Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.

INTRODUCTION: Atrial fibrillation (AF) in mitral regurgitation (MR) is a complex disease where multiple factors may induce left-atrial structural remodeling (SR). We explored the differential SR of the left-atrial posterior wall (LAPW) of patients affected by MR with or without persistent AF, and the expression of key proteins involved in its pathogenesis. METHODS AND RESULTS: Light microscopy of LAPW samples from 27 patients with MR and persistent AF (group 1), 33 with MR in sinus rhythm (group 2), and 15 autopsy controls (group 3) was used to measure myocyte diameter, percentage of myocytolytic myocytes, interstitial fibrosis, and capillary density; RT-PCR and Western blotting were used to assess the mRNA and protein levels of SOD-1, SOD-2, HO-1, calpain, MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF; immunofluorescence was used to locate these proteins. Myocyte diameter was similar in groups 1 and 2, but larger than controls. Compared to group 2, group 1 had more myocytolytic myocytes (20.8 ± 5.6% vs 14.7 ± 4.5%; P < 0.0001), increased interstitial fibrosis (10.4 ± 5.1% vs 7.5 ± 4.2%; P < 0.05), and decreased capillary density (923 ± 107 No/mm(2) vs 1,040 ± 100 No/mm(2); P < 0.0001). All of the proteins were more expressed in groups 1 and 2 than in controls. The protein and mRNA levels of SOD-1, SOD-2, MMP-2, and MMP-9 were higher in group 1 than in group 2. CONCLUSIONS: The LAPW of MR patients with or without AF shows considerable SR. The former has more severe histopathological changes and higher levels of proteins involved in SR, thereby reaching a threshold beyond which the sinus impulse cannot normally activate atrial myocardium.

Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients.

OBJECTIVE: Cardiovascular mortality and morbidity are major problems in type 1 diabetic patients with end-stage renal disease (ESRD). The aim of this study was to determine whether islet transplantation can improve cardiovascular function in these patients. RESEARCH DESIGN AND METHODS: We assessed various markers of cardiac function at baseline and 3 years later in a population of 42 type 1 diabetic patients with ESRD who received a kidney transplant. Seventeen patients then received an islet transplant that had persistent function as defined by long-term C-peptide secretion (kidney-islet group). Twenty-five patients did not receive a functioning islet transplant (kidney-only group). RESULTS: GHb levels were similar in the two groups, whereas the exogenous insulin requirement was lower in the kidney-islet group with persistent C-peptide secretion. Overall, cardiovascular parameters improved in the kidney-islet group, but not in the kidney-only group, with an improvement of ejection fraction (from 68.2 +/- 3.5% at baseline to 74.9 +/- 2.1% at 3 years posttransplantation, P < 0.05) and peak filling rate in end-diastolic volume (EDV) per second (from 3.87 +/- 0.25 to 4.20 +/- 0.37 EDV/s, P < 0.05). Time to peak filling rate remained stable in the kidney-islet group but worsened in the kidney-only group (P < 0.05). The kidney-islet group also showed a reduction of both QT dispersion (53.5 +/- 4.9 to 44.6 +/- 2.9 ms, P < 0.05) and corrected QT (QTc) dispersion (67.3 +/- 8.3 to 57.2 +/- 4.6 ms, P < 0.05) with higher erythrocytes Na(+)-K(+)-ATPase activity. In the kidney-islet group only, both atrial natriuretic peptide and brain natriuretic peptide levels decreased during the follow-up, with a stabilization of intima-media thickness. CONCLUSIONS: Our study showed that type 1 diabetic ESRD patients receiving a kidney transplant and a functioning islet transplant showed an improvement of cardiovascular function for up to 3 years of follow-up compared with the kidney-only group, who experienced an early failure of the islet graft or did not receive an islet graft.

Myocyte changes and their left atrial distribution in patients with chronic atrial fibrillation related to mitral valve disease.

It has been found that the pulmonary veins and adjacent left atrial posterior wall (LAPW) are deeply involved in both the initiation and maintenance of atrial fibrillation (AF), and the identification of these high-risk sites has aroused great interest in investigating their histopathologic substrate. We used light and conventional electron microscopy to evaluate the differential myocyte and interstitial changes in LAPW and left atrial appendage (LAA) samples from 28 patients with chronic AF undergoing mitral valve surgery and from 12 autoptic controls. There were always more myocytes with loss of sarcomeres in the LAPW than in the LAA (19.9% +/- 7.7% versus 8.2% +/- 5.0%; P < .0001), and the LAPW showed more marked immunohistochemical evidence of dedifferentiation, characterized by the reexpression of smooth muscle actin. In pathological left atria, myocyte diameter in the LAPW and LAA was comparable (19.0 +/- 1.5 versus 18.5 +/- 2.0 microm; not significant) but larger than in the controls (11.9 +/- 0.8 and 12.1 +/- 1.3 microm, respectively; P < .0001). A terminal deoxynucleotidyltransferase assay did not reveal any myocyte apoptosis. The LAPW also showed more interstitial fibrosis than the LAA (7.49% +/- 3.34% versus 2.80% +/- 1.35%; P < .0001). Ultrastructural examination confirmed the presence of myocyte myocytolysis in the perinuclear area and showed changes in mitochondrial shape. In conclusion, the LAPW in patients with chronic AF related to mitral valve disease seems to be a particular anatomical site in which major myocyte and interstitial changes are concentrated, whereas the LAA is more protected. This remodeling may increase the heterogeneity of LAPW electrical conduction, thus confirming this location as an elective target for the ablation treatment of AF.

Circadian blood pressure and heart rate changes in patients in a persistent vegetative state after traumatic brain injury.

Alteration of autonomic nervous system regulation is known to be present in the persistent vegetative state after traumatic brain injury, termed the dysautonomic syndrome. This study assessed the circadian blood pressure and heart rate pattern and variability in the persistent vegetative state through noninvasive 24-hour ambulatory blood pressure monitoring. The study was performed in 20 subjects: 10 patients (six men and four women; mean age, 29.5+/-9.9 years; range, 19-39 years) in a vegetative state (mean, 27.3+/-5.6 days after trauma) and 10 healthy subjects as controls (six men and four women; mean age, 28+/-5.7 years; range, 29-37 years). The patients showed a blood pressure nondipper pattern; 24-hour, daytime, and nighttime values of blood pressure and heart rate were significantly higher in patients than in controls. The day-night difference in heart rate and blood pressure was also significantly lower in patients. Finally, SD and variation coefficients were significantly lower in patients. The results show changes in the variability and circadian blood pressure and heart rate patterns in persistent vegetative state patients with dysautonomic syndrome, as an expression of the sympathetic-parasympathetic activity imbalance in the control of vasomotor tone.

Regional left atrial interstitial remodeling in patients with chronic atrial fibrillation undergoing mitral-valve surgery.

Ablation of the left atrial free wall around the pulmonary vein ostia (LAFW) may be effective in the treatment of chronic atrial fibrillation associated with mitral disease (CAF-MVD). Using light and conventional electron microscopy analyses, we wanted to evaluate, in CAF-MVD, the interstitial remodeling in the LAFW as well as in a more remote region, such as the left atrial appendage (LAA). LAFW and LAA samples were obtained from 33 CAF-MVD patients during combined mitral surgery and radiofrequency ablation and from 16 autoptic controls. Interstitial fibrosis (IF) and perivascular fibrosis (PF), capillary densities and the maximal oxygen diffusion distance were morphometrically determined. In CAF-MVD patients, the LAFW, compared with the LAA, showed a higher percentage of IF (7.16+/-3.23% versus 2.51+/-1.40%, respectively), a lower myocardial capillary density per mm(2) (830+/-106 versus 989+/-173) and an increased oxygen maximal diffusion distance (19.70+/-1.27 microm versus 18.13+/-1.58 microm). All these values were also significantly different than controls. No differences were found in evaluating PF. At variance with the LAA, in CAF-MVD patients, the LAFW around the pulmonary vein ostia is a region characterized by a marked interstitial remodeling such that it may be morphologically indicated as an appropriate target for ablation treatment aimed at sinus rhythm restoration.

Correlation between non-reversible thallium-201 myocardial perfusion defect and ECG criteria in the diagnosis of apical myocardial infarction.

BACKGROUND: ECG identification of apical myocardial infarction (MI) is controversial and lacks of accuracy. Our aim was to investigate the sensitivity of different proposed ECG criteria in the presence of apical perfusion defects assessed with SPECT analysis. METHODS: One hundred twenty-four (98 M, 26 F) out of 1500 patients with suspected coronary artery disease, showed apical perfusion defect not reversible at rest and after reinjection at tomographic SPECT analysis during thallium-201 scintigraphy. RESULTS: In the group of 29 patients presenting wide isolated apical perfusion defect (wAPD) Q waves in anterior segments with definition of antero-septal MI was prevalent (51.7%), while few patients (41.3%) presented the ECG criteria of apical MI as proposed in the literature. In 19 of the 25 patients with partial isolated apical perfusion defect (pAPD), the absence of Q wave was clearly prevalent. Fifty patients had a wAPD partially extended in surrounding regions, as anterior or septal, inferior or lateral myocardial segments, in these patients, the site of Q wave location was more variable, with prevalent Q wave in anterior leads, but with more incidence of Q waves in leads II III aVF, especially in patients with associated perfusion defect in inferior segments. Substantially, the same finding resulted in the 20 patients showing a pAPD extended in surrounding myocardial segments. CONCLUSION: In conclusion, the low diagnostic sensitivity of the ECG criteria of identification of apical MI is clearly demonstrated by our analysis carried out using SPECT perfusion scintigraphy, with ECG findings of anterior/anterior-septal myocardial necrosis in the patients with wAPD.

Apoptotic/mytogenic pathways during human heart development.

OBJECTIVE: The aim of our study was to assess myocytes apoptosis/mitosis and associated intracellular signalling pathways during heart development. SETTING AND PATIENTS: Eight human fetal hearts (at different gestation ages) and seven human adult hearts were chosen as controls (five normal and two pathological) and studied from both a histological and a molecular point of view. RESULTS: Our results are as follows: (i) all Shc isoforms are expressed and activated in the human fetal heart; (ii) a progressive fading of Shc and ERK expression are evident during gestation; (iii) JNK is present but it is not activated in the human fetal heart; (iv) CD95 is present in the first week of gestation and fades progressively; (v) apoptotic/proliferative processes are present in the early gestation phase and fades progressively; (vi) in the human heart, Shc isoform with medium weight is 55 kD and not 52 kD and it is upregulated in adult myocardial ischaemia. CONCLUSIONS: Myocyte underwent apoptosis/mitosis during gestation. Shc isoforms, together with ERK maintain the homeostasis of the heart.

Coronary artery disease in young patients with systemic lupus erythematosus: two case reports.

The cardiovascular system is often involved during systemic lupus erythematosus (SLE), but only few studies have documented myocardial ischemia and myocardial infarction in young patients. We observed 2 cases of coronary artery disease in young patients with SLE and different clinical presentations. In the first case, a 26-year-old woman, with SLE diagnosed at the age of 12 years, was evaluated for angina (CCS class II). Myocardial scintigraphy revealed a clear reversible thallium-201 apical perfusion defect. During the following 5 years worsening effort angina led to coronary angiography which revealed the presence of a complete obstruction of the left anterior descending coronary artery (LAD) treated with surgical myocardial revascularization (internal mammary artery implantation on the LAD). The second patient had myopericarditis and an acute myocardial infarction 1 year before coming to our observation. Coronary angiography revealed the presence of 100% obstruction of the LAD. On this basis, a diagnosis of SLE was made. Our data constitute two relevant examples of coronary artery disease with different clinical presentation in young SLE patients.

Heme oxygenase-1 expression in the left atrial myocardium of patients with chronic atrial fibrillation related to mitral valve disease: its regional relationship with structural remodeling.

Atrial fibrillation becomes a self-perpetuating arrhythmia as a consequence of electrophysiologic and structural remodeling involving the atrium. Oxidative stress may be a link between this rhythm disturbance and electrophysiologic remodeling. The aim of this study was to evaluate whether the heme oxygenase-1 (HO-1) marker of oxidative stress was more expressed in left atrial sites with stronger structural remodeling in patients affected by chronic atrial fibrillation (CAF) and mitral valve disease (MD). Myocardial samples were taken from the left atrial posterior wall (LAPW) and left atrial appendage (LAA) of 24 patients with CAF-MD in addition to 10 autopsy controls. The levels of HO-1 messenger RNA (mRNA) and HO-1 protein in each pathologic LAPW and LAA were quantified using reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Furthermore, light microscopy was used to morphometrically evaluate the differential myocyte and interstitial changes in the same CAF-MD LAPW and LAA samples. In controls, HO-1 protein was quantified using enzyme-linked immunosorbent assay. Unlike controls, patients with CAF-MD had higher levels of HO-1 mRNA and its protein product, expressed as LAPW/LAA ratios, in the LAPW (2.18 +/- 1.18, P < .0001, and 1.55 +/- 0.67, P < .005), and their LAPW also showed greater histologic changes in myocytolytic myocytes (15.1% +/- 3.1% versus 6.9% +/- 3.3%, P < .0001), interstitial fibrosis (8.2% +/- 2.2% versus 2.8% +/- 1.2%, P < .0001), and capillary density (816 +/- 120 number/mm(2) versus 1114 +/- 188 number/mm(2); P < .05). In addition, markers of oxidative stress were immunohistochemically studied with antinitrotyrosine and anti-iNOS antibodies. In patients with CAF-MD, the inducible enzyme HO-1 is more expressed in the left atrial areas that show greater structural remodeling. This finding strongly suggests a pathogenetic relationship between oxidative stress and the degree of histologic change.

Apical hypertrophic cardiomyopathy and atrial septal defect: part of a multi-organ syndrome?

AIM: We describe a case of non-obstructive apical hypertrophic cardiomyopathy with atrial septal defect, in a 48-year-old caucasian female patient with chronic renal failure, hypothyroidism and primary amenorrhea, referred to our hospital for syncope, palpitation and shortness of breath. METHODS AND RESULTS: Electrocardiogram, transthoracic echocardiogram and cardiac magnetic resonance showed classical features of apical hypertrophic cardiomyopathy. Apical hypertrophic cardiomyopathy is morphologically characterized by apical ventricular hypertrophy, and is reported to be a relatively benign prognosis compared with the other type of hypertrophic cardiomyopathy. CONCLUSION: Apical hypertrophic cardiomyopathy is very rare in the West, is occasionally encountered in Japanese persons, but there have been only a few reports of its coexistence with atrial septal defect. Our present report is the first case of apical hypertrophic cardiomyopathy with atrial septal defect associated with renal failure, hypothyroidism and primary amenorrhea that could represent a multi-organ syndrome. This hypothesis was supported by the finding of the same characteristics in a sister of the patient.

Junctional rhythm in hypertrophic cardiomyopathy: a case report.

We observed a case of a 47-year-old male patient with hypertrophic cardiomyopathy and family history of sudden death. During cardiac catheterization, the patient presented spontaneous intermittent atrioventricular junctional rhythm without significant changes related to sinus heart rate. The gradient was absent with sinus beats, but the junctional rhythm induced the appearance of a left ventricular-aorta gradient, with parallel reduction of aortic pressure from 156 to 120 mm Hg. Subsequently, a couple of pre-mature ventricular beats induced an important post-extrasystolic potentiation of the gradient, followed in the last beats by sinus rhythm with disappearance of the gradient. Our case suggests that the decrease of left ventricular volume, due to the absence of an effective atrial systole, leads to left ventricular increased gradient, not imputable to an increased inotropic effect or heart rate modifications but to the decrease of pre-load.