Biomarkers in the clinical management of patients with atrial fibrillation and heart failure

Atrial fibrillation (AF) and heart failure (HF) are two cardiovascular diseases with an increasing prevalence worldwide. These conditions share common pathophysiologiesand frequently co-exit. In fact, the occurrence of either condition can ‘cause’ the development of the other, creating a new patient group that demands different management strategies to that if they occur in isolation. Regardless of the temproral association of the two conditions, their presence is linked with adverse cardiovascular outcomes, increased rate of hospitalizations, and increased economic burden on healthcare systems. The use of low-cost, easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF. Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information. These will then guide patient centred therapeutic management. The current biomarkers that offer potential for guiding therapy, focus on the physiological pathways of miRNA, myocardial stretch and injury, oxidative stress, inflammation, fibrosis, coagulation and renal impairment. Each of these has different utility in current clinincal practice.

Atrial fibrillation (AF) is the most common type of arrhythmia having an annual prevalence of 33 million patients worldwide, along with a three times higher prevalence in women than in men.^[1] There are a number associated risk factors including heart failure, diabetes, hypertension, hyperthyroidism, obesity, structural and ischemic heart disease. However, up to 20% of AF cases cannot be connected with those factors.^[2] The development of AF involves a complex interplay between genetic, molecular and environmental factors. Their better identificationcould alter the possible management and treatment of symptomatic and asymptomatic patients, incuding those that are yet diagnosed via the ECG.^[3-5] Atrial fibrosis is likely play a key role in the development and prognsosi of AF. The extent of the fibrotic process can predict the response to the use of ablation as a treatment.^[6-8] The fibrotic mechanism is not yet fully clarified, but according to some studies, the renin-angiotensin axis^[9] and transforming growth factor (TGF) β1, play a key role in the cardiac fibrosis.^[10]Atrial fibrillation is linked with cardiovascular diseases, mortality, central nervous system side effects.^[11] Most specifically, AF often precedes or follows the development of HF, both share pathophysiological paths that contribute to cardiac remodelling and the combined presence of the two conditions is connected with an adverse prognosis.^[12]Heart failure (HF) is a clinical syndrome presenting with typical symptoms (breathlessness on exertion, paroxysmal nocturnal dyspnea, orthopnea and fatigue) and signs (elevated jugular venous pressure, pulmonary oedema and peripheral oedema) as a result of a structural and/or functional cardiac abnormalities. These lead to a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress, which result in many physiological changes, including multiple morphological, biochemical and molecular alterations referred to cardiac remodeling.^[13,14] The current definition includes stages based on the symptoms observed in the patients requiring medical assistance, however prior to any clinical symptoms patients can present with asymptomatic structural or functional cardiac abnormalities [systolic or diastolic left ventricular (LV) dysfunction]. The early recognition of these precursors can lead to better outcomes, in terms of both hospitalization and mortality in patients with HF. The prevalence of HF varies according to the definition used, but is approximately 1%–2% of the adult population in developed countries, rising to ≥ 10% among people > 70 years of age worldwide. ^[15-18] Among people > 65 years old presenting to primary care with breathlessness on exertion, one in six will have undiagnosed HF. ^[19,20] The lifetime possibility of developing HF at age 55 is 33% for men and 28% for women.^[17] The pathophysiology of HF is mediated by a variety of biological mechanisms, with complex interactions between endothelial cells, monocytes, macrophages, cardiomyocytes, fibrocytes and the neuro-endocrine system. On top is the interplay with systemic conditions such as diabetes, advanced age, hypertension, obesity, dyslipidemia and chronic kidney disease. Cardiac troponins and natriuretic peptides are the most widely used diagnostic biomarkers in the management of HF,^[21] although there are a number of novel ones are also available, but not widely used in clinical practice.     

Cytogenetic findings in metastases from colorectal cancer

Eighteen tumor samples from 11 patients with metastatic colorectal cancer were cytogenetically analyzed after short-term culturing. Of the 13 metastases examined, 11 were from lymph nodes, 1 from the peritoneum and 1 from the lung. In 5 of the 11 patients, matched samples from the primary tumor and lymph node metastases were analyzed. Cytogenetic similarities between the primary and secondary lesions were found in all 5 cases, indicating that many of the chromosomal aberrations presumably occurred before disease spreading took place. Compared with the primaries, the metastases appeared to exhibit decreased clonal heterogeneity but, concurrently, an increase in the karyotypic complexity of individual clones. Among the aberrations recurrently found in metastatic lesions were del(1)(p34), i(17)(q10), −18, −Y, −21, +7 and +20, all of which have been seen repeatedly in previous series of primary colorectal carcinomas, and del(10)(q22) and add(16)(p13), which so far have not been associated with primary tumors and which may play a particular pathogenetic role in the metastatic process. Int. J. Cancer 72:604–607, 1997. © 1997 Wiley-Liss, Inc.     

Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions

Whether macroscopically distinct carcinomas in the same breast are clonally related (multifocal breast carcinoma) or unrelated (multicentric breast carcinoma) is no longer only a scientific-pathological issue but, because different therapeutic strategies may be preferable for cases with intramammary metastatic disease compared with cases of multiple primary breast carcinomas, one that may have profound clinical implications. We studied the evolutionary relationship among macroscopically distinct, ipsilateral breast carcinomas by cytogenetic analysis of 26 tumorous lesions from 12 patients. Sixteen of the 26 foci (62%) were found to contain clonal chromosome abnormalities. Two carcinoma foci were karyotypically abnormal in each of seven patients. Four of these cases had an evolutionarily related, cytogenetically abnormal clone in the two lesions from the same breast, whereas the remaining three cases had completely different clonal karyotypic aberrations in the separate foci. These results, together with our previous findings in five other informative cases, show that multiple, synchronous breast tumors sometimes arise through intramammary spreading of a single primary carcinoma, whereas on other occasions they are the result of the simultaneous emergence of pathogenetically independent carcinomas within the breast. In the total material, an association was seen between the proximity of the foci and the likelihood of them being karyotypically related. Genes Chromosom. Cancer 18:170–174, 1997. © 1997 Wiley-Liss, Inc.     

Association between family history of cancer and breast cancer defined by estrogen and progesterone receptor status

There are recent data to suggest that risk factors for breast cancer may differ according to whether the tumor expresses detectable levels of the estrogen receptor (ER) and progesterone receptor (PR). While a family history of breast cancer is one of the most consistent predictors of the disease, we recently reported a modest inverse association with ER+PR− tumors. However, the definition of a family history of cancer did not consider second-degree relatives or cancer sites that may be etiologically related. The current report presents additional data analysis from the Iowa Women's Health Study, a prospective population-based cohort study conducted among 41,837 postmenopausal women. At baseline in 1986, respondents provided information on family history of cancers of the breast, ovaries, or uterus/endometrium in their mothers, sisters, daughters, maternal and paternal grandmothers, and maternal and paternal aunts. Data on family history of prostate cancer in fathers and brothers and age at onset of breast cancer in mothers and sisters were collected in 1992. Cohort members were followed for cancer incidence through the statewide tumor registry. After 7 years and more than 235,000 person-years of follow-up, 939 incident cases of breast cancer were identified. Information was obtained from the tumor registry on ER (+/−) and PR (+/−) status for 610 cases (65.0%). A family history of breast cancer in first-degree relatives was associated with increased risk (relative risk [RR] = 1.4; 95% confidence interval [CI]: 1.1–1.6) for all receptor-defined subtypes of breast cancer except ER+PR− tumors (RR = 0.7; 95% CI: 0.3–1.4). These results were unchanged when data on second-degree relatives were included. When the onset of breast cancer in relatives occurred at or before the age of 45 years, increased risks were evident only for ER−PR+ and ER−PR− tumors (RR = 2.3 and 3.3, respectively). Conversely, when relatives were affected with breast cancer after the age of 45 years, increased risks were most apparent for ER+PR+ and ER−PR+ tumors (RR = 1.3 and 3.2, respectively). A family history of prostate cancer in first-degree relatives was associated with a 1.2-fold increased risk of breast cancer (95% CI: 0.98–1.50), largely a reflection of the association with ER−PR− tumors (RR = 1.5; 95% CI: 0.8–3.0). The small numbers of cases in some categories and the corresponding wide CIs preclude definitive conclusions, but these data are at least suggestive that joint stratification of breast tumors on ER and PR status may be useful in partitioning breast cancer families into more homogeneous subsets. © 1996 Wiley-Liss, Inc.     

Apolipoprotein E and presenilin-1 genotypes in Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant degenerative disease of the central nervous system manifested by involuntary movements (chorea), psychiatric manifestations, and cognitive impairment with a variable age at onset. This variability is mainly attributed to genetic factors. The so-called aging genes [e.g., those for apolipoprotein E (APOE) and presenilin-1 (PS-1) have been implicated in determining the age at onset of Alzheimer’s disease, a disease sharing common clinical features with HD. In 60 unrelated patients suffering from HD (mean age at onset 40.1 years, range 20–65) we determined number of CAG repeats and the distribution of the APOE alleles (ɛ2, ɛ3, ɛ4) and PS-1 alleles. The results showed that: (a) The age at onset was higher in the group of patients with the ɛ4 allele (51.6 vs. 38.0 P < 0.002), (b) The correlation between the age at onset and the number of CAG repeats was strong in patients with the ɛ3/ɛ3 genotype while it was not detected in patients with ɛ3/ɛ4 genotype. (c) No correlation was found between age at onset and PS-1 alleles. In conclusion, APOE seems to be a significant factor influencing the age at onset of Huntington’s disease. Received: 13 May 1998 Received in revised form: 9 December 1998 Accepted: 31 December 1998     

Characteristics and re-offending outcomes of ‘limiting-term’ forensic patients found unfit to stand trial in New South Wales,Australia

There are little published data on the characteristics or outcomes of offenders found unfit to stand trial who receive a ‘qualified finding of guilt’ in a Special Hearing in New South Wales (NSW) and are detained for a ‘limiting term’ (LT) under the supervision of the NSW Mental Health Review Tribunal (MHRT). We examined NSW MHRT records linked to re-offending data, to report on the characteristics and outcomes of 69 LT patients in a cohort spanning two decades. The most common diagnoses were schizophrenia (54%) and intellectual disability (33%). Patients were detained on average for 4.2 years, which is slightly shorter than the average maximum term imposed. Of the 55 people for whom criminal record data were available, 9.1% were charged with an offence during the first year post-release and 60% overall were charged for at least one post-release offence during a follow-up period ranging from 4.7 to 11.1 years.     

Genetic analysis,in silico prediction,and family segregation in long QT syndrome

The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality.