Long-standing Hypertension Research Articles

Aberrant Extracranial Branch Prevents Internal Carotid Artery Occlusion

The internal carotid artery (ICA) is a terminal vessel that does not give rise to branches in the extracranial segment. The ICA occlusion typically extends to the first intracranial branch, the ophthalmic artery. We present a rare case of isolated ICA occlusion with distal patency due to an aberrant extracranial branch. A 52-year-old man with longstanding tobacco use, hypertension, hyperlipidemia, diabetes, and extensive coronary artery disease was referred to the vascular laboratory for evaluation of carotid disease. The patient had no history of transient ischemic attack (TIA), amaurosis fugax, or cerebrovascular accident. Carotid duplex results prompted further evaluation by computed tomography angiography (CTA). Duplex imaging demonstrated right common carotid artery (CCA) plaque with significantly elevated velocities and turbulent flow extending into the ICA. Mild heterogeneous plaque was noted proximally in the left ICA followed by less than 2-cm occlusion and reconstitution of flow in the distal extracranial segment. The CTA testing revealed a moderate right CCA stenosis, mild proximal left ICA plaque and an isolated occlusion of the mid-ICA and distal reconstitution via an aberrant collateral branch. The left intracranial ICA segment remained patent throughout its course but was of smaller caliber. Aberrant branches of the extracranial ICA are unusual and rarely identified by carotid duplex analysis. Awareness of this anomaly underscores the importance of determining patency of distal ICA flow in the presence of an occluded proximal segment; aberrant collaterals can make surgical exploration and endarterectomy in these patients feasible.

Right ventricular dysfunction in arterial hypertension: still terra incognita?

The effects of systemic hypertension on left ventricular function have been well described, as has been the response of the resulting alterations to antihypertensive treatment. However, hypertension effects on the right ventricle (RV) have not been sufficiently investigated; only in recent years, with the development of new imaging modalities, has its importance become widely recognized. Indeed, evidence from clinical trials suggestive of RV functional and structural impairment early in the course of arterial hypertension continues to accumulate. Newer imaging techniques, especially speckle-tracking-derived myocardial deformation imaging, have provided new insights into the effect of systemic hypertension on this previously neglected cardiac chamber. Two- and three-dimensional echocardiography, along with cardiac magnetic resonance imaging, forms the cornerstone of RV structural and functional assessment. This article provides an overview of the effect of longstanding hypertension on RV structure and function, the respective underlying mechanisms, and the potential therapeutic implications. It summarizes the available options for RV structural and functional assessment, and evaluates the existing evidence with respect to RV alterations in hypertensive disease, aiming to assess the current limits of scientific knowledge about a heart chamber that has only recently become the focus of greater interest.

MON-323 Metastatic Adrenocortical Carcinoma Presenting with Mixed Cushing's and Virilization Syndrome along with Bilateral Pulmonary Emboli

Background: Adrenocortical carcinoma is a rare, often aggressive tumor that is more common in women than men. The tumors are more often than not biochemically active in adults, and the majority secrete glucocorticoids alone (1,2).Clinical case: A 57yo woman w/ longstanding hypertension and history of total abdominal hysterectomy presented with shortness of breath. She reported worsening of her hypertension over the past six months associated with male pattern balding, body hair growth, anxiety, facial and abdominal swelling for the past four months. Computed tomography PE protocol showed bilateral pulmonary emboli and multiple pulmonary nodules. Subsequent computed tomography chest/abdomen/pelvis revealed pulmonary nodules in both lungs, the largest being 3.7cm x 2.5cm in the right upper lobe, and a large right retroperitoneal mass centered at the expected position of the right adrenal gland measures 12.4cm x 10.5cm causing mass effect on the inferior surface of the liver along with bulky mediastinal, hilar, paratracheal, gastrohepatic, portocaval, and retroperitoneal lymphadenopathy. Exam was significant for cushingoid habitus with central obesity, rounded facies, supraclavicular and dorsocervical fat pads, proximal muscle weakness, frontotemporal balding, severe hirsutism consistent with modified ferriman-gallwey score of 13, and an annular, scaly rash along gluteal cleft. 8am serum cortisol was 65mcg/dL. 24 hour urinary cortisol was 450mcg/24 hour. ACTH was undetectable <2.0pg/mL. Total Testosterone was 835ng/dL. DHEAS was 1,000mcg/dL. Renin, aldosterone, plasma fractionated metanephrines were normal. Excisional supraclavicular lymph node biopsy was positive for metastatic adrenocortical carcinoma. Subsequent FDG PET/CT also showed metastatic disease in the liver, right humeral head, sacrum, and bilateral iliac bones. Punch biopsy of the rash was consistent with tinea cruris. The patient was moved to the oncology service and started on therapy with mitotane, cisplatin, doxorubicin and etoposide.Conclusion: Rapid virilization is concerning for an underlying malignancy and should always include androgen evaluation with a high index of suspicion for ovarian or adrenal tumors.

Hypertension-induced subclinical vascular and cognitive changes are reversible-An observational cohort study.

Beside the well-known complications of poorly controlled, long-standing hypertension, milder abnormalities induced by early-stage hypertension have also been described. In our study, the authors examined the reversibility of changes induced by early-stage hypertension. The authors performed laboratory testing, ambulatory blood pressure monitoring, carotid intima-media thickness (IMT) measurement, evaluation of stiffness parameters, assessment of various cardiac and cerebral hemodynamic parameters during head-up tilt table (HUTT) testing, and neuropsychological examinations in 49 recently diagnosed hypertensive patients. Following baseline assessment, antihypertensive therapy was commenced. After one year of therapy, lower IMT values were found. Pulse wave velocity showed a borderline significant decrease. During HUTT, several hemodynamic parameters improved. The patients performed better on neuropsychological testing and reached significantly lower scores on questionnaires evaluating anxiety. The present study shows that early vascular changes and altered cognitive function observed in newly diagnosed hypertensive patients may improve with promptly initiated antihypertensive management.

Atypical intracerebral hemorrhage-etiology and acute management

Acute management as well as establishing the etiology of an intracerebral hemorrhage is still achallenge for clinicians. The location of the intracerebral hemorrhage alone should not be used to determine the cause because atypically located hemorrhages can be caused by long-standing arterial hypertension and typically located hemorrhages can occur due to non-hypertensive causes. Besides discussing the classification of intracerebral hemorrhages, this article focuses on adiagnostic algorithm as well as the presentation of potential (rarer) causes of non-traumatic intracerebral hemorrhages. Furthermore, the acute treatment of intracerebral hemorrhage with respect to recent data on blood pressure management as well as the management of bleeding under oral anticoagulant treatment are described.

Stiff Left Atrial Syndrome; Prospects and Possibilities. Retrospective Analysis and Review of the Literature.

Stiff left atrial syndrome is an intriguing clinical phenomena characterized by reduced left atrial compliance, pulmonary venous hypertension and exacerbations of volume overload. We conducted a retrospective review of patients diagnosed with stiff left atrial syndrome at our center. All patients admitted to our hospital with volume overload and pulmonary venous hypertension who were diagnosed with stiff left atrial syndrome based on evidence by echocardiogram and right heart catheterization between July 2011 and July 2013 were included in this retrospective review. Twentythree patients (mean age 73 ± 11 years, 39% male and 61% female) were diagnosed with stiff left atrial syndrome at our center. Thirty-five percent had persistent while 39% had permanent atrial fibrillation. Mean duration of atrial fibrillation was 7.6 ± 2.1 years. Forty-three percent of patients had long standing hypertension. There was no mitral regurgitation in 39% of patients while 48% had mild mitral regurgitation. On right heart catheterization, mean right atrial pressure was 12.6±4.8 mm of Hg, mean pulmonary arterial pressure was 33±7.2 mm of Hg, mean pulmonary capillary wedge pressure was 24.8± 4.2mm of Hg while peak V waves were seen at mean of 37.8± 5.3 mm of Hg. Mean left atrial volume index was 49.8±17.1 mL/m 2. After the initial diagnosis with a two year follow- up, there were no readmissions in 65% of patients who were on appropriate diuretic therapy and had regular clinical visits. Frequent readmissions were seen in 35% of patients inspite of appropriate diuretic therapy. All-cause mortality rate was 4.3% at two year follow up. In patients with stiff left atrial syndrome, the presence of left atrial dilation, long standing atrial fibrillation and hypertension are the key factors associated with pathogenesis and clinical course. Close follow up and monitoring of volume status is essential to prevent hospital readmissions and improve long term prognosis.

Effect of duration of hypertension on heart rate variability

Background: Hypertension is the most prevalent noncommunicable disease. It is a multisystem disorder that affects many organs of the body including cardiovascular system, and it markedly increases both morbidity and mortality in the population. Hypertension causes dysfunction of the cardiac autonomic nervous system leading to sympathovagal imbalance. Heart rate variability (HRV) is a non-invasive tool used to detect variation in RR intervals and has been proposed as early markers of vulnerability to ventricular arrhythmias. The present study was taken up to measure the effect of duration of the hypertension on HRV for early detection and early management of cardiac abnormalities. Aims and Objectives: The objectives of the study were to evaluate the effect of duration of the hypertension on cardiac autonomic function in patients with primary hypertension by measuring HRV. Materials and Methods: HRV test was performed on 50 male hypertensive patients who were divided into 2 groups, based on the duration of hypertension, i.e., duration of hypertension >5 years and 5 years duration (P 5 years, and it was highly significant. P < 0.001 showing decreased in parasympathetic activity in long-standing hypertension. Conclusion: Study showed reduced HRV parameters showing decreased parasympathetic activity in long-standing hypertension leading to an imbalance in cardiac autonomic function. It is very much important to evaluate the cardiac autonomic function status in long-standing hypertension using simple non-invasive tools for early detection and treatment of cardiac arrhythmias and other variations in cardiac function status.

Recent Advances in Imaging of Hypertensive Heart Disease.

To review recent advances in the imaging of hypertensive heart disease (HHD) with an emphasis on developments in the imaging of diffuse myocardial fibrosis using cardiac magnetic resonance (CMR). HHD results from long-standing hypertension and is characterized by the development of left ventricular hypertrophy and diffuse interstitial fibrosis. Diffuse fibrosis traditionally required endomyocardial biopsy to diagnose, but recent developments using T1 mapping in CMR allow for noninvasive assessment. Studies using T1 mapping have shown an increase in extracellular volume fraction (ECV) in patients with HHD compared to normal controls, suggesting ECV can be used as a noninvasive marker for fibrosis in HHD. In addition to T1 mapping, other recent advances in HHD imaging include improvements in three-dimensional echocardiography, allowing for accurate real-time volumetric measurements, and the use of speckle tracking echocardiography to detect subclinical systolic dysfunction. Measurement of ECV using T1 mapping in CMR can be used as a noninvasive marker of diffuse myocardial fibrosis in HHD. While further studies are needed to validate this approach with larger patient cohorts, ECV can potentially be used to both monitor disease progression and assess therapeutic interventions in HHD.

Correlation of renal volume on ultrasound with renal function tests in hypertensives in University of Benin Teaching Hospital

Background: Long-standing essential hypertension can initiate changes in renal size and alteration in renal function which can be assessed using ultrasound and biochemical tests, respectively. Ultrasound is a noninvasive and affordable investigative modality that is readily available. Patients and Methods: One hundred and fifty patients consisting of 54 (36%) males and 96 (64%) females with essential hypertension attending cardiology outpatient clinic were recruited and investigated after obtaining an informed consent. Renal volume was calculated from ultrasound measurement of renal dimensions. Blood sample was assessed for serum creatinine and estimated glomerular filtration rate calculated using the Cockcroft and Gault (CG) and modification of diet in renal disease (MDRD) formulae. Data analysis was performed using Statistical package for Social Sciences version 17.0. Results: The mean renal volume was 115.7 ± 29.2 cm3 on the right and 132.4 ± 40.2 cm3 on the left. The mean renal volumes for males were 126.1 ± 27.9 cm3 and 141.1 ± 40.6 cm3 while values for female patients were 109.9 ± 28.2 cm3 and 127.5 ± 9.4 cm3 on the right and left, respectively. Differences in renal sizes on both sides were not statistically significant, P = 0.120 and 0.063. Values were significantly higher in male patients compared to the female patients, for both sides (P = 0.001 and 0.046 on the right and left, respectively). Mean serum creatinine was 0.9 ± 0.03 mg/dl. Conclusion: Male hypertensive patients had significant higher renal volume values than females. However, renal volume did not correlate with duration of hypertension for all the patients. There was no correlation between renal volume and renal function using CG and MDRD formula.

Связь изменений относительной длины теломер в течение пятнадцати лет с маркерами возрастных изменений сердечно- сосудистой системы у лиц среднего возраста по результатам исследования питания и рака в Мальмё (Швеция)

Objective. To analyse the association between long-term changes in relative telomere length (RTL) and selected markers of cardiovascular ageing such as history of myocardial infarction (MI), pulse pressure or usage of antihypertensive (AHT) drugs during 15 years of follow-up. Subjects and methods. 332 middle-aged subjects were recruited from a population-based, case-control study of patients with MI. RTL in blood at baseline and after 15 years of follow-up was investigated through quantitative PCR. Z-statistics was used to compare the log-distribution of RTL at baseline and at follow-up, respectively. The difference ( Δ z-score) was calculated for each individual as a marker of relative change in telomere length over 15 years. Multiple regression analysis was used with Δ z-score as dependent variable, and age, sex, RTL at baseline, and clinical markers of cardiovascular ageing as independent variables. Results. We found that Δz-score of RTL was independently associated with both total (prevalent/incident) MI (p < 0.039) and usage of AHT drugs (p < 0.015) at baseline. Subjects with MI or on AHT drugs showed a greater reduction in the z-score for RTL during follow-up, implying a higher degree of telomere shortening. Conclusion. Changes in blood relative telomere attrition (RTL) is a potential marker of cardiovascular ageing, as illustrated by significant and independent associations between Δ z-score and prevalent/incident MI, as well as with base-line usage of antihypertensive drugs — a marker of longstanding hypertension in need of treatment.

Management of Cerebral Microbleeds in Clinical Practice.

Cerebral microbleeds (CMBs) are very frequent diagnoses with MRI imaging in the elderly or in patients with cerebral infarction, intracranial hemorrhage (ICH), and dementia. The mechanisms for CMBs are not fully understood but may be secondary to injury to the vascular wall from long-standing hypertension or amyloid deposition in the tissue. The presence of CMB increases the risk for stroke, dementia, and death. The increasing number of CMBs is also associated with a higher risk of hemorrhagic complications with the long-term use of anticoagulants in atrial fibrillation and in patients requiring thrombolysis for acute stroke. The presence of CMBs is however not a contraindication for anticoagulation or thrombolysis as was recently shown from the results of the CROMIS-2 study. This review will summarize our current understanding of the natural history of CMBs and offer suggestions on the best management in common clinical settings.

Asymptomatic thoracic aortic aneurysm in a resource limited hospital in a 70-year-old man

Aortic aneurysm is a term used to describe more than 50% dilatation of a segment of the aorta (artery) from its original diameter. The etiological factors include hypertension, artherosclerosis, trauma, congenital syphilis, mycotic bacterial dissection, inflammation etc. A case of a 70-year-old man with well-controlled long-standing hypertension whose check chest X-ray showed aortic aneurysm as an incidental finding which latera ruptured was discussed. The case report discusses the importance of follow up imaging in a hypertensive patient even with regular medication as absence of routine medical checkup including X-ray may lead to missing important complication like aortic aneurysm that can rupture if untreated. This is what prompted this case report so as to underscore the importance of at least check chest radiograph in a hypertensive patient.

Clinical Associations, Treatment, and Outcomes of Renal-Limited Thrombotic Microangiopathy

BackgroundThrombotic microangiopathy (TMA) is a clinicopathologic diagnosis that can be characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and end-organ damage. Though most patients will present with the hematologic abnormalities of MAHA and thrombocytopenia, there are some that never demonstrate those features and only present with acute renal injury. Here we describe the clinical presentation, laboratory assessment, management, and outcomes of patients with renal-limited TMA (rTMA).MethodsAfter IRB approval, the electronic medical record was searched from 2008-March 2017 for patients managed at our institution with a clinical diagnosis of rTMA supported by renal biopsy. Inclusion criteria were as follows: 1) Presence of TMA on renal biopsy, 2) Absence of MAHA 3) No history of renal transplant prior to diagnosis of TMA. Clinical notes were reviewed to document the physician-determined cause of TMA. If no cause was listed, cause of TMA was based off of labs and clinical observation.ResultsThirty-five patients (18 female) met clinical criteria for a diagnosis of rTMA. Median age at time of biopsy was 59 years (range 9 to 87). Creatinine at time of biopsy was 2.4 mg/dL (range 0.55 to 6.4). Evidence of chronic TMA was noted on 17 specimens and an additional 3 had findings of chronic and acute TMA.Ten patients had ADAMTS13 activity performed and all were >10% with negative inhibitor screen (median 66%(26-100)). 24 patients (68.6%) had complement serology assessed. Three patients (12.5%) had low C3 while C4 was normal in 19 patients (79%). One patient in our cohort had complement mutational testing performed with no evidence of a pathogenic variant.Most common etiology of rTMA was medications (28.5%) and underlying rheumatologic disorder (20%)(Table 1). In 6 patients (17%), an identifiable cause was not elucidated.Management of TMA was dependent on underlying etiology of rTMA. Discontinuation or dose adjustment of TMA-causative medications was recommended in 4 patients and 25% of patients had normalization of Cr. Four patients received therapeutic plasma exchange (TPE) for median 5 (2-5) days. Causes of rTMA for those receiving TPE were gemcitabine, bevacizumab, unspecified connective tissue disease, and rTMA due to an unknown cause. 50% of patients were noted to have improvement in Cr with TPE. Antihypertensive medications were used for rTMA secondary to uncontrolled hypertension (n=4) and scleroderma (n=4). 11 patients (31%) were observed or treatment for causative underlying etiology was pursued, while 7 patients were treated with glucocorticoids. Of 6 patients, with no identifiable underlying cause, 4 were treated with observation, 1 was treated with GC, and one was treated with TPEFourteen patients (38.9%) required dialysis; 6 of these patients were able to discontinue dialysis less than two months after initiation. Three patients (8.3%) with rTMA, respectively due to tacrolimus toxicity, longstanding hypertension, and systemic lupus erythematosus, received a renal transplant, and one additional pt (2.8%) with rTMA due to scleroderma remained on the renal transplant waiting list at time of death.In a median follow-up time of 8.73 months (range 0 to 47.9), 16 patients (44.4%) died. Median time from diagnosis of TMA to death was 12.1 months (range 1.47 to 58.2). No deaths were directly attributable to underlying TMA.ConclusionRenal-limited TMA is a pathologic diagnosis that in our cohort was most likely to medications or underlying rheumatologic conditions. rTMA was managed by treating the underlying disorder or removing the causative medication. Though cause of rTMA was evident in the majority of patients, 17% had no identifiable precipitating factor predisposing to rTMA. Larger studies are required to delineate optimal management and surveillance strategies for these patients. DisclosuresNo relevant conflicts of interest to declare.

High Prevalence of CKD of Unknown Etiology in Uddanam, India

IntroductionThere were concerns raised regarding a high prevalence of chronic kidney disease (CKD) in Uddanam, a fertile subtropical low-altitude territory in the southern Indian state of Andhra Pradesh. The present study was undertaken to ascertain the prevalence of CKD, disease characteristics, and risk factor profile in this area.MethodsWe selected 2210 subjects (age >18 years) using multistage sampling. After obtaining demographic and anthropometric data, urinary protein-creatinine ratio, serum creatinine, and blood glucose were measured in all the subjects. Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation.ResultsMean age of the subjects was 43.2 ± 14.2 years (range: 18–98), 44.3% were men and 55.7% were women. Mean eGFR of subjects was 94.3 ± 33.4. Low eGFR (<60 ml/min per 1.73 m2) was seen in 307 (13.98%) patients with a mean eGFR of 34.8 ± 16.6. The prevalence of subjects having low eGFR and with proteinuria (CKD) was 18.23%. Major risk factors, such as diabetes, long-standing hypertension, and significant proteinuria, were absent in 73% of patients with CKD, implying that a significant proportion of the population is afflicted with the entity “CKD of unknown etiology (CKDu).”ConclusionThe prevalence of CKD and CKDu in Uddanam is much higher than other earlier studies in either rural or urban communities in India. We suggest that there is a dire need to review health policies and allocate resources for prevention and treatment of CKD in the Uddanam region.

Longstanding Non-Cirrhotic Portal Hypertension May Lead to Decreased Synthetic Function: A Case Report

Longstanding Non-Cirrhotic Portal Hypertension May Lead to Decreased Synthetic Function: A Case Report

Quality of Life Improvement Following Medication Adherence in Long-Standing Hypertension: Insight from the Highest Hypertension Prevalence in Indonesia

Quality of Life Improvement Following Medication Adherence in Long-Standing Hypertension: Insight from the Highest Hypertension Prevalence in Indonesia

Martorell’s ulcers

There is description in the article of a case of hypertensive ulcer pathology of legs or Martorell’s ulcers diagnostics, which are complications of long-standing and poor-controlled essential hypertension. The patient 42 years old male presented with complaints of long-standing, non-healing and painful ulcer on the left leg, sustained blood pressure elevation (up to 230/120 mm Hg). History disease revealed blood pressure elevations since 16 years old age, but the patient sought medical advice extremely seldom and did not take antihypertensive treatment in fact. He noted when was 35 years old a painful ulcer located on anterolateral surface of the leg. Concerning it he treated by himself unsuccessfully and then — in differ ent health care centers. The condition deteriorated in 2016, when ulcer defect become larger and more painful. On admission at examination the ulcer of oval shape (size 7 × 4 cm and depth 0.6 cm) on anterolateral surface of the lower third of left leg is present. In clinical and biochemistry analyses no pathology was found. There were signs of left ventricle hypertrophy on the data of electroand echocardiographic inves tigations. No alterations during complex ultrasound examination of vessels of both lower extremities were revealed. Examination of angiosurgeon: no pathology. With the purpose to diagnosis specification path omorphologic study of tissue fragments of injured zone was performed. The results of this study showed that revealed changes are relevant for hypertensive ulcers of legs or Martorell’s ulcers. The presented case illustrates the necessity of more broad informing medical community about possibility of incidence of Martorell’s ulcers that in turn assumes application of adequate measures of local treat ment, including dermatoplasty, and effective antihypertensive therapy.

22 QUALITY OF LIFE AND FUNCTIONAL CAPACITY IMPROVEMENT FOLLOWING MEDICATION ADHERENCE IN LONG-STANDING HYPERTENSION

Objective: Bangka Belitung province has the highest prevalence of hypertension in Indonesia with the rate of 30.9% based on the National Report on basic health research in Indonesia. Whether or not medication adherence improves the quality of life and functional capacity in patients with long-standing hypertension remains unclear. Methods: We enrolled 61 patients with long-standing hypertension in Puskesmas Manggar, East Belitung. MMAS-8 was used to assess the level of compliance in each patient. This assessment resulted in two groups; the adherents and the non-adherents. With a prospective, non-randomized study, we assessed the patients’ quality of life by using WHO-5 QoL Questionnaire on the first month and the fourth month of treatment and 6MWT distances. The results were then analyzed with generalized linear model after data normalization. Results: A significant higher 6MWT distances in adherents group vs non-adherents group (281.9 + 75.15 vs 263.1 + 56.16 m). A significant increment of mean QoL scores was found in the adherents group (77.7 ± 1.0 to 80.2 ± 1.2) after a fourmonth follow-up. Conversely, reduced QoL scores were seen in the non-adherents group (64.5 ± 1.2 to 62.2 ± 1.3). Hence, there was a marked improvement of QoL scores in the adherents group compared to the non-adherents groups (2.5 vs −2.3, p value = 0.006). Conclusion: Medication adherence significantly improves the quality of life and functional capacity in patients with long-standing hypertension.

Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees.

We have previously described 19 pedigrees with apparent lamin (LMNA)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families. Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants. In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant. Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.