Luke J. Laffin

Prognosis of Myocardial Damage in Sarcoidosis Patients With Preserved Left Ventricular Ejection Fraction: Risk Stratification Using Cardiovascular Magnetic Resonance.

Background—Cardiac sarcoidosis is associated with an increased risk of heart failure and sudden death, but its risk in patients with preserved left ventricular ejection fraction is unknown. Using cardiovascular magnetic resonance in patients with extracardiac sarcoidosis and preserved left ventricular ejection fraction, we sought to (1) determine the prevalence of cardiac sarcoidosis or associated myocardial damage, defined by the presence of late gadolinium enhancement (LGE), (2) quantify their risk of death/ventricular tachycardia (VT), and (3) identify imaging-based covariates that predict who is at greatest risk of death/VT. Methods and Results—Parameters of left and right ventricular function and LGE burden were measured in 205 patients with left ventricular ejection fraction >50% and extracardiac sarcoidosis who underwent cardiovascular magnetic resonance for LGE evaluation. The association between covariates and death/VT in the entire group and within the LGE+ group was determined using Cox proportional hazard models and time-dependent receiver–operator curves analysis. Forty-one of 205 patients (20%) had LGE; 12 of 205 (6%) died or had VT during follow-up; of these, 10 (83%) were in the LGE+ group. In the LGE+ group (1) the rate of death/VT per year was >20× higher than LGE− (4.9 versus 0.2%, P<0.01); (2) death/VT were associated with a greater burden of LGE (14±11 versus 5±5%, P<0.01) and right ventricular dysfunction (right ventricular EF 45±12 versus 53±28%, P=0.04). LGE burden was the best predictor of death/VT (area under the receiver-operating characteristics curve, 0.80); for every 1% increase of LGE burden, the hazard of death/VT increased by 8%. Conclusions—Sarcoidosis patients with LGE are at significant risk for death/VT, even with preserved left ventricular ejection fraction. Increased LGE burden and right ventricular dysfunction can identify LGE+ patients at highest risk of death/VT.

Renal denervation for the treatment of resistant hypertension: review and clinical perspective

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Overcoming toxicity and side-effects of lipid-lowering therapies

Lowering serum lipid levels is part of the foundation of treating and preventing clinically significant cardiovascular disease. Recently, the American Heart Association/American College of Cardiology released cholesterol guidelines which advocate for high efficacy statins rather than LDL-c goals for five patient subgroups at high risk for cardiovascular disease. Therefore, it is critical that clinicians have an approach for managing side-effects of statin therapy. Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. Statin-related adverse effects might be minimized by careful assessment of patient risk factors. Strategies to continue statin therapy despite adverse effects include switching to another statin at a lower dose and titrating up, giving intermittent doses of statins, and adding non-statin agents. Non-statin lipid-lowering drugs have their own unique limitations. Management strategies and algorithms for statin-associated toxicities are available to help guide clinicians. Clinical practice should emphasize tailoring therapy to address each individuals cholesterol goals and risk of developing adverse effects on lipid-lowering drugs.

Endothelin Antagonism and Hypertension: An Evolving Target

The impact of endothelin antagonism for the management of hypertension is a topic explored in multiple preclinical and clinical studies. Endothelin-receptor antagonists are an effective therapy for primary and resistant hypertension, but they are not widely used. This is owing to side effects shown in large clinical trials as well as the availability of many alternative agents to manage blood pressure effectively. However, the study of endothelin and its close ties to hypertension is evolving. Recent preclinical studies have explored new applications of more selective endothelin-receptor antagonists. The studies suggested that patients with certain subtypes of hypertension may benefit more from endothelin-receptor blockade than simply patients with primary hypertension. We review this and other data on this topic.

Hypertension and new treatment approaches targeting the sympathetic nervous system.

The prevalence of primary and resistant hypertension in the United States is increasing. Even with an ever-expanding array of pharmacotherapy available, a large percentage of patients do not meet guideline blood pressure (BP) goals. Not achieving BP goals clearly increases cardiovascular morbidity and mortality, and results in the progression of kidney disease. The inability to adequately control BP is multifactorial, however a major contributing factor, besides inadequate diuretic therapy, is the failure of pharmacotherapy to inhibit the sympathetic nervous system (SNS) effectively. Tolerability of anti-hypertensives targeting the SNS is moderate at best. Consequently, device-driven approaches are being developed and tested. Recent investigation includes renal denervation and baroreflex activation therapy, which show promising, but at times conflicting, results.

One size does not fit all: Case report of two percutaneous closures of aortic pseudoaneurysm and review of the literature

Aortic pseudoaneurysms (PSAs) are common complications following cardiac surgery, and carry significant morbidity and mortality. Surgical management of aortic PSAs is associated with high mortality, however there are emerging reports of transcatheter techniques for closure of aortic PSAs. We present two cases of ascending aorta PSA which developed following cardiac surgery and were treated percutaneously with novel closure devices. We also describe a comprehensive review of the literature of all published cases of ascending aorta PSA which have been closed percutaneously, and report on the success rate and available devices for percutaneous closure.

Reproducibility and experience dependence of echocardiographic indices of left ventricular function: Side-by-side comparison of global longitudinal strain and ejection fraction

Although left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) are recommended by the current echocardiographic chamber quantification guidelines, these measurements are not performed routinely. Because EF measurements rely on manual tracing of LV boundaries, and are subject to inter‐reader variability and experience dependence, we hypothesized that semiautomated GLS measurements using speckle tracking would be more reproducible and less experience‐dependent.

Relationship Between Obesity, Hypertension, and Aldosterone Production in Postmenopausal African American Women: A Pilot Study.

Increased abdominal obesity is associated with increased cardiovascular risk, especially in African American women. The adipocyte is documented to produce a number of inflammatory factors including the hormone aldosterone. There are very few data documenting aldosterone production from adipocytes of postmenopausal women as well as data demonstrating the effects of angiotensin receptor blockade (ARB) on its production in predominately African American women. The authors hypothesize that increased central adipocyte mass in obese postmenopausal women contributes to increased production of aldosterone that is suppressed with the ARB azilsartan medoxomil. The authors tested this hypothesis in a double‐blind, placebo‐controlled pilot study of 34 hypertensive postmenopausal women (mean age 57.5±7.5 years), 91% of whom were African American. Patients had a mean 24‐hour ambulatory systolic blood pressure of 127±13 mm Hg off any blocker of the renin‐angiotensin system but while taking other antihypertensive medications. The authors further validated aldosterone production in a nested cohort of women using fat cells from a fat pad biopsy. Azilsartan reduced 24‐hour urinary aldosterone by 47.3% from baseline (P=.03), with between‐groups differences in urine aldosterone of −5.3±52.3% placebo vs −47.3±32.9% azilsartan (P=.07) at 6 months. An adrenal cell line treated with adipocyte‐conditioned media from subcutaneous abdominal adipocytes of postmenopausal women (n=3) showed an increase in aldosterone production blocked by an ARB (1948±1297 pg/mL fat alone vs 894±438 pg/mL fat + ARB; P=.022). The authors conclude that aldosterone is produced from subcutaneous adipocytes of obese postmenopausal women. Moreover, use of an ARB significantly reduces aldosterone production within 6 months of use in these women as well as in cells exposed to their adipocytes.

Renal Denervation: a Field in Flux

SYMPLICITY HTN-3 was a pivotal moment for renal denervation as a treatment option for resistant hypertension. Prior unblinded studies were called into question given the negative results of the first sham-controlled trial of renal denervation. Reevaluation of the renal denervation procedure demonstrated that a more precise approach was needed to adequately denervate the kidney. This new approach has been implemented in two ongoing clinical trials, one on and one off medications to assess the new procedure’s efficacy and safety. These and other ongoing trials will be discussed in the context of older studies in this field. We focus on novel findings published following the release of SYMPLICITY HTN-3 data in early 2014 and look to the future of renal denervation in the treatment of primary hypertension.

Renal Denervation for Resistant Hypertension and Beyond

Despite the availability of more than 125 approved antihypertensive medications, 36 million (48%) of 75 million people with hypertension, including 16 million treated with antihypertensive medications in the United States, do not achieve guideline blood pressure goals known to reduce cardiovascular morbidity and mortality and progression of kidney disease; 3% to 6% of these 75 million hypertensive individuals are estimated to have resistant hypertension. A major contributing factor for poor blood pressure control, besides inadequate diuretic therapy, is failure of antihypertensive agents to inhibit the sympathetic nervous system effectively. Consequently, alternative device-driven approaches have been developed. Recent technical advances targeting renal sympathetic nerves, that is, renal denervation therapy, are the focus of more invasive therapies to treat resistant hypertension. Encouraging results from the SYMPLICITY HTN-2 trial, regarding efficacy and safety of renal denervation therapy, were countered by disappointing efficacy results of SYMPLICITY HTN-3. Reasons for these divergent results and the future of the field are discussed.