fold larger current amplitude and carrying about 8 times as much total charge. In the KN-93þISO g... more fold larger current amplitude and carrying about 8 times as much total charge. In the KN-93þISO group, IKs showed an about 2.5 times smaller amplitude and carried roughly half as much total charge compared to the ISO group. IK1 current amplitude did not differ among the studied groups, the total carried charge however was significantly, about 25 % larger in the ISO group compared to CTRL, and about 15 % larger compared to KN-93þISO. Under beta-adrenergic stimulation, IK1 starts to activate earlier during the AP plateau. IK1 density was about 3 times greater both at þ20 mV and at 0 mV membrane potential under the command "canonical" AP in ISO compared to CTRL. Similarly, IK1 density was about 60 % and 90 % larger at þ20 mV and at 0 mV, respectively, in KN-93þISO compared to KN-93. Conclusion: CaMKII activation has an important role in beta-adrenergic stimulation of potassium currents. Part of the beta-adrenergic enhancement of IKs and IK1 is caused by CaMKII activation.
Chinese journal of cardiovascular diseases, Apr 1, 2009
Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic ca... more Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), and represents an important complication in the clinical course of the disease, with adverse consequences on functional status and outcome. Studies on community-based HCM patient populations have shown that AF is associated with long-term clinical deterioration, cardioembolic stroke and increased cardiovascular mortality due to heart failure and stroke. Moreover, acute onset of AF may cause severe hemodynamic impairment and represent a trigger of potentially lethal ventricular arrhythmias. However, the consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable, and may be compatible with an uneventful course, when properly managed. Management of AF in HCM is challenging, particularly when onset occurs at a young age. Both paroxysmal and permanent AF represent clear indications for oral anticoagulation. In most patients, maintenance of sinus rhythm is highly desirable but made difficult by the limited long-term efficacy and potentially hazardous side effects of available pharmacological options. In selected patients with HCM and severely symptomatic AF, radiofrequency catheter ablation may represent an effective therapeutic alternative, improving functional status, and reducing or postponing the need for antiarrhythmic drugs. In patients with persistent AF, in whom maintenance of sinus rhythm is not feasible, adequate ventricular rate control should be pursued aggressively by atrio-ventricular node blocking agents.
We present the case of a 73-year-old patient with a recent diagnosis of hypertrophic cardiomyopat... more We present the case of a 73-year-old patient with a recent diagnosis of hypertrophic cardiomyopathy (HCM). He was asymptomatic and has no family history of sudden cardiac death (SCD), syncope or ventricular arrhythmias. An echocardiogram performed at the moment of diagnosis (2020), showed left ventricular (LV) asymmetric apical hypertrophy with maximal wall thickness of 21 mm. Cardiac magnetic resonance (CMR) confirmed LV apical hypertrophy with mid-ventricular obliteration, and late gadolinium enhancement in the apical segments, without wall motion abnormalities present at rest. According to 2014 ESC guidelines, his calculated risk score for sudden cardiac death was low (1.23% at 5 years). On 2021, a comprehensive transthoracic echocardiographic examination including advanced techniques (three-dimensional echo-3DE-, and two-dimensional speckle-tracking-2DSTE) was done as part of his routine follow-up in our cardiomyopathy outpatient clinic. The echo study showed an asymmetric patte...
Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of... more Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of ...
Molecular genetics & genomic medicine, Jan 12, 2018
The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fab... more The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events...
European journal of nuclear medicine and molecular imaging, 2017
Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CM... more Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CMD), which is detected by measuring myocardial blood flow (MBF) with PET. Whether CMD may be associated with ischemic left ventricular (LV) dysfunction is unclear. We therefore assessed LV ejection fraction (EF) reserve in HCM patients undergoing dipyridamole (Dip) PET. Resting and stress (13)NH3 dynamic as well as gated PET were performed in 34 HCM patients. Segmental MBF and transmural perfusion gradient (TPG = subendocardial / subepicardial MBF) were assessed. LVEF reserve was considered abnormal if Dip LVEF decreased more than 5 units as compared to rest. Eighteen patients had preserved (group A) and 16 abnormal LVEF reserve (group B; range -7 to -32). Group B patients had greater wall thickness than group A, but resting volumes, LVEF, resting and Dip MBF, and myocardial flow reserve were similar. Group B had slightly higher summed stress score and summed difference score in visual an...
Farmeconomia. Health economics and therapeutic pathways, 2004
Diuretics are still a cornerstone of acute heart failure. Their role in chronic heart failure has... more Diuretics are still a cornerstone of acute heart failure. Their role in chronic heart failure has recently been reconsidered, as Ace-inhibitors and Beta-blockers have been shown to be highly effective in reducing cardiovascular morbidity and mortality in patients with heart failure. Loop diuretics and aldosterone antagonists, however, are still used in chronic heart failure, at the lowest dose needed in order to mantain haemodynamic balance. The use of effective loop diuretics with longer half-lives and constant bioavailability may be beneficial, resulting in fewer hospital readmissions, both for congestive heart failure and all cardiovascular events, in improved quality of life and in health costs reduction.
European Journal of Nuclear Medicine and Molecular Imaging, 2016
Aims Myocardial blood flow <1.1 mL/min/g following dipyridamole (Dip-MBF) assessed by positron em... more Aims Myocardial blood flow <1.1 mL/min/g following dipyridamole (Dip-MBF) assessed by positron emission tomography (PET) was identified in 2003 as an important outcome predictor in hypertrophic cardiomyopathy (HCM), based on scans performed in the 90s. However, such extreme Dip-MBF impairment is rarely observed in contemporary cohorts. We, therefore, reassessed the Dip-MBF threshold defining high-risk HCM patients. Methods Dip-MBF was measured using 13 N-ammonia in 100 HCM consecutive patients, prospectively enrolled and followed for 4.0 ± 2.2 years. Outcome was assessed based on tertiles of Dip-MBF. The study end-point was a combination of cardiovascular death, progression to severe functional limitation, cardioembolic stroke, life-threatening ventricular arrhythmias. Results Global Dip-MBF was 1.95 ± 0.85, ranging from 0.7 to 5.9 mL/min/g. Dip-MBF tertile cutoff values were: 0.73 to 1.53 mL/min/g (lowest), 1.54 to 2.13 mL/min/g (middle), and 2.14 to 5.89 mL/min/g (highest). During follow-up, lowest tertile Dip-MBF was associated with sevenfold independent risk of unfavorable outcome compared to the other two tertiles. Dip-MBF 1.35 mL/min/g was identified as the best threshold for outcome prediction. Regional perfusion analysis showed that all cardiac deaths (n = 4) occurred in patients in the lowest tertile of lateral wall Dip-MBF (≤1.72 mL/min/g); septal Dip-MBF was not predictive. Conclusions Dip-MBF confirms its role as potent predictor of outcome in HCM. However, the threshold for prediction in a contemporary cohort is higher than that reported in earlier studies. Dip-MBF impairment in the lateral wall, possibly reflecting diffuse disease extending to non-hypertrophic regions, is a sensitive predictor of mortality in HCM.
Background :Coronary Angiodysplasia (CA) is a rare congenital anomaly. Its prevalence as well as ... more Background :Coronary Angiodysplasia (CA) is a rare congenital anomaly. Its prevalence as well as histological and clinical implications in Hypertrophic Cardiomyopathy (HCM) are unknown. Methods and...
Anderson-Fabry disease (AFD) is an Xlinked lysosomal storage disorder of glycosphingolipid catabo... more Anderson-Fabry disease (AFD) is an Xlinked lysosomal storage disorder of glycosphingolipid catabolism, due to deficiency or absence of a galactosidase A (α-gal A) enzyme. The disease may affect males and females, the latter with an average 10 years delay. Metabolites storage (mostly Gb3 and lyso-Gb3) leads to progressive cellular and multiorgan dysfunction, with either early and late onset variable clinical manifestations that usually reduce quality of life and life expectancy. Heart and kidney failure, stroke and sudden death are the most devastating complications. AFD is always been considered a very rare disease, although new epidemiologic data, based on newborn screening, showed that AFD prevalence is probably underestimated and much higher than previously reported, especially for late-onset atypical phenotypes. Currently, the diagnosis may be easier and simpler by evaluating α-gal A enzyme activity and genetic analysis for GLA gene mutations on dried blood spot. While a marked ...
Journal of the American College of Cardiology, 1998
BaCkground: A genetic polymorpht~m of the anglotensln-II type I receptor (AGT1R A11000) Is though... more BaCkground: A genetic polymorpht~m of the anglotensln-II type I receptor (AGT1R A11000) Is thought to be involved In the development of varlotl~ cardlevs~c~iar diseases, H~weve~, the undetiylng, mechanism i~ nat cl0ar. W~ aimed to study the eflect~ o! the AGT1R polymorphlsm on the contraction to Ang I and II (0,1 nM~t oM) and pbonylophrlna (10 I~M) In ADmen ofletio~, M#th~f~; Exoes~ segments el Ihn tntomsl mammary artery liMA) wore obtained from 12t patients during eofenan~ bypass autgerv, Contractions oi affatisl tings Ware measured in organ bath expetimonts, Oenotypos wore a~osssd using a standard pplymerasa chain rea0llon, Re,trite: NO differences In pattont ehare(~terl~tls~ weto taunt, The maxim,,im contraction rettpon~e~ In the CO (n ,-14) versu~ the AA/AC (n = 1071 grotlp were re=pootlvely; Ang l: 394 ~ 65 pm re, 167 ~ t0 ~m (p ~ 0.0O;~), Ang IL 31t4 ~h 72 t,m vs, 195 • 18 .m (p ~ 0,001]), wheron~ the control re~penl~e 'to phenylephtino was cotnpatab~0 in both ~lre~4p~ (~.71 ~t 49 ~,m VS, ~10 :t: 15 i~m', P ~ 02.P.}, Cot~lll~/an: iMKs oi patients with ti~e AGT1R CC gonetypr~ showed an In~rea~Od va~nr0a(,4ivRy lo AnD II ~t simlisr oonvemlon of Ang l, while the m~,pon,fls ta ~honyt~phrine~ did net d~fler P.Ign~flcantly. Tho~o m.s;dts indicate #,listed Ang II re~pons~veness In ptllioats wlll~ tl~e CC gonotypo.
The prognostic relevance of a rapid rate of hemodynamic progression of aortic stenosis (AS) has b... more The prognostic relevance of a rapid rate of hemodynamic progression of aortic stenosis (AS) has been predominantly investigated in tertiary centers. We reviewed the clinical and echocardiographic data from 153 asymptomatic patients with AS (age 77 ؎ 9 years; 65% men), with normal left ventricular function and paired echocardiograms >4 months apart (mean 2.9 ؎ 2.1 years), evaluated in a nonreferral echocardiographic laboratory. The severity of AS was graded by the peak aortic velocity (Vmax) and progression was classified as slow or fast according to a cutoff value of 0.3 m/s increase annually. The end points were all-cause mortality and a composite of all-cause mortality and aortic valve replacement (AVR). At baseline, 135 patients (88%) had mild-to-moderate and 18 (12%) severe AS. Of the 153 patients, 49 (32%) showed fast progression (0.61 ؎ 0.32 m/s/yr) and 104 (68%) had slow progression (0.10 ؎ 0.16 m/s/yr). Among the 144 patients (94%) with clinical follow-up data, 40 died and 48 underwent AVR. The mortality rate was greater than that of the general population (p <0.001). On multivariate analysis, the independent predictors of mortality were the yearly change in Vmax (hazard ratio [HR] 13.352 per m/s increase, 95% confidence interval [CI] 5.136 to 34.713, p <0.001) and age (HR 1.122 per year, 95% CI 1.0728 to 1.735, p <0.001). The predictors of the composite end point of death and AVR were the yearly change in Vmax (HR 12.307, 95% CI 6.024 to 25.140, p <0.001) and Vmax on the initial echocardiogram (HR 2.684, 95% CI 1.921 to 3.750, p <0.001). In conclusion, primary care patients with asymptomatic AS are usually elderly and frequently develop rapid hemodynamic progression, which independently predicts, not only AVR, but also overall mortality.
| the majority of genetic mutations associated with hypertrophic cardiomyopathy (HcM) occur in ge... more | the majority of genetic mutations associated with hypertrophic cardiomyopathy (HcM) occur in genes encoding sarcomeric proteins, which are expressed only in cardiomyocytes. However, some manifestations of the HcM phenotype, such as myocardial disarray, interstitial fibrosis, mitral valve abnormalities, and microvascular remodeling, indicate the involvement of other cell lineages. the link between sarcomeric gene defects and these 'extended' HcM phenotypes remains elusive. Based on novel insights provided by cardiac developmental biology, we propose that a common lineage ancestry of the diverse HcM phenotypes not involving the cardiomyocyte can be traced to the pluripotent epicardium-derived cells (epDcs). During cardiac colonization, epDcs differentiate into interstitial fibroblasts, coronary smooth-muscle cells, and atrioventricular endocardial cushions as mesenchymal cells. We propose that the crosstalk between healthy epDcs and abnormally contracting cardiomyocytes might account for the diverse manifestations of HcM, by a putative mechanism of mechanotransduction leading to abnormal gene expression and differentiation.
fold larger current amplitude and carrying about 8 times as much total charge. In the KN-93þISO g... more fold larger current amplitude and carrying about 8 times as much total charge. In the KN-93þISO group, IKs showed an about 2.5 times smaller amplitude and carried roughly half as much total charge compared to the ISO group. IK1 current amplitude did not differ among the studied groups, the total carried charge however was significantly, about 25 % larger in the ISO group compared to CTRL, and about 15 % larger compared to KN-93þISO. Under beta-adrenergic stimulation, IK1 starts to activate earlier during the AP plateau. IK1 density was about 3 times greater both at þ20 mV and at 0 mV membrane potential under the command "canonical" AP in ISO compared to CTRL. Similarly, IK1 density was about 60 % and 90 % larger at þ20 mV and at 0 mV, respectively, in KN-93þISO compared to KN-93. Conclusion: CaMKII activation has an important role in beta-adrenergic stimulation of potassium currents. Part of the beta-adrenergic enhancement of IKs and IK1 is caused by CaMKII activation.
Chinese journal of cardiovascular diseases, Apr 1, 2009
Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic ca... more Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), and represents an important complication in the clinical course of the disease, with adverse consequences on functional status and outcome. Studies on community-based HCM patient populations have shown that AF is associated with long-term clinical deterioration, cardioembolic stroke and increased cardiovascular mortality due to heart failure and stroke. Moreover, acute onset of AF may cause severe hemodynamic impairment and represent a trigger of potentially lethal ventricular arrhythmias. However, the consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable, and may be compatible with an uneventful course, when properly managed. Management of AF in HCM is challenging, particularly when onset occurs at a young age. Both paroxysmal and permanent AF represent clear indications for oral anticoagulation. In most patients, maintenance of sinus rhythm is highly desirable but made difficult by the limited long-term efficacy and potentially hazardous side effects of available pharmacological options. In selected patients with HCM and severely symptomatic AF, radiofrequency catheter ablation may represent an effective therapeutic alternative, improving functional status, and reducing or postponing the need for antiarrhythmic drugs. In patients with persistent AF, in whom maintenance of sinus rhythm is not feasible, adequate ventricular rate control should be pursued aggressively by atrio-ventricular node blocking agents.
We present the case of a 73-year-old patient with a recent diagnosis of hypertrophic cardiomyopat... more We present the case of a 73-year-old patient with a recent diagnosis of hypertrophic cardiomyopathy (HCM). He was asymptomatic and has no family history of sudden cardiac death (SCD), syncope or ventricular arrhythmias. An echocardiogram performed at the moment of diagnosis (2020), showed left ventricular (LV) asymmetric apical hypertrophy with maximal wall thickness of 21 mm. Cardiac magnetic resonance (CMR) confirmed LV apical hypertrophy with mid-ventricular obliteration, and late gadolinium enhancement in the apical segments, without wall motion abnormalities present at rest. According to 2014 ESC guidelines, his calculated risk score for sudden cardiac death was low (1.23% at 5 years). On 2021, a comprehensive transthoracic echocardiographic examination including advanced techniques (three-dimensional echo-3DE-, and two-dimensional speckle-tracking-2DSTE) was done as part of his routine follow-up in our cardiomyopathy outpatient clinic. The echo study showed an asymmetric patte...
Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of... more Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of ...
Molecular genetics & genomic medicine, Jan 12, 2018
The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fab... more The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events...
European journal of nuclear medicine and molecular imaging, 2017
Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CM... more Ischemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CMD), which is detected by measuring myocardial blood flow (MBF) with PET. Whether CMD may be associated with ischemic left ventricular (LV) dysfunction is unclear. We therefore assessed LV ejection fraction (EF) reserve in HCM patients undergoing dipyridamole (Dip) PET. Resting and stress (13)NH3 dynamic as well as gated PET were performed in 34 HCM patients. Segmental MBF and transmural perfusion gradient (TPG = subendocardial / subepicardial MBF) were assessed. LVEF reserve was considered abnormal if Dip LVEF decreased more than 5 units as compared to rest. Eighteen patients had preserved (group A) and 16 abnormal LVEF reserve (group B; range -7 to -32). Group B patients had greater wall thickness than group A, but resting volumes, LVEF, resting and Dip MBF, and myocardial flow reserve were similar. Group B had slightly higher summed stress score and summed difference score in visual an...
Farmeconomia. Health economics and therapeutic pathways, 2004
Diuretics are still a cornerstone of acute heart failure. Their role in chronic heart failure has... more Diuretics are still a cornerstone of acute heart failure. Their role in chronic heart failure has recently been reconsidered, as Ace-inhibitors and Beta-blockers have been shown to be highly effective in reducing cardiovascular morbidity and mortality in patients with heart failure. Loop diuretics and aldosterone antagonists, however, are still used in chronic heart failure, at the lowest dose needed in order to mantain haemodynamic balance. The use of effective loop diuretics with longer half-lives and constant bioavailability may be beneficial, resulting in fewer hospital readmissions, both for congestive heart failure and all cardiovascular events, in improved quality of life and in health costs reduction.
European Journal of Nuclear Medicine and Molecular Imaging, 2016
Aims Myocardial blood flow <1.1 mL/min/g following dipyridamole (Dip-MBF) assessed by positron em... more Aims Myocardial blood flow <1.1 mL/min/g following dipyridamole (Dip-MBF) assessed by positron emission tomography (PET) was identified in 2003 as an important outcome predictor in hypertrophic cardiomyopathy (HCM), based on scans performed in the 90s. However, such extreme Dip-MBF impairment is rarely observed in contemporary cohorts. We, therefore, reassessed the Dip-MBF threshold defining high-risk HCM patients. Methods Dip-MBF was measured using 13 N-ammonia in 100 HCM consecutive patients, prospectively enrolled and followed for 4.0 ± 2.2 years. Outcome was assessed based on tertiles of Dip-MBF. The study end-point was a combination of cardiovascular death, progression to severe functional limitation, cardioembolic stroke, life-threatening ventricular arrhythmias. Results Global Dip-MBF was 1.95 ± 0.85, ranging from 0.7 to 5.9 mL/min/g. Dip-MBF tertile cutoff values were: 0.73 to 1.53 mL/min/g (lowest), 1.54 to 2.13 mL/min/g (middle), and 2.14 to 5.89 mL/min/g (highest). During follow-up, lowest tertile Dip-MBF was associated with sevenfold independent risk of unfavorable outcome compared to the other two tertiles. Dip-MBF 1.35 mL/min/g was identified as the best threshold for outcome prediction. Regional perfusion analysis showed that all cardiac deaths (n = 4) occurred in patients in the lowest tertile of lateral wall Dip-MBF (≤1.72 mL/min/g); septal Dip-MBF was not predictive. Conclusions Dip-MBF confirms its role as potent predictor of outcome in HCM. However, the threshold for prediction in a contemporary cohort is higher than that reported in earlier studies. Dip-MBF impairment in the lateral wall, possibly reflecting diffuse disease extending to non-hypertrophic regions, is a sensitive predictor of mortality in HCM.
Background :Coronary Angiodysplasia (CA) is a rare congenital anomaly. Its prevalence as well as ... more Background :Coronary Angiodysplasia (CA) is a rare congenital anomaly. Its prevalence as well as histological and clinical implications in Hypertrophic Cardiomyopathy (HCM) are unknown. Methods and...
Anderson-Fabry disease (AFD) is an Xlinked lysosomal storage disorder of glycosphingolipid catabo... more Anderson-Fabry disease (AFD) is an Xlinked lysosomal storage disorder of glycosphingolipid catabolism, due to deficiency or absence of a galactosidase A (α-gal A) enzyme. The disease may affect males and females, the latter with an average 10 years delay. Metabolites storage (mostly Gb3 and lyso-Gb3) leads to progressive cellular and multiorgan dysfunction, with either early and late onset variable clinical manifestations that usually reduce quality of life and life expectancy. Heart and kidney failure, stroke and sudden death are the most devastating complications. AFD is always been considered a very rare disease, although new epidemiologic data, based on newborn screening, showed that AFD prevalence is probably underestimated and much higher than previously reported, especially for late-onset atypical phenotypes. Currently, the diagnosis may be easier and simpler by evaluating α-gal A enzyme activity and genetic analysis for GLA gene mutations on dried blood spot. While a marked ...
Journal of the American College of Cardiology, 1998
BaCkground: A genetic polymorpht~m of the anglotensln-II type I receptor (AGT1R A11000) Is though... more BaCkground: A genetic polymorpht~m of the anglotensln-II type I receptor (AGT1R A11000) Is thought to be involved In the development of varlotl~ cardlevs~c~iar diseases, H~weve~, the undetiylng, mechanism i~ nat cl0ar. W~ aimed to study the eflect~ o! the AGT1R polymorphlsm on the contraction to Ang I and II (0,1 nM~t oM) and pbonylophrlna (10 I~M) In ADmen ofletio~, M#th~f~; Exoes~ segments el Ihn tntomsl mammary artery liMA) wore obtained from 12t patients during eofenan~ bypass autgerv, Contractions oi affatisl tings Ware measured in organ bath expetimonts, Oenotypos wore a~osssd using a standard pplymerasa chain rea0llon, Re,trite: NO differences In pattont ehare(~terl~tls~ weto taunt, The maxim,,im contraction rettpon~e~ In the CO (n ,-14) versu~ the AA/AC (n = 1071 grotlp were re=pootlvely; Ang l: 394 ~ 65 pm re, 167 ~ t0 ~m (p ~ 0.0O;~), Ang IL 31t4 ~h 72 t,m vs, 195 • 18 .m (p ~ 0,001]), wheron~ the control re~penl~e 'to phenylephtino was cotnpatab~0 in both ~lre~4p~ (~.71 ~t 49 ~,m VS, ~10 :t: 15 i~m', P ~ 02.P.}, Cot~lll~/an: iMKs oi patients with ti~e AGT1R CC gonetypr~ showed an In~rea~Od va~nr0a(,4ivRy lo AnD II ~t simlisr oonvemlon of Ang l, while the m~,pon,fls ta ~honyt~phrine~ did net d~fler P.Ign~flcantly. Tho~o m.s;dts indicate #,listed Ang II re~pons~veness In ptllioats wlll~ tl~e CC gonotypo.
The prognostic relevance of a rapid rate of hemodynamic progression of aortic stenosis (AS) has b... more The prognostic relevance of a rapid rate of hemodynamic progression of aortic stenosis (AS) has been predominantly investigated in tertiary centers. We reviewed the clinical and echocardiographic data from 153 asymptomatic patients with AS (age 77 ؎ 9 years; 65% men), with normal left ventricular function and paired echocardiograms >4 months apart (mean 2.9 ؎ 2.1 years), evaluated in a nonreferral echocardiographic laboratory. The severity of AS was graded by the peak aortic velocity (Vmax) and progression was classified as slow or fast according to a cutoff value of 0.3 m/s increase annually. The end points were all-cause mortality and a composite of all-cause mortality and aortic valve replacement (AVR). At baseline, 135 patients (88%) had mild-to-moderate and 18 (12%) severe AS. Of the 153 patients, 49 (32%) showed fast progression (0.61 ؎ 0.32 m/s/yr) and 104 (68%) had slow progression (0.10 ؎ 0.16 m/s/yr). Among the 144 patients (94%) with clinical follow-up data, 40 died and 48 underwent AVR. The mortality rate was greater than that of the general population (p <0.001). On multivariate analysis, the independent predictors of mortality were the yearly change in Vmax (hazard ratio [HR] 13.352 per m/s increase, 95% confidence interval [CI] 5.136 to 34.713, p <0.001) and age (HR 1.122 per year, 95% CI 1.0728 to 1.735, p <0.001). The predictors of the composite end point of death and AVR were the yearly change in Vmax (HR 12.307, 95% CI 6.024 to 25.140, p <0.001) and Vmax on the initial echocardiogram (HR 2.684, 95% CI 1.921 to 3.750, p <0.001). In conclusion, primary care patients with asymptomatic AS are usually elderly and frequently develop rapid hemodynamic progression, which independently predicts, not only AVR, but also overall mortality.
| the majority of genetic mutations associated with hypertrophic cardiomyopathy (HcM) occur in ge... more | the majority of genetic mutations associated with hypertrophic cardiomyopathy (HcM) occur in genes encoding sarcomeric proteins, which are expressed only in cardiomyocytes. However, some manifestations of the HcM phenotype, such as myocardial disarray, interstitial fibrosis, mitral valve abnormalities, and microvascular remodeling, indicate the involvement of other cell lineages. the link between sarcomeric gene defects and these 'extended' HcM phenotypes remains elusive. Based on novel insights provided by cardiac developmental biology, we propose that a common lineage ancestry of the diverse HcM phenotypes not involving the cardiomyocyte can be traced to the pluripotent epicardium-derived cells (epDcs). During cardiac colonization, epDcs differentiate into interstitial fibroblasts, coronary smooth-muscle cells, and atrioventricular endocardial cushions as mesenchymal cells. We propose that the crosstalk between healthy epDcs and abnormally contracting cardiomyocytes might account for the diverse manifestations of HcM, by a putative mechanism of mechanotransduction leading to abnormal gene expression and differentiation.
Uploads
Papers by Franco Cecchi