linked inheritance was frequently observed in Fabry disease (40/44, 91%). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and >55yo. Ophthalmological signs/symptoms (22/23) were specifically find in FD, whereas muscolo-skeletal RF were rare and non-specific. Neurological phenotype was prevalent in FD patients (38/44, 86%), as well as in TTR amyloidosis (carpal tunnel in 29/56, (52%)), in mithocondropathies and Friederich's Ataxia. Cutaneous involvement was frequent in FD (12 patients with angiokeratomata) (Tab.1). Giant T waves inversion was the most prevalent ECG alteration, but aspecific (61 patients, 32/84 sarcomeric HCM, 16/44 FD). Short PR interval was found in 24 (12%) of patients and specific for FD (15/44) and mitochondrial disease (3/7). Low QRS voltage was present in 17 (8%) patients, and of these 16 had TTR amyloidosis. Inferior leads Q waves was uncommon and non-specific. Mitral valve disease (SAM and anterior mitral leaflet elongation) and apical LVH were present respectively in 57/210 (28%) and 9/210 (4%) of the patient and were almost entirely observed in sarcomeric HCM. Concentric LVH and severe left posterior wall hypertrophy were extremely specific for non sarcomeric HCM (108/109 cases). Strain apical sparing was useful in the identification of TTR amyloidosis.
Conclusions
Clinical RF in patients with primary LVH are common and can be highly specific for correct phenotypisation of the patient. An extensive diagnostic work-up should therefore be conducted by the physician to identify potentially treatable primary LVH causes.
Funding Acknowledgement
Type of funding sources: None.
Chronic renal disease is associated with advanced age,diabetes,hypertension,obesity,musculoskeletal problems and cardiovascular disease,the latter being the main cause of mortality in patients ...receiving haemodialysis(HD).Cooled dialysate(35 ℃-36 ℃) is recently employed to reduce the incidence of intradialytic hypotension in patients on chronic HD.The studies to date that have evaluated cooled dialysate are limited,however,data suggest that cooled dialysate improves hemodynamic tolerability of dialysis,minimizes hypotension and exerts a protective effect over major organs including the heart and brain.The current evidence-based review is dealing with the protective effect of cold dialysis and the benefits of it in aspects affecting patients’ quality of care and life.There is evidence to suggest that cold dialysis can reduce cardiovascular mortality.However,large multicentre randomized clinical trials are urgently needed to provide further supporting evidence in order to incorporate cold dialysis in routine clinical practice.
Abstract
Background
Women with HCM have worse cardiopulmonary exercise performance compared to men. We used non-invasive pressure-volume (PV) analysis to delineate sex related hemodynamic differences ...in HCM.
Methods
PV loops were constructed from echocardiograms using left ventricular (LV) volumes indexed to body surface area, Doppler estimates of LV end-diastolic pressure and blood pressure. The end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR) were derived from validated single-beat techniques. The area between the ESPVR and EDPVR (isovolumetric PV area), was indexed to an LV end-diastolic pressure of 30mmHg (PVAiso30), as the integrated metric of LV function. LV volume at an end-diastolic pressure of 30mmHg (V30) indexed ventricular capacity.
Results
202 patients were included, 56 women. Women were older (51 vs 44 yrs, p=0.012) and had reduced exercise capacity (5.6 vs 6.9 METs, p<0.001). Only 32 patients (16%) had a peak gradient >30mmHg at rest with no sex differences. Women had significantly lower indexed PVAiso30 (6577 vs 7767 mmHg·mL/m2, p<0.001) driven by reduced ventricular capacitance (V30 54 vs 62 ml/m2, p<0.001). In multivariable linear regression indexed V30 was an independent predictor of exercise capacity.
Conclusion
Impaired exercise capacity in women with HCM appears strongly related to abnormalities in passive diastolic properties, suggesting a unique pathophysiology compared to men, and a potential difference in viable therapeutic molecular targets
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
Anderson-Fabry disease (AFD) is a rare genetic lysosomal storage disorder which often goes unnoticed until symptom onset requires aggressive treatment. Prompt diagnosis remains ...crucial. Dedicated multidisciplinary centres are a remarkable opportunity to develop early detection strategies and appropriate management.
Purpose
To describe the long-term outcomes of patients diagnosed with AFD followed at a Cardiomyopathy Referral Centre according to baseline phenotype (clinical involvement vs sub-clinical involvement).
Methods
All consecutive patients with AFD visited at our Cardiomyopathy Unit from 1989 to 2020 with >1-year follow-up were retrospectively reviewed. Clinical involvement was defined by one among left ventricular hypertrophy (LVH)>15mm, presence of conduction blocks or cardiac implantable electronic devices (CIED), atrial fibrillation, kidney disease (CKD), stroke or transient ischemic attack (TIA). The primary outcome was disease progression, defined as de novo CIED implantation, increased or de novo LVH, de novo Stroke/TIA, or progression of CKD. Of 110 patients diagnosed with AFD, 86 (78%) with >1-year follow-up were selected.
Results
Clinical involvement was present in 60 (70%) patients. Age at diagnosis was similar between patients with clinical and subclinical phenotype (42+17 vs 39+15, p=0.277). Patients with clinical involvement were more frequently men (N=25 42% vs 4 15%, p=0.025) and probands (p=0.01). Overall, 1-organ involvement was present in 31 (52%) patients, 2-organ involvement in 24 (40%) patients and 3-organ in 5 (8%). A total of 46 (77%) patients were referred to enzyme replacement therapy (ERT): 52% received agalsidase α, 26% agalsidase β, and 22% migalastat. Among those with a clinical involvement not on ERT, 9 (15%) were scheduled for ERT initiation, 3 (5%) were considered old for ERT, 1 (1.5%) refused ERT and 1 (1.5%) had an allergic reaction to ERT.
At 7 3–12 years follow up, both study cohorts manifested signs and symptoms of disease progression: N=28 (47%) vs N=4 (15%), p=0.01, in patients with vs. without baseline clinical involvement, respectively. The main causes for diseases progression were increase (28%) or de novo LVH (13%), CKD (7%) and CIED implantation (5%). At Cox multivariable analysis, however, after adjustment for age at diagnosis, late onset phenotype and gender, the impact of clinical vs subliclinical involvement on disease progression was lost (Hazard Ratio 0.92, 95% C.I. 0.30–2.81).
Conclusion
Clinical involvement in AFD is frequent, irrespective of age at diagnosis, being present in more than 1-in-2 patients at baseline. Prompt referral to dedicated centres is warranted for appropriate care as the disease may progress in both patients with and without initial overt clinical phenotype despite optimal medical management.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIM 125310) is a rare inherited disease, caused by NOTCH3 gene mutations. Main ...clinical manifestations of CADASIL include recurrent subcortical ischemic events, migraine, cognitive impairment and psychiatric disturbances. CADASIL is a systemic microangiopathy and cardiac involvement has been observed in a series of Dutch patients, presenting higher frequency of myocardial infarction compared to non-mutated relatives and general population. In particular, electron microscopic examination of myocardial tissue of a study participant demonstrated CADASIL characteristics.
We sought to investigate the relationship between CADASIL and microvascular dysfunction (MVD).
Seventeen patients with genetically-confirmed CADASIL, aged <60 years, with ≤1 cardiovascular risk factor (current smoke, diabetes, hypertension, dyslipidemia), recent (<3 months) neurological evaluation with neuropsychological tests and 3 Tesla brain magnetic resonance imaging (MRI) underwent 12-lead ECG, echocardiography, and measurement of maximal myocardial blood flow following Regadenoson infusion (Reg-MBF) by 13NH3positron emission tomography (PET), to investigate the presence of coronary microvascular dysfunction (CMD). Coronary flow reserve (CFR) was defined as Reg-MBF/resting MBF. PET results were compared to those of 15 healthy controls matched for age and sex recruited among a historical cohort of healthy patients. The study was approved by the institutional review board and all the subjects gave informed consent.
Mean age was 40±9 years (range 28–57 years); 6 patients (35%) were male. One was a current smoker and 3 ex-smokers; 1 patient was on aspirin, 1 on acetazolamide and 2 on escitalopram, none was taking statins. 12 patients (71%) presented with migraine, 9 (53%) had psychiatric disturbances and 1 (6%) had a previous stroke. Brain MRI showed mild-moderate and severe leukoencephalopathy in 11 (65%) and 5 (29%) patients respectively, lacunes were present in 14 patients and microbleeds in 1; one patient had normal findings. Both Reg-MBF and CFR were blunted in CADASIL patients compared with controls (Reg-MBF 2.46±0.54 versus 3.09±0.44 ml/gr/min respectively, p<0.001; CFR 2.74±0.36 vs. 3.28±0.66, respectively, p<0.01). In 3 male patients (17%), CFR reduction was severe (<2). Segmental Reg-MBF analysis of left ventricular flow showed diffuse hypoperfusion, excluding preferential regional involvement. No correlations were found between Reg-MBF values and neuropsychological performance or cerebral lesion burden, suggesting that neurological and cardiac involvement might be independent in CADASIL.
These data represent the first documentation of coronary microvascular involvement in a group of young and mildly symptomatic CADASIL patients, confirming the systemic nature of the disease. This proof of concept study expands our understanding of genetically-driven CMD.
Funding Acknowledgement
Type of funding source: None
Abstract
Introduction
Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both ...physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions.
Purpose
We developed and validate a free digital support tool in the form of an App to provide support and to guide the physician in the differential diagnostic process of patients presenting with primary LVH.
Methods
We studied 210 consecutively genotyped patients (54±21 years, 118 (56% males) referred to our center for the suspicion of primary LVH. A systematic literature analysis was conducted to classify disease specific red-flags (RFs) associated with sarcomeric and non sarcomeric hypertrophic cardiomyopathy (HCM). RFs were categorized into two subgroups: extremely specific RFs (features only described associated to the given disease) and specific RF (characteristics typical for the disease but also associated with other conditions). Pre-specified RF were categorized into four domains: family history; signs/symptoms; electrocardiography and imaging. The outcome of the digital support tool was categorized as follows: (a) most likely diagnosis (if contemplated age range for the condition, at least 1 extremely specific RFs or more than 1 specific RF were satisfied); (b) possible diagnosis (if contemplated age range for the condition, 1 specific RF were satisfied); (c) less likely diagnosis (outside age range for disease and no RF selected).
Results
Of the 210 patients, 84 (40%) were diagnosed with sarcomeric HCM, 56 (27%) with TTR amyloidosis, 44 (21%) with Fabry disease (FD), 7 (4%) with a mitochondrial disease, 4 (2%) with Pompe disease, 4 (2%) with PRKAG2 cardiomyopathy, 3 (1%) with Noonan, 3 (1%) with Friederich's Ataxia, 3 (1%) with LEOPARD and 2 (1%) with Danon disease. A total of 942 RFs has been identified in the cohort, of which 327 were extremely specific RFs (41 from family history; 107 from signs/symptoms; 111 from electrocardiography and 113 from imaging sections). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and >55yo. One-hundred-ninety-five patients (92%) were correctly categorized in the most likely and possible diagnosis section. The App proved to be sensible for sarcomeric HCM, FD (0.99 and 0.91, NPV 0.98 and 0.83) and extremely capable in the identification of rare causes of LVH (Danon, Friederich's ataxia, LEOPARD, Pompe, Noonan and PRKAG2 diseases). By design, specificity was not high, in particular for sarcomeric HCM and FD.
Conclusions
The present free digital support tool in the form of an App proved to be extremely sensible in providing the support to the screening of different causes of primary LVH in patients presenting with a HCM phenotype. Further external and multicenter validation is warranted.
Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Amicus therapeutics
Abstract
Purpose
We described the incidence and ECG factors associated with de novo atrial fibrillation (AF) in patients diagnosed with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) to ...drive tailored arrhythmia screening.
Background
Data on the incidence rate and factors associated with de novo AF in patients with ATTRwt-CA is limited.
Methods
Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >1-year follow up (FU) were enrolled in the study and were divided into three groups according to presence of AF: (1) patients with “known AF”; (2) patients in “sinus rhythm” and (3) patients developing “de novo AF” during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes.
Results
Overall, 266 patients were followed for a median of 469 days: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. Age and gender were similarly distributed. At multivariable analysis, PR (Hazard Ratio HR: 1.008; 95% CI: 1.001–1.016), QRS (HR: 1.022; 95% CI: 1.002–1.043) and left atrial dilatation >50mm (HR: 3.429, 95% CI: 1.565–7.329) were associated with de novo AF at FU. Patients presenting with at least two risk factors (PR >200ms, QRS >120ms or LAD >50mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918; 95% CI: 3.242–31.646).
Conclusions
Incidence of de novo AF in patients with ATTRwt is 20.7%/year. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.
Funding Acknowledgement
Type of funding sources: None.
Abstract
In the early days, Hypertrophic cardiomyopathy (HCM) has long been considered a malignant disease.
However, contemporary descriptions of HCM report low mortality rates, largely due to ...heart failure-related complications (HF), while sudden cardiac death (SCD) rates are consistently low. Ageing with HCM is not uncommon and competing risk of acquired cardiovascular (CV) and non-CV diseases becomes relevant over time.
Purpose
To describe the disease stage at presentation and the modes of death in a cohort of consecutive HCM patients followed at a national referral centre over the last two decades. Stages of disease were defined according to Circ. Heart Fail. 2012, as follows:
1) “Classic HCM phenotype” characterized by LV ejection fraction (EF) >65%.
2) “Adverse remodeling” characterized by LVEF in the range of 50% to 65%.
3) “Overt dysfunction” is the end-stage clinical evolution characterized by a LVEF <50%.
Methods
By searching our centralized database, we identified 1491 HCM patients with at least >1 year of follow-up between January 2000 and December 2020, 191 of whom died in the same period. In 30 the cause of death could not be ascertained. The remaining 161 constituted our study cohort.
Results
Of the 161 patients who died, 103 (64%) died due to HCM-related causes, whereas 58 (36%) died from non-HCM-related causes such as coronary artery disease (other CV) or other non CV causes.
Modes of death varied based on the stage of disease at diagnosis:
– Fifty-six (35%) patients had a “classic” HCM phenotype at diagnosis. Of these, about half died of HCM-related causes (n=30; 54%), versus 45% with non-HCM-related death. Differently from the other 2 stages, the single most common cause of death was “other non-CV related” mortality, in 44%. Among HCM-related causes, SCD prevailed (n=15; 27%) while HF-related events were only 8 (14%).
– Of the 86 (53%) patients with “adverse remodeling” at diagnosis, more than half died of HCM-related causes (n=57, 66%), largely due to HF (n=33, 38%); SCD occurred in 18 (21%) individuals. This stage included the highest percentage of patients who died of stroke (n=6; 7%).
– Of the 19 (12%) patients in “overt dysfunction” at diagnosis, HF represented the cause of demise in almost three quarters (n=14, 74%); SCD and non-HCM causes accounted for only 10% and 16% respectively.
Conclusions
Most HCM patients die due to complications of their own disease, mainly in the context of HF. Modes of death vary with the stage of disease, with SCD becoming less prevalent in more advanced phases of progression, when competitive risks of HF-related events become overwhelming. These data highlight an unmet medical need in the prevention of disease progression associated with HCM.
Funding Acknowledgement
Type of funding sources: None.
Abstract
Background
The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored.
Purpose
We sought to characterise the trends in the ...incidence of permanent PM and to identify baseline predictors of future PM implantation in light chain (AL) and transthyretin (ATTR) CA.
Methods
Multicentre, retrospective, observational study. Consecutive patients with AL and ATTR-CA diagnosed or referred at participating Centres between 2017 and 2020 were included. Clinical data recorded within ± 1 month from baseline evaluation were collected from electronic medical records. The primary outcome of the study was the need for clinically-indicated PM implantation. Reversible causes of conduction system disease were systematically ruled out before PM implantation. Patients with PM (n=41) and/or permanent defibrillator in situ (n=13) at the time of CA diagnosis were excluded.
Results
The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were males, with median age 76 years. During a median follow-up of 33 months (interquartile range 21–46), 36 (8.9%) patients experienced the primary outcome: 10 patients with AL-CA, 2 with variant ATTR-CA and 24 with wild-type ATTR-CA (p=0.08). At multivariable analysis, history of atrial fibrillation (hazard ratio HR 3.80, p=0.002), PR interval (HR 1.013, p=0.002) and QRS >120 ms (HR 4.7, p=0.001) on baseline ECG were independently associated with PM implantation (Figure 1). In the individual patient, the contemporary presence of these 3 factors yielded the highest risk of PM implantation (HR 6.26, p=0.003).
Conclusion
In a large cohort of AL and ATTR-CA, the incidence of PM implantation was high accounting for ≈9% of patients in the 3 years following the diagnosis. History of atrial fibrillation, longer PR interval and QRS >120 ms identified CA patients at high-risk of future PM implantation (Figure 2).
CA patients with these features might need close monitoring during follow-up for the development of conduction system disease requiring PM implantation.
Funding Acknowledgement
Type of funding sources: None.
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