Eleni S. Nakou

Healthy aging and myocardium: A complicated process with various effects in cardiac structure and physiology

It is known that there is an ongoing increase in life expectancy worldwide, especially in the population older than 65years of age. Cardiac aging is characterized by a series of complex pathophysiological changes affecting myocardium at structural, cellular, molecular and functional levels. These changes make the aged myocardium more susceptible to stress, leading to a high prevalence of cardiovascular diseases (heart failure, atrial fibrillation, left ventricular hypertrophy, coronary artery disease) in the elderly population. The aging process is genetically programmed but modified by environmental influences, so that the rate of aging can vary widely among people. We summarized the entire data concerning all the multifactorial changes in aged myocardium and highlighting the recent evidence for the pathophysiological basis of cardiac aging. Keeping an eye on the clinical side, this review will explore the potential implications of the age-related changes in the clinical management and on novel therapeutic strategies potentially deriving from the scientific knowledge currently acquired on cardiac aging process.

Myocardial regeneration therapy in heart failure: Current status and future therapeutic implications in clinical practice

Despite multiple treatment regimens the morbidity and mortality of patients with advanced heart failure (HF) have reached pandemic proportions. In an effort to address the root cause of the problem, curative strategies are increasingly being considered. A case in point is the evolution of regenerative medicine technologies aiming to halt or even reverse progressive organ deterioration in the HF setting. The prevailing unmet clinical needs in HF therapy have provided a major incentive for the development of cell-based treatment strategies, which have shown encouraging results in experimental studies. In turn, this has led to a significant international effort in cell-based clinical trials. In order to translate the promise of biotherapies into clinical benefit many more questions need to be addressed. In this review we analyze current clinical experience regarding cell therapy in the setting of ischemic/nonischemic HF and address key issues that could be a guide for future successful cell-based therapeutic application in HF patients in clinical practice.

Cardiac resynchronization therapy (CRT) device replacement considerations: upgrade or downgrade? A complex decision in the current clinical setting.

There are limited data about the management of patients presenting for elective generator replacements in the setting of previously implanted cardiac resynchronization therapy (CRT) devices that are nearing end-of-life. The individual patients clinical status and concomitant morbidities may evolve so that considerations may include not only replacement of the pulse generator, but also potentially changing the type of device [e.g. downgrading CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) or ICD or upgrading of CRT-P to CRT-D]. Moreover, the clinical evidence for CRT-D/CRT-P implantation may change over time, with ongoing research and availability of new trial data. In this review we discuss the ethical, clinical and financial implications related to CRT generator replacements and the need for additional clinical trials to better understand which patients should undergo CRT device downgrading or upgrading at the time of battery depletion.

Anticoagulation in heart failure without atrial fibrillation: gaps and dilemmas in current clinical practice

Data from observational and post‐hoc analyses suggest that heart failure (HF) itself may be associated with higher risk of thromboembolic events compared to populations without HF. Although oral anticoagulants (OACs) might be a therapeutic option in individual cases, anticoagulation therapy in HF patients in sinus rhythm is not generally recommended, as the implementation of OACs in clinical practice in this HF population is not supported by large randomized clinical trials to date. Indeed, the available data suggest that the risk of major bleeding overshadows the potential anti‐thromboembolic benefit of OACs in HF patients in sinus rhythm with no net beneficial effect on mortality rates. In this review we explore the current available evidence for the clinical outcomes of anticoagulation therapy in patients with HF in sinus rhythm, highlighting the current gaps in knowledge, which may guide the design of future randomized clinical trials focusing on the efficacy and safety of anticoagulant therapy in this HF population.

The clinical relevance of drug–drug interaction between co-trimoxazole and sacubitril/valsartan treatment in a heart failure patient: a case report and overview of mechanisms and management in clinical practice

Given the high prevalence of comorbidities needed to be treated in heart failure (HF) population, sacubitril/valsartan, which is the new promising therapy in HF, has been assessed for potential pharmacokinetic or pharmacodynamic drug–drug interactions that could result in adverse events. These potential complications pose a therapeutic dilemma, since they may deter the majority of patients from enjoying the cardiovascular benefits of sacubitril/valsartan (LCZ696) treatment [1] or even increase the burden of morbidity. Despite the existing evidence, real-world data on its safety in combination with concurrent medications are eagerly expected. We present an interesting case of a patient presenting with hyperkalemia caused by the co-administration of LCZ696 and co-trimoxazole (sulfamethoxazole/trimethoprim), highlighting the underlying pathophysiological mechanisms and the clinical approach to patients at risk of hyperkalemia caused by the drug interactions with the novel therapy, which may direct better the guide on the use of sacubitril/valsartan in clinical practice in the future. A 50-year-old male with known HF with reduced ejection fraction (HFrEF) due to dilated cardiomyopathy [left ventricular ejection fraction (LVEF = 25%), NYHA III] was presented to our department to a scheduled ambulatory visit at 3 months after a previous HF hospitalization. His medical history included diabetes mellitus, arterial hypertension, permanent atrial fibrillation and dyslipidemia. Blood pressure values constantly were around 110 mmHg systolic and 80 mmHg diastolic. Pre-existing medication included lisinopril 10 mg/day, eplerenone 50 mg/day, carvedilol 50 mg/day, furosemide 80 mg/day, rosuvastatin 20 mg/ day, metformin 850 mg/day and apixaban 10 mg/day. The patient was considered for sacubitril/valsartan treatment because of increasing exertional dyspnea and progressive ankle oedema, despite the optimal doses of beta-blocker and mineralocorticoid receptor antagonists (MRAs), while the prescribed dose of 10 mg lisinopril was equivalent to a daily dose of 10 mg enalapril based upon PARADIGM-HF protocol [2]. Table 1 shows all the concurrent medications prescribed in this patient. A lisinopril-free washout period of 36 was applied before the initiation of sacubitril/valsartan to avoid overlapping of angiotensin-converting-enzyme inhibitor (ACEi) and LCZ696 that would increase the risk of angioedema [3]. The starting dose was 50 mg 1 × 2 daily up-titrated to 100 mg 1 × 2 daily after 3 weeks, which is actually the recommended starting dose in patients taking the equivalent of enalapril 10 mg daily, while the target dose of sacubitril/valsartan is 97/103 mg twice daily provided that the patient does not experience any adverse effects (symptomatic hypotension, potassium levels > 5.4 mmol/L or significant deterioration in renal function) [1, 2]. Interestingly, 10 days after 100 mg LCZ696 initiation, the laboratory investigation carried out in the context of urinary tract infection treated with co-trimoxazole (sulfamethoxazole/trimethoprim 800/160 mg 1 × 2 daily) for the last 7 days, showed an unremarkable decrease in glomerular filtration rate (GFR) values from 62 ml/min to 58.3 ml/min, while the potassium levels increased significantly from the baseline value of 4.9–6.0 mEq/L. Additionally, the patient made occasional use of ibuprofen 1200 mg/ day due to osteoarthritis during this period without medical prescription. The clinical evaluation showed no symptoms or electrocardiographic signs of hyperkalemia, while the arterial blood gas analysis showed compensated metabolic * Eleni S. Nakou EleniSNakou@yahoo.gr

Troponin-I levels as a potential prognostic biomarker of sacubitril/valsartan treatment response in heart failure with reduced ejection fraction: Who will benefit most?

Despite robust data on the benefits of sacubitril/valsartan (LCZ696) in patients with chronic heart failure with reduced ejection fraction (HFrEF), there is no evidence yet on prespecified predictive markers of its efficacy.

Chronotropic incompetence presenting as sudden sinus slowing during exercise stress test: the pathophysiological mechanisms.

The term ‘‘chronotropic incompetence’’ is used to denote failure to achieve maximal heart rate (HR) or inadequate submaximal HR during exertion. There is evidence that an attenuated HR response to exercise is predictive of increased mortality and coronary heart disease risk, independent of other confounding factors, including age, gender, physical fitness, traditional cardiovascular risk factors, and ST-segment changes during exercise [1]. Various protocols have been proposed to quantify subphysiological heart rate responses to exercise, but none of these approaches have been validated clinically [2]. We present an interesting case of sudden and paradoxical sinus slowing during exercise, which could be attributed to autonomic nervous system dysfunction, as an alternative manifestation of chronotropic incompetence. A 53-year-old man was sent for exercise radionuclide myocardial perfusion imaging (rMPI) to be evaluated for suspected coronary heart disease (CHD). The patient complained of occasional mild, atypical, nonpredictable chest discomfort. He had neither history nor risk factors for coronary heart disease. An echocardiogram had been performed showing normal findings. He underwent Bruce protocol treadmill exercise that was the first part of exercise 201Tl myocardial singlephoton emission computed tomography (SPECT). Physical examination was normal, with heart rate 55 beats/min and blood pressure 110/75 mmHg before the test. The baseline 12-lead electrocardiogram (ECG) showed normal sinus rhythm, right axis deviation and RBBB. PR and QT intervals were normal. During exercise test, the ECG did not show any ischemic ST-segment change nor conduction disturbance and the heart rate increased gradually up to 126 beats/min at 10 min. Blood pressure increased from 110/75 to 155/80 mmHg. Although the exercise was continued, the heart rate dropped suddenly to 72 beats/min. Even during this deceleration period, ECG recordings showed normal sinus rhythm without any type of atrioventricular (AV) conduction block or other obvious ischemic findings in any leads. On recovery, heart rate instability with alterations of bradycardia and tachycardia was observed. Surprisingly, the patient neither lost consciousness nor mentioned any kind of symptoms. Although the exercise rMPI was normal, we performed a coronary angiography which revealed normal coronary arteries. The sinoatrial (SA) node branch was intact, as well (Fig. 1). An electrophysiological study was subsequently performed. Both the conduction intervals and sinus node recovery time were normal (Fig. 2). However, the sinoatrial conduction time was prolonged. One month later, a new exercise test confirmed the aforementioned findings. Sinus node dysfunction is expressed clinically as sinus bradycardia, sinus pause or arrest, atrial chronotropic incompetence and SA node exit block. Various conditions that have in common the capability to depress automaticity and electrical conduction from the sinus node and perinodal and atrial tissues cause sinus node dysfunction. These conditions are relatively common in patients with coronary artery disease, heart failure [1] and less common in variety of other disorders such as infiltrative diseases, toxins and drugs intoxication [3]. E. M. Kallergis E. S. Nakou (&) E. N. Simantirakis P. E. Vardas Department of Cardiology, University Hospital of Heraklion, Heraklion, Crete, Greece e-mail: EleniSNakou@yahoo.gr

A case report of hemosiderosis-induced ventricular pacing exit block

cases was very advanced. These findings could support the above hypothesis. If reactional myocardial hypertrophy gradually increases over a long period, myocardial ischemia induced by a coronary steal phenomenon could occur more easily, and chest pain may result. CALVCs are a rare clinical entity whose clinical significance has been overlooked, given that they may cause myocardial ischemia resulting in chest pain or discomfort, and are associated with reactive LVH. We should be aware of the existence of such unusual features of the coronary circulation, which we may find incidentally during CAG. I would like to express my graduate to Dr. Takahashi for his valuable and constructive suggestions during the planning and development of this research. His willingness to give his time so generously is much appreciated. I would also like to thank the staff of the Sakurakai Takahashi Hospital. Furthermore, we are indebted to Editage, an editing company, for critical reading of the manuscript.